FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - "A NOVEL PROCESS FOR THE PREPARATION OF
GEMCITABINE HYDROCHLORIDE OF FORMULA I"
2. Applicant(s)
(a) NAME : ARCH PHARMALABS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali,
Andheri (East), Mumbai-400 072, India.
(a) NAME: SHANGHAI PARLING PHARMATECH CO., LTD.
(b) NATIONALITY : A Chinese Company
(c) ADDRESS: Suite 2, No. 868 Zhenchen Road, Baoshan District, Shanghai
200444, China.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention:
Disclosed herein is an novel process for the preparation of Gemcitabine Hydrochloride (2'-deoxy-2',2'-difluorocytidine hydrochloride) of the formula I comprising asymmetrical chemical reaction between difluoroacetic acid coupled with chiral auxiliary of formula IV and protected glyceraldehydes of formula V to obtain a sterospecific isomer of the lactose of the formula II which can be converted into the desired nucleoside.

Background of Invention:
Gemcitabine Hydrochloride is a nucleoside analogue that exhibits anti-tumor activity and belongs to a general group of chemotherapy drug known as antimetabolites. Gemcitabine prevents cells from producing DNA and RNA by interfering with the

synthesis of nucleic acid, thus stopping the growth of cancer cells and causing them to die.
Gemcitabine is a synthetic glucoside analog of cytosine, which is chemically described as, 4-amino-l -(2-deoxy-2,2-difluoro-p-D-ribofuranosyl)-pyrimidin-2(lH)-one or 2'-deoxy-2'2,-difluorocytidine (p isomer). The key intermediate of Gemcitabine is 3, 5-diprotected-2-deoxy-2,2-difluoro-P-D-ribofuranose and has the following structure (II)

In the schematic representation under the invention protecting groups are also shown by R2 and R3.
There are generally, two synthetic routes of Gemcitabine. US4526988, 4808614, 5223608 and J.Org.Chem. (1988, 2406) describe a process comprising Reformatsky reaction between ethyl 2-bromide-2,2-difluoro acetate of formula VI and 2,3-0-isopropylidene-D-glyceraldehyde of formula V in presence of zinc as a key step resulting finally into lactone of the formula III which is reduced further to get lactose of formula II another key intermediate for Gemcitabine..

The process described as:


The key feature of the process described in above process is the preparation and isolation of the lactone of formula III, 2-deoxy-2,2-difluoro-D-erythro pentafuranose-l-ulose-3,5-dibenzoate . The above process comprises Reformatsky reaction for the preparation of aldol of formula VII comprising the reaction between ethyl 2-bromo-2,2-difluoro acetate VI and 2,3-O-isopropylidene-D-glyceraldehyde V. Aldol of formula VII obtained is a racemic mixture of erythro to threo isomers in the ratio of 3 -.1. This is further subjected to hydrolysis, hydtoxyl group protection and cyclisation to get the lactone of the formula III having erythro and threo in the ratio of 3:1.The drawback associated with this process comprising Reformatsky reaction is that it results into the lactone of formula III comprising mixture of erythro and threo isomers. The desired erythro isomer (also referred as anti isomer) is separated from the mixture by cumbersome purification process. The desired erythro isomer is obtained in lower yield. Lactone is then reduced to lactose of formula II followed by its conversion to gemcitabine by the processes disclosed in the prior art.
Tetrahedron Letters, 29(15), 1803-06 (1988) describes the preparation of 2,2-difluoro-2,2-dimethyl-p -[(trialkylsilyl)oxy]-l,3-dioxaIan -4-propanoic acid methyl ester comprising the reaction between 2,3-O-isopropylidene-D-glycer-aldehyde and difluoro ketene silyl acetals generated insitu with highlighting feature of using difluoro ketene silyl acetals of formula VIII prepared insitu results in the higher ratio of erythro isomer in the mixture of erythro and threo isomeric mixture than Reformatsky reaction as used in the prior art. The preparation of difluoro ketene silyl acetals comprises reaction between methyl iododifluoro acetate with zinc in acetonitrile and treating resulting organozinc species (Reformatsky reagent) with


trialkylsilyl chloride.

