FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
A PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE /J -ISOMER OF 2'-
DEOXY-2',2' DIFLUOROCYTIDINE
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400 059, MAHARASHTRA, INDIA
The following specification particularly describes and ascertains the nature of this invention and
the manner in which it is to be performed.

The present invention relates to a process for preparation of substantially pure /3-isomer of 2 -deoxy-2',2'- difluorocytidine, compound of formula 1, commonly known as gemcitabine, or its pharmaceutical^ acceptable salts. Gemcitabine (INN name) is used in the treatment of locally advanced or metastatic non-small cell lung cancer.
NH2

N

N
^
-v

O

HO
formula 1
BACKGROUND OF THE INVENTION
United States Patent No. 4808614 (the '614 patent; Indian reference not available) discloses a process for the preparation of an enantiomeric mixture of a & p-isomers of 2'-deoxy-2',2'-difluorocytidine by condensing 3,5-bis(t-butyldimethylsilyloxy)-l-methanesulfonyloxy-2-desoxy-2,2-difluroribose with bis(trimethylsilyl)-N-acetylcytosine followed by deprotection.
The process of this patent does not provide substantially pure /3- anomer of 2'-deoxy-2',2'-difluorocytidine from an enantiomeric mixture of 2'-deoxy-2',2'- difluorocytidine or its acid addition salt.


Pri O
°v

O^^^O F
Ph
formula 2
2

United States Patent No. 5606048 (the '048 patent; IN 180000) provides a stereoselective glycosylation process for preparing /3-anomer enriched 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, by reacting concentrated oanomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-l-methane sulfonate, compound of formula 3, with greater than molar equivalent of protected cytosine, compound of formula 4 .
o

X)V0MS NHR,
Ph
Ph
formula 3 Formula 4
In this process the reaction between compounds of formula 3 (a-rich) and compound of formula 4 is a stereoselective SN2 reaction involving inversion of configuration so that from the a-rich compound of formula 3 a P-rich isomer of compound of formula 2 is obtained.
United States Patent No. 5223608 (the '608 patent; Indian reference not available) This patent exemplifies deprotection of the benzyloxy protecting groups by reacting compound of formula 2 with ammonia in methanol in poor yield of about 50%. Also, the patented process selectively isolates /3 -anomer of 2'-deoxy-2',2'- difluorocytidine hydrochloride by dissolving 1:1 anomeric mixture of a and j3-2'-deoxy-2',2'- difluorocytidine hydrochloride in hot water, adding acetone raising the pH to 7-9 followed by cooling the solution to isolate the desired product.
United States Patent No. 5420266 (the '266 patent; Indian reference not available) discloses a process for preparing /3- anomer of 2'-deoxy-2',2'- difluorocytidine by contacting a-anomer of 2'-deoxy-2',2'- difluorocytidine with a hydroxide base in an organic solvent. This patent does not disclose selective isolation of the /3- anomer of 2'-deoxy-2',2'- difluorocytidine from enatiomeric mixture of a & (3-isomers of 2'-deoxy-2',2'- difluorocytidine.
The object of the present invention is to provide a process for isolating substantially pure 0 isomer of 2'-deoxy-2',2'- difluorocytidine from a mixture of o: and /3 isomers of 2'-deoxy-2',2'- difluorocytidine having a a : P-ratio from 1-2:1 to 1:1.
DESCRIPTION OF THE INVENTION
We have surprisingly found that it is possible to isolate substantially pure (3 isomer of 2'-deoxy-2',2'-difluorocytidine from a mixture of a and /S isomers of 2'-deoxy-2',2'- difluorocytidine having a a:P-ratio from 1-2:1 to 1:1 by treating with aqueous alkali having a pH greater than 9.4 and isolating the undissolved substantially pure /3 isomer.
In particular the process of the present invention prepares substantially pure (3 isomer of 2'-deoxy-2',2'- difluorocytidine, compound of formula 1, or its acid addition salt by
3


NH2
N
HO F

formula 1 formula 2
reacting a mixture of aand /3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methane sulfonate, compound of formula 3, having a a.: (3 ratio in the range from 1-1:1 to 1:1 with compound of formula 4 (R, is amino protecting group and R2 is hydroxy protecting group) in anisole wherein the concentration of compound of formula 3 in anisole is about 20-30% w/w and the ratio of compound of formula 3 to compound of formula 4 is 1:15 to 1:25 and the reaction is carried out at 105 to 125 C; treating the reaction mixture with aqueous mineral acid, neutralizing and filtering to obtain a mixture of aand /3 isomers of 2'-deoxy-2',2'-difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a a: (3 ratio ranging from 1-2:1 to 1:1;