Formula VIII
Rl, R2, R3 are independently selected from alkyl and aryl groups

JP2270841 describes the preparation of erythro a, a-difluoro-2,2-dimethyl- p-[trialkylsilyl)oxy]-l,3-dioxalan-4-propanoic acid methyl ester comprising reaction between methyl iododifluoro acetate with trialkyl silyl chloride and zinc in acetonitrile and treating the resulting mixture with 2,3'-0-isopropylidene-D-glycer-aldehyde and titanocene dichloride.
US6001994 describes another process for the preparation of aldol of formula X comprising reaction between t-butyl 2-bromide-2,2-difluoro thioacetate IX and 2,3-O-isopropylidene-D-glycer-aldehyde in a solvent and a base without a catalyst and also in absence of a silyl containing compound. The resulting compound, D-erythro-2-Deoxy-2,2-difluoro-4,5-0-(l-ethyl propyl id ine)pentanoic acid tert butyl thioester of formula XI is obtained as the mixture of erythro to threo isomer in the ratio of (85:15), purified further by chromatography. Purified D-erythro-2-Deoxy-2,2-difluoro-4,5-0-(l-ethyl propy!idine)pentanoic acid tert butyl thioester is then converted into lactone intermediate of the formula III as per the process disclosed in US4526988, columns 7,8. The process illustrated as;


Prior art disclose the processes for the preparation oflactone of formula III which is
reduced to lactose comprising hydride or vitride reduction to obtain lactose as a
mixture of erythro and threo isomers which are separated by cumbersome purification
process.
Thus it is evident from the prior art as cited above that the lactone, a key intermediate
for the preparation of gemcitabine involves key steps as:
1) Preparation of erythro isomer a, a-difluoro - (3-[hydroxy]-1, 3-dioxaIan~4-propanoic acid O or S esters, that involves Reformatsky reaction in one or other way.
2) Conversion of above esters into key intermediate lactone of the formula III as isomeric mixture of erythro and threo isomers comprising hydrolysis, protection and cyclisation.
3) Erythro isomer of lactone is then separated from the erythro/threo isomeric mixture of lactone.
4) Desired erythro isomer of lactone is then reduced to get erythro isomer of lactose by using diisobutylaluminium hydride or vitride as disclosed in the prior art.
5) Desired erythro isomer of lactose is further converted into gemciabine as per the process described in the art.
There is no process disclosed in the prior art wherein 2-halo-2,2-difIuoro O or S esters is not used as a starting material nor the lactose of formula II is obtained as a single pure erythro isomer which does not require any purification which results in lowering the yield to obtain the desired erythro isomer. There is a dire need for the preparation of the erythro isomer of the key intermediate lactose of formula-II

wherein the use of halo difluoro acetic acid ester, formation of enantiomeric mixture of lactone, hydride reduction, separation and isolation of erythro isomer from the enantiomeric mixture can be avoided.
Disclosed herein is a process for the preparation of lactose of formula II wherein in the shortcomings of the prior art have been bridged by asymmetric reaction between auxiliary coupled difluoro acetic acid and protected glyceraldehydes to obtain a desired erythro isomer of the corresponding lactose without formation of lactone.
Brief summary of the invention:
The present invention discloses an improved process for the preparation of Gemcitabine Hydrochloride (2'-deoxy-2',2'-difiuorocytidine hydrochloride) of the formula I comprising reaction between difluoroacetic acid coupled with chiral auxiliary and protected glyceraldehydes to obtain compound of formula XII which can be converted into stereo specific erythro isomer lactose of formula II avoiding the formation of lactone, hydride reduction and purification of racemic mixture of erythro and threo isomers. The stereo specific pure erythro (anti) isomer of the lactose intermediate of the formula II can be converted into the desired nucleoside.
Detailed Description of the Invention:
Present invention discloses a novel improved process for the preparation of Gemcitabine Hydrochloride (I). The process comprises:
i) Asymmetric preparation of compound of formula XII by reacting difluoro
acetic acid coupled with optically active auxiliary of compound of formula IV with ketal of glyceraldehydes of formula V in a solvent and in the presence of a base and catalyst, ii) protecting the new hydroxyl formed in the key step to get compound of formula XIII, iii) hydrolysis of acetal to get compound of formula XIV iv) protecting the primary hydroxyl group

to get compound of formula XV v) reduction of compound of formula XV to decouple the optically active auxiliary and cyclization to get lactose vi) sulfonylation, vii) condensation, viii) deprotection and isolation as Gemcitabine hydrochloride. The process is shown below:

The advantages of this invention are as follows:
1. The new chiral center is introduced by asymmetric aldol reaction.
2. There is no isomer of pyranose as the primary OH is already protected
3. The optically active auxiliary is removed easily. At the same time, the imide is reduced to aldehyde directly and the ribofuranose is formed.
4. Use of Zinc is eliminated thereby reducing sludge and presence of Zn metal in finished good.
5. Erythro (Anti) isomer of the lactose is directly formed as a single isomer
6. No purification is required for intermediates formed; they are used as such for the next step minimizing number of operations.
Auxiliary used for the preparation of compound of the formula XII may be selected from the group of la, lb or lc of the formulae.



Rl-Benzyl, Phenyl, iso-propyl
Solvents used for the process for the preparation of compound of formula XII can be
selected from dimethylsulfoxide, dimethylformamide, acetone, methylene dichloride,
chloroform, tetrahydrofuran, methanol, ethanol or propanol or mixtures thereof and
the like. The catalyst or metal halide for the purpose could be used from the group of
titanium tetrachloride, stannous chloride or magnesium chloride preferably titanium
tetra chloride and the like. Base could be from group comprising
tetramethy lethylened iami ne, tetram eth y propene-d i am ine, tr i ethylamine,
diisopropylethylamine, sparteine and the like. Preferably base is
tetramethylethylenediamine.
-OH group generated in the compound of the formula XII could be protected from by any -OH protecting moiety to give a compound of formula XIII. -OH protecting group can be selected from benzoyl, subsitituted benzoyl, trialkyl silyl and the like. Preferably -OH protection group can be triethyl silyl (TES), tert butyldimethyl silyl (TBS), methoxy methyl(MOM ).More preferably -OH protecting group is benzoyl group.
Acetal of the compound of the formula XIII is taken in a solvent and hydrolysed using a acid to give a compound of formula XIV. The acid used for hydrolysis can be inorganic or organic, Inorganic acid can be selected from hydrochloride or sulphuric acid, organic acid is selected from p-toluene sulphonic acid, trifiuoroacetic acid, methanesulfonic acid or trifluoromethane sulfonic acid and the like. Preferable the

acid is p-toluene sulphonic acid. Solvent used for hydrolysis reaction for converting compound of formula XIII to compound of formula XIV is C1-C4 alcoholic solvent. Preferably alcoholic solvent is methanol. In compound of formula XIV a primary -OH group is formed as a result of hydrolysis of compound of formula XIII. The primary -OH group is protected by any of the protecting agent as stated above to give a compound of formula XV.
Compound of formula XV is reacted with a base to remove the optically active auxiliary group. Preferable base is hydride base such as sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, red-AI, diisobutyl aluminium hydride (DIBAL) and the like. Most preferable base is sodium borohydride
The compound of formula II is converted into the compound of formula XVI by taking a compound of formula in an organic solvent and reacting with a O salt forming compound for the activation of-OH group to make it a better leaving group. The O salt forming compound can be methylsulfonyl chloride, p- tohiyl sulfonyl chloride, dicresyl chlorophodsphate and the like. Solvents can be selected from methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or toluene and the like.
The compound of the formula XVI is the condensed with Cytimidine (Cytosine) in suitable organic solvent in presence of HMDS to form protected gemcitabine of the formula XVII.
Suitable inert organic solvents that can be employed include but are not limited to acetonitrile, toluene, xylene and its isomers, chlorobenzene, ortho-dichlorobenzene, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, anisol. The preferred inert solvent is anisol.