OMs
NHRi

in.

formula 3 formula 4
deprotecting the mixture obtained in step (i) with sodium methoxide, treating with aqueous mineral acid, evaporating, suspending residue in organic solvent(s) selected from the group consisting of aliphatic or cyclic ethers, nitriles, ketones, aliphatic or aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons and mixtures thereof; cooling to 0 to 5°C, filtering to obtain mixture of aand (3 isomers of 2'-deoxy-2',2'- difluorocytidine having a«:(3 ratio from 1-2:1 to 1:1, and treating the solids obtained in step (ii) with aqueous alkali(s) solution at pH greater than 9.4, isolating the undissolved substantially pure |3 isomer of 2'-deoxy-2',2'-difluorocytidine followed by optionally converting it into an acid addition salt.

DETAILED DESCRIPTION OF THE INVENTION
As referred to herein substantially pure /3 isomer of 2'-deoxy-2',2'- difluorocytidine is defined as (3 isomer of 2'-deoxy-2',2'- difluorocytidine which is atleast 99% pure, preferably 99.5% pure.
4

According to one embodiment of the process of the present invention substantially pure (3 isomer of 2'-deoxy-2',2'- difluorocytidine may be isolated from a mixture of a and /3 isomers of 2'-deoxy-2',2'-difluorocytidine having a«:|3 ratio ranging from 1-2:1:1 to 1:1, by treatment with an aqueous alkali(s) solution at pH greater than 9.4, isolating the undissolved substantially pure /3 isomer of 2'-deoxy-2',2'-difluorocytidine followed by optionally converting into its acid addition salt.
The treatment with aqueous alkali(s) solution may be carried out with an alkali selected from sodium and potassium hydroxide under ambient conditions. The aqueous alkali solution may be 50-80% w/v solution in water.
Substantially pure compound of formula 1 may be converted to its acid addition salt using conventional techniques. Acid addition salts may be selected from hydrochloride, hydrobromide, sulfate, phosphate and the like, preferably hydrochloride.
According to another embodiment of the process of the present invention a mixture of a and /3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-l-methane sulfonate, compound of formula 3, having a a : /3 ratio in the range from 11:1 to 1:1, is reacted with compound of formula 4, wherein R| is amino protecting group and R2 is hydroxy protecting group, to obtain a mixture of a and /3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a a: /3 ratio ranging from 1-2:1 to 1:1
The amino protecting group R| may be selected from benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, benzoyl, formyl, acetyl, pivalamido, methoxymethyl. allyl, t-butyl, benzyl, tetrahydropyranyl and silyl protecting groups such as trialkylsilyl, t-butyldialkylsilyl and t-butyldiarylsilyl.
The hydroxy protecting group R2 may be selected from phenoxycarbonyl, ethoxycarbonyl,
vinyloxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl, N-phenylcarbamate, N-imdazoyl carbamate,
methxoymethyl, methoxyacetyl, 2-methoxyethoxymethyl, fomyl, allyl, acetyl, 2-chloroacetyl,
propionyl, butynyl, substituted acetyl, pivaloyl, t-butyl, benzoyl, substituted benzoyl, 2,2,2-
trichloroethoxycarbonyl, benzyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl,
tetrahydropyranyl, tetrahydrothienyl, trialkylsilyl, trimethylsilyl, isoproyldialkylsilyl,
alkyldiisopropylsilyl, triisopropylsilyl, t-butyldialkylsilyl, tetraisopropyldisiloxanyl and the like.
The compound of formula 4 may be prepared from cytosine and isolated or the reaction with compound of formula 3 may be carried out insitu to obtain mixture of a. and (3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a a: |8 ratio ranging from 1-2:1 to 1:1. Reaction of mixture of a and /3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methane sulfonate, compound of formula 3, having a a : /3 ratio in the range from 1-1:1 to 1:1, with compound of formula 4 maybe carried out in organic solvent(s), preferably in aromatic hydrocarbon such as anisole at temperature ranging from 105°C to 125°C. The reaction mixture is treated with aqueous mineral acid and neutralized to yield mixture of a and /3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a : /3 ratio ranging from 1-2:1:1 to 1:1.
5

The mixture of a and j3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a : /3 ratio ranging from 1-2:1:1 to 1:1, is then treated with base(s) such as sodium methoxide or ammonia to deprotect compound of formula 2. The deprotected material is then suspended in an organic solvent. The organic solvent is a solvent capable of dissolving the mixture & co-distilling water. Examples of such organic solvents are aliphatic or cyclic ethers, nitriles, ketones, aliphatic or aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons and mixtures thereof.