Compound of the formula XVII is converted into Gemcitabine of formula I by treating the compound of formula XVI in a organic solvent with a base. The base may be selected from ammonia, alkali metal alkoxide. Preferably base is sodium methoxide. The solvent is C1-C4 alcohol. Preferably solvent is methanol.
The present invention may be illustrated by example. The following Examples illustrate specific embodiments of the present invention. These Examples are only intended to illustrate the present invention and are not intended to limit the scope thereof. Many variations in the process may be made without departing from the spirit and scope of the present invention. Example 1

To a solution of la (55g) in methylene dichloride (250ml), cooled in ice-water bath. Added dropwise fresh distilled titanium tetrachloride (40g) and tetramethyl ethylenediamine (30g) successively. After addition, the mixture was stirred for two hours followed by drop- wise addition of solution of 2,3-O-isopropyIidene-D-glyceraldehyde (27g) in DMC. Stirring was continued till starting material was not identified by TLC in the reaction mixture. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 2a (~64g). No further purification of compound 2a was required to be used in the next step.

To a solution of 2a (64g) and triethyl amine (50ml) in methylene dichloride (250ml), cooled in ice-water bath drop-wise benzoyl chloride (28g) was added. After the addition, the cooling bath was removed and temperature was brought to room temperature and mixture was stirred overnight. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 3a (~72g). No further purification of compound 3a required and was used as such in the next step. To a solution of 3a (~72g) in methanol (250ml) p-toluene sulphonic acid (TsOH) (5g) was added. The mixture was refluxed until the reaction was complete. Contents were quenched by adding sodium bicarbonate solution and separated the organic phase to obtain compound 4a (~64g). No further purification of compound 4a required and was used as such in the next step.
To a solution of 4a (64g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride was added dropwise (25g). After the addition, cooling bath was removed and temperature was brought to room temperature and stired overnight. Contents were quenched by adding 5% NH4CI (aq.) and separate organic phase to obtain compound 5a (~72g). No further purification of compound 5a was required and and used as such in the next step.
To a solution of 5a (~72g) in ethanol (250ml) cooled to 10°C, sodium borohydride
(lOg) was added in portions controling the temperature below 20°C. After the
addition, the cooling bath was removed and temperature was brought to room temperature and stired overnight. Methanol (20ml) was added to destroy unreacted sodium borohydride. Ethanol was removed under vacuum. Added water and dilute hydrochloric acid and extracted with ethyl acetate. The residue was dissolved in acetic acid and stirred at room temperature. Acetic acid was removed under vacuum to obtain compound 6a (~44g). No further purification of compound 6a was required

and was used in the next step.
To a solution of 6a (44g) and triethylamine (30ml) in methylene dichloride (250ml), cooled in ice-water bath. Methylsulfonyl chloride (I2g) was added drpowise. After the addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% ammonium chloride solution and separated the organic phase to obtain compound 7a (~48g). No further purification of compound 7a was required and was used as such in the next step.
The solution of Cytimidine (12g) in hexamethyl disilazane(HMDS) (50ml) was heated under reflux for 4 hours and excess HMDS was removed. To the residual, added solution of compound 7a (~48g) in Anisole and stirred the mixture overnight. Contents were quenched by adding 5% NH4C1 (aq.) and separated the organic phase to obtain compound 8a (~44g). No further purification of compound 8a was required and to be used in the next step.
To a solution of 8a (~44g) in methanol (250ml), cooled in ice-water bath solid sodium methoxide (12g) was added in portions. After the addition, cooling bath was removed and temperature was brought to room temperature. After the reaction was complete, mixture was cooled in an ice-water bath followed by the addition of mixture of methanol (100ml) and HC1 (8.2g) in the same.. After stirring for 30 minutes, sodium chloride was filtered off. Operation was repeated with methanol (50ml) and HCI (4.1g) mixture and stirred for 30 minutes. Product was further recrystallized after concentrating the residual from acetone and water to obtain Gemcitabine Hydrochloride (20g). Spectroscopic data: Mass peak at 299
The 'H-NMR analysis of Gemcitabine hydrochloride was recorded on BRUKER AV-400 MHz spectrometer in DMSO as solvent. The chemical shifts are reported on 6

scale in ppm with respect to TMS (5 O.OOppm) as an internal standard. 6 (ppm) values: 3.846, 3.966, 4.06, 4.338, 6.21, 6.239 , 7.976
The IR spectrum of Gemcitabine Hydrochloride was recorded on Shimadzu 8400s spectrophotometer by suspending the title compound in KBr. Peaks were observed at 3390.63(s), 3257.55(m), 3080.1 l(s),l679.88(s), 1535.23(s), 1282.57(s), 1199.64(s), 1064.63(s), 856.34(s)