formula la
The deprotected material, compound of formula la, mixture of a : (3 having a ratio ranging from 1-2:1:1 to 1:1 is then subjected to treatment with aqueous alkali(s) solution, at pH greater than 9.4, preferably 9.4 to 10.0, most preferred being 9.4 to 9.8 to obtain the undissolved substantially pure /3 isomer of 2'-deoxy-2',2'- difluorocytidine which is isolated by filtration or centrifugation and dried.
The treatment with aqueous alkali(s) solution may be carried out with an alkali selected from sodium and potassium hydroxide under ambient conditions. The aqueous alkali solution may be 50-80% w/v solution in water.
Substantially pure compound of formula 1 may be converted to its acid addition salt using conventional techniques. Acid addition salts may be selected from hydrochloride, hydrobromide, sulfate, phosphate and the like, preferably hydrochloride.
The invention is illustrated but not restricted by the description in the following examples.
6

Examples
Example 1 to 3 (Plant scale):
(i) Preparation of mixture of a and p" isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2:
175 kg of hexamethyldisilazine (HMDS), 45 kg of cytosine (nucleobase) and 0.51 kg of ammonium sulfate were added into a reactor, heated to 100°C and stirred for 5-7 hours. The contents were cooled to 80 C and HMDS distilled out under vacuum to obtain the bissilylated nucleobase. A solution of 8-5 kg of mixture of a and j3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-l-methanesulfonate, compound of formula 3 (protected carbohydrate— HPLC analysis of three batches are given in Table 1), in 35 kg of anisole was added, the contents heated to 100°C and stirred for 20 hrs. The reaction was monitored by TLC for absence of compound of formula 3 and formation of compound of formula 2. The contents were cooled, ethylacetate added and the contents stirred for 30 mins - 1 hr at 70-90°C. Aqueous hydrochloric acid solution was added to the contents and stirred between 70-90 C for 3 to 5 hrs. The contents were cooled to 25-30°C, demineralised water was added and stirred for 15-30 mins. The pH was adjusted to 6-7 with sodium bicarbonate, centrifuged and the solids dried. The product was washed with water and then dried at 100°C to obtain 57-5 kg of crude mixture of a and (3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2 & compound of formula 4. (Crude mixture of protected nucleoside and bissilylated nucleobase).
Table 1 : Mixture of a and p* isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-
dibenzoyl-1-methanesulfonate, compound of formula 3

Alpha anomer beta anomer Ratioa: 3
Example 1 47.46 43.06 1.10 : 1.0
Example 2 45.08 41.80 1.08 : 1.0
Example 3 43.37 41.94 1.07 : 1.0
The pH of mixture of 57-5 kg crude solids in water was adjusted to pH 1 -25 to 1 -75 by the addition of aqueous HC1 solution and the solids were filtered. (This step is referred to herein as "leaching"). The content of compound of formula 4 was determined and the process of leaching with aqueous HC1 solution was repeated until the content of compound of formula 4 was <5%. The crude solids of mixture of a and (3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2 (crude protected nucleoside) were filtered, dried and analysed by HPLC. HPLC analysis of three batches are as given in Table 2.

difluorocytidine-3',5'-dibenzoate,
Table 2 : Mixture of a and p" isomers of 2'-deoxy-2',2'-compound of formula 2
Alpha anomer beta anomer Ratioa:p
Example 1 49.02 41.79 1.17 : 1.0
Example 2 47.73 42.50 1.12 : 1.0
Example 3 43.30 40.29 1.07 : 1.0