To a solution of lb (52g) in methylene dichloride (250ml), cooled in ice-water bath. fresh distilled titanium tetrachloride (40g) was added dropwise and TMEDA (30g) successively. After addition, the mixture was stirred for two hours. Solution of 2,3-0-isopropylidene-D-glyceraldehyde (27g) in dichloro methane (DMC) was added and reaction mixture was stirred till starting material was not identified by TLC. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 2b (~54g). No further purification of compound 2b was required and was used as such in the next step.
To a solution of 2b (54g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath. Benzoyl chloride (28g) was added dropwise. After the addition, cooling bath was removed and temperature was brought to room

temperature and stirred overnight. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 3b (~65g). No further purification of compound 3b required and was used as such in the next step.
To a solution of 3b (~65g) in methanol (250ml), TsOH (5g) was added and mixture was refluxed until the reaction was completed. Contents were quenched by adding sodium bicarbonate solution and separated the organic phase to obtain compound 4b (~54g). No further purification of compound 4b was required and was used as such in the next step.
To a solution of 4b (54g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath was added dropwise benzoyl chloride (25g). After the addition, the cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% NH4C1 (aq.) and separated organic phase to obtain compound 5b (~56g). No further purification of compound 5b was required and was used as such in the next step.
To a solution of 5a (~56g) in ethanol (250ml) cooled to 10°C sodium borohydride
(lOg) was added in portions controlling the temperature below 20°C. After the
addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Methanol (20ml) was added to destroy unreacted sodium borohydride. Ethanol was removed under vacuum. Added water and dilute hydrochloric acid and extracted with ethyl acetate. The residue was dissolved in acetic acid and stirred at room temperature. Acetic acid was removed under vacuum to obtain compound 6b (~35g). No further purification of compound 6b was required and was used in the next step.
To a solution of 6b (35g) and triethylamine (30ml) in methylene dichloride (250ml),

cooled in ice-water bath. Methylsulfonyl chloride (12g) was added dropwise. After the addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% ammonium chloride solution and separated the organic phase to obtain compound 7b (~40g). No further purification of compound 7b was required and was used as such in the next step.
The solution of Cytimidine (12g) in HMDS (50ml) was refluxed for 4 hours and the excess HMDS removed. To the residual, added solution of compound 7b (~40g) in Anisole and stirred the mixture overnight. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 8b (~36g). No further purification of compound 8b was required and was used in the next step. To a solution of 8b (~36g) in methanol (250ml), cooled in ice-water bath solid sodium methoxide (12g) was added in portions. After the addition, cooling bath was removed and temperature was brought to room temperature. After the reaction is complete, the mixture was cooled in ice-water bath followed by the addition of mixture of methanol (100ml) and HC1 (8.2g) in the same.. After stirring for 30 minutes, sodium chloride was filtered off. Operation was repeated with methanol (50ml) and HC1 (4.1g) mixture and stirred for 30 minutes. Product was further recrystallized after concentrating the residual from acetone and water to obtain Gemcitabine Hydrochloride (20g). Spectroscopic data: Mass peak at 299
The 'H-NMR analysis of Gemcitabine hydrochloride was recorded on BRUKER AV-400 MHz spectrometer in DMSO as solvent. The chemical shifts are reported on 8 scale in ppm with respect to TMS (8 O.OOppm) as an internal standard. 8 (ppm) values: 3.846, 3.966, 4.06,4.338, 6.21, 6.239 , 7.976
The IR spectrum of Gemcitabine Hydrochloride was recorded on Shimadzu 8400s spectrophotometer by suspending the title compound in KBr. Peaks were observed at

3390.63(s), 3257.55(m), 3080.11(s),1679.88(s), 1535.23(s), 1282.57(s), I199.64(s),
1064.63(s),856.34(s)
Example 3