(ii) Preparation of mixture of a and /? isomers of 2'-deoxy-2',2'- difluorocytidine
30 kgs of dried solids obtained from Examples 1 to 3 were mixed together to prepare mixture of a and (3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2, (crude protected nucleoside). The crude protected nucleoside, 170 liters of methanol, and 2 kg of sodium methoxide were stirred for 30 minutes and distilled to remove methanol. Aqueous HC1 was added to adjust pH between 1 and 2 and stirred for 2 hrs at 25-30°C. 25 liters acetone was added and stirred for 30 minutes and distilled. Additionally 70 litres of acetone was added, stirred for 30 mins. cooled to 30"C and then till 5"C. The mixture was filtered and dried to give hydrochloride salt of mixture of 5 54 kg of a and (3 isomers of 2'-deoxy-2',2'- difluorocytidine, compound of formula 1. (crude deprotected nucleoside hydrochloride)
(iii) Selective separation of /3 isomer of 2'-deoxy-2',2'- difluorocytidine
5-54 kg of crude hydrochloride salt was converted to its free base with aqueous sodium hydroxide solution by stirring at pH 9-4 to 9-8 at temperature of 25-30°C . The contents were cooled and stirred to 0 to 5°C for 6-8 hrs. The solids were filtered, washed with chilled demineralised water and dried. The solids were analysed by HPLC and the deprotected nucleoside was converted to its hydrochloride salt. Treatment with aqueous sodium hydroxide was repeated until % purity of compound of formula 1 is more than 99.5%. 2.5 kg of wet compound of formula 1 was charged into a reactor followed by 37-5 liters of methanol to dissolve the solids. 1-78 kg of A.R. grade hydrochloric acid was added and stirred for 2 hrs at 25-30°C, methanol was distilled out and acetone was charged, the mixture of acetone and methanol was distilled out under vacuum between 40-45°C. Acetone addition and distillation was repeated. The contents were cooled to 25-30°C and then 0 to 5°C for 1-2 hrs. The cooled suspension was filtered, washed with chilled acetone and dried to obtain 2-2 kg of (3 anomer of 2'-deoxy-2\2'-difluorocytidine having a HPLC purity of 99-7%.
8

Example 4 (Laboratory scale)
(i) Preparation of mixture of a and /3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2:
175 kg of hexamethyldisilazine (HMDS), 45 kg of cytosine (nucleobase) and 0.51 kg of ammonium sulfate were added into a reactor, heated to 100°C and stirred for 5-7 hours. The contents were cooled to 80'C and HMDS distilled out under vacuum to obtain the bissilylated nucleobase. A solution of 8-5 kg of mixture of a and /3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-l-methanesulfonate, compound of formula 3 (protected carbohydrate— HPLC analysis: a : (3 ratio = 1-07:1), in 35 kg of anisole was added, the contents heated to 100°C and stirred for 20 hrs. The reaction was monitored by TLC for absence of compound of formula 3 and formation of compound of formula 2. The contents were cooled, ethylacetate added and the contents stirred for 30 mins - 1 hr at 70-90°C. Aqueous hydrochloric acid solution was added to the contents and stirred between 70-90°C for 3 to 5 hrs. The contents were cooled to 25-30°C, demineralised water was added and stirred for 15-30 mins. The pH was adjusted to 6-7 with sodium bicarbonate, centrifuged and the solids dried. The product was washed with water and then dried at 100°C to obtain 57-5 kg of crude mixture of a and /3 isomers of 2'-deoxy-2',2'- difluorocytidine-3',5'-dibenzoate, compound of formula 2 & compound of formula 4. (Crude mixture of protected nucleoside and bissilylated nucleobase).
500 gm of the crude mixture of protected nucleoside and bissilylated nucleobase was added to 7-5 liters of demineralised water and this mixture was stirred at 25-30°C for 1 hr and its pH adjusted to 1.5 +/- 0-25 with aqueous hydrochloric acid solution (1:1) over 1 to 2 hrs. The mixture was stirred for 1 hr and its pH rechecked. The product was washed with water (at pH 1 -5) and dried at 80-90°C for 4 hrs to obtain 63 gms of compound of formula 2. HPLC analysis of the product gives a : /3 ratio as 115:1 (48-86% a: 42-37% 0 with 4.9% cytosine)
(ii) Preparation of mixture of a and j3 isomers of 2'-deoxy-2',2'- difluorocytidine
The process of step (ii) of Examples 1 to 3 was followed to obtain 28.5 gms hydrochloride salt of mixture of a and 0 isomers of 2'-deoxy-2',2'- difluorocytidine. HPLC analysis of the mixture has a : @ ratio of 1-2:1.
(iii) Selective separation of /? isomer of 2'-deoxy-2',2'- difluorocytidine
28.5 gm of hydrochloride salt of mixture of a and (3 isomers of 2'-deoxy-2',2'- difluorocytidine was dissolved in 275 ml of demineralised water at 25-30°C for 1 hr and the pH was adjusted to 9-45 using 3-5 ml of 70% aqueous sodium hydroxide solution (w/v). The contents were stirred for 1 hr and the pH rechecked. The mixture was cooled to 0 to 5°C, stirred for 2 hrs and the solids were filtered, washed with chilled demineralised water and dried to obtain 17 gms of /3 isomer of 2'-deoxy-2',2'-difluorocytidine of 99-2% HPLC purity.
9

We claim
A process for preparation of substantially pure (3 isomer of 2'-deoxy-2',2'- difluorocytidine, compound of formula 1, or its acid addition salt by


NHo

N
%^o
HO-""^/°\/

0
J.
PrT "O

°v

HO

Ph

formula 1 formula 2
reacting a mixture of a and (3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methane sulfonate, compound of formula 3, having a a: (3 ratio in the range from 1-1:1 to 1:1 with compound of formula 4 (R, is amino protecting group and R2 is hydroxy protecting group) in anisole wherein the concentration of compound of formula 3 in anisole is about 20-30% w/v and the ratio of compound of formula 3 to compound of formula 4 is 1:15 to 1:25 and the reaction is carried out at 105 to 125°C; treating the reaction mixture with aqueous mineral acid, neutralizing and filtering to obtain a mixture of a and /3 isomers of 2'-deoxy-2',2'-difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a a: (3 ratio ranging from 1-2:1 to 1:1;


OMs
R20

NT
*^

NHRi
NT

in.

formula 3 formula 4
deprotecting the mixture obtained in step (i) with sodium methoxide, treating with aqueous mineral acid, evaporating, suspending residue in organic solvent(s) selected from the group consisting of aliphatic or cyclic ethers, nitriles, ketones, aliphatic or aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons and mixtures thereof; cooling to 0 to 5°C, filtering to obtain mixture of aand /3 isomers of 2'-deoxy-2' ,2'- difluorocytidine having a a : (3 ratio from 1-2:1 to 1:1, and treating the solids obtained in step (ii) with aqueous alkali(s) solution at pH greater than 9.4, isolating the undissolved substantially pure /3 isomer of 2'-deoxy-2',2,-difluorocytidine followed by optionally converting it into an acid addition salt.

10

2. A process for isolating substantially pure @ isomer of 2'-deoxy-2',2'- dilluorocytidine, compound of formula I, by treating a mixture of a and /3 isomers of 2'-deoxy-2\2'-difluorocytidine having a a: ft ratio from 1-2:1 to 1:1, with aqueous alkali(s) solution having a pH greater than 9.4; and isolating the undissolved substantially pure /3 isomer ol deoxy-2',2'- difluorocytidine.
NH2

N

N
^
HO^N^°v/

0

HO
formula 1
3. A process for the preparation of compound of formula 1 as claimed in claims 1 to 2 substantially as herein described and illustrated by examples 1 to 4.
Dated this 17lh day of October, 2006
, '
DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LTD

ABSTRACT
A process for preparation of substantially pure /3 isomer of 2'-deoxy-2',2'- difluorocytidine, compound of formula 1, or its acid addition salt by

NH2
O
°v
X

Prv" "O
HO^^°V
O^^^O F
HO p
Ph
formula 1
formula 2

reacting a mixture of aand (3 isomers of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-l-methane sulfonate, compound of formula 3, having a a: (3 ratio in the range from 1:1 to 1 • 1: lwith compound of formula 4 (R| is amino protecting group and R2 is hydroxy protecting group) in anisole wherein the concentration of compound of formula 3 in anisole is about 20-30% w/v and the ratio of compound of formula 3 to compound of formula 4 is 1:15 to 1:25 and the reaction is carried out at 105 to 125°C; treating the reaction mixture with aqueous mineral acid, neutralizing and filtering to obtain a mixture of aand |8 isomers of 2'-deoxy-2',2'-difluorocytidine-3',5'-dibenzoate, compound of formula 2, having a a: /3 ratio ranging from 1-2:1 to 1:1;


OMs
Ph

O
X

o

°-y

N'

NHR

O

in.
To

NT
Ph formula 3
R20
formula 4 deprotecting the mixture obtained in step (i) with sodium methoxide, treating with aqueous mineral acid, suspending residue in organic solvent(s) selected from the group consisting of aliphatic or cyclic ethers, nitriles, ketones, aliphatic or aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons and mixtures thereof; cooling to 0 to 5°C, filtering to obtain mixture of aand /3 isomers of 2'-deoxy-2',2'- difluorocytidine having a a : j3 ratio from 1 -2:1 to 1:1, and
treating the solids obtained in step (li) with aqueous alkali(s) solution at pH greater than 9.4. isolating the undissolved substantially pure (i isomer of 2'-deoxy-2',2'- difluorocytidine followed by optionally converting it into an acid addition salt.
The Controller of Patents, The Patent Office, Mumbai - 400037

12