To a solution of lc (48g) in methylene dichloride (250ml), cooled in ice-water bath. Freshly distilled titanium tetrachloride (40g) was added drop wise and tetramethyl ethylenediamine(TMEDA) (30g) successively. After addition, the mixture was stirred for two hours. Added drop-wise solution of 2,3-O-isopropylidene-D-gIyceraldehyde (27g) in DMC, The reaction mixture was stirred till starting material was not identified by TLC. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 2c (~50g). No further purification of compound 2c required and to be used in the next step.
To a solution of 2c (50g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath was added with benzoyl chloride (28g) drop-wise. After the addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 3c (~61g). No further purification of compound 3c was required and was used as such in the next step.
To a solution of 3c (-61 g) in methanol (250ml), was added TsOH (5g) and mixture

was refluxed until the reaction was complete. Contents were quenched by adding sodium bicarbonate solution and separated the organic phase to obtain compound 4c (~51g) . No further purification of compound 4c was required and was used in the next step.
To a solution of 4c (51g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath was added dropwise benzoyl chloride (25g). After the addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% NH4C1 (aq.) and separated organic phase to obtain compound 5c (~52g). No further purification of compound 5c was required and was used as such in the next step.
To a solution of 5c (~52g) in ethanol (250ml) cooled to 10°C, sodium borohydride
(lOg) was added in portions controlling the temperature below 20°C. After the
addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Methanol (20ml) was added to destroy the unreacted sodium borohydride. Ethanol was removed under vacuum followed by adding water and dilutes hydrochloric acid and extracted with ethyl acetate. The residue was dissolved in acetic acid and stirred at room temperature. Acetic acid was removed under vacuum to obtain compound 6c (~3lg). No further purification of compound 6c was required and was used as such in the next step.
To a solution of 6c (31 g) and triethylamine (30ml) in methylene dichloride (250ml), cooled in ice-water bath. Methylsulfonyl chloride (12g) was added drop wise. After the addition, cooling bath was removed and temperature was brought to room temperature and stirred overnight. Contents were quenched by adding 5% ammonium chloride solution and separated the organic phase to obtain compound 7c (~36g). No further purification of compound 7c was required and was used as such in the next

step.
The solution of Cytimidine (12g) in HMDS (50ml) was refluxed for 4 hours and the excess HMDS was removed. To the residual, added solution of compound 7c (~36g) in Anisole and stirred the mixture overnight. Contents were quenched by adding 5% NH4CI (aq.) and separated the organic phase to obtain compound 8c (~32g). No further purification of compound 8c was required and was used as such in the next step.
To a solution of 8c (~32g) in methanol (250ml), cooled in ice-water bath was added solid sodium methoxide (12g) in portions. After the addition, cooling bath was removed and temperature was brought to room temperature. After the reaction was complete, contents were cooled in ice-water bath. Mixture of methanol (100ml) and HC1 (8.2g) was added in the same.. After stirring for 30 minutes, sodium chloride filtered off was. Operation was repeated with methanol (50ml) and HCI (4.1g) mixture and stirred for 30 minutes.. Pruduct was further recrystallized after concentrating the residual from acetone and water to obtain Gemcitabine Hydrochloride (15g). Spectroscopic data: Mass peak at 299
The 'H-NMR analysis of Gemcitabine hydrochloride was recorded on BRUKER AV-400 MHz spectrometer in DMSO as solvent. The chemical shifts are reported on 6 scale in ppm with respect to TMS (8 O.OOppm) as an internal standard. δ (ppm) values: 3.846, 3.966, 4.06, 4.338, 6.21, 6.239 , 7.976
The IR spectrum of Gemcitabine Hydrochloride was recorded on Shimadzu 8400s spectrophotometer by suspending the title compound in KBr. Peaks were observed at 3390.63(s), 3257.55(m), 3080.1 l(s),1679.88(s), 1535.23(s), 1282.57(s), 1199.64(s), 1064.63(s), 856.34(s)

We Claim:
1. A process for preparing gemcitabine and its pharmaceutically acceptable salts comprising:
Reacting difluoro acetic acid coupled chiral auxiliary compound of formula IV in a organic solvent, base and a catalyst

With compound of formula
to obtain compound of formula XII;

- compound of formula XII is reacted with -OH protecting agents to giv< compound of formula XIII


wherein
Rl= Benzyl., Phenyl, isopropyl
R2= Benzoyl, Trimethyl silyl, tertbutyldimethyl silyl
- compound of formula XIII is treated with an acid to give a compound of
formula XIV;

- compound of formula XIV is treated with a -OH protecting group to protect the primary -OH group to give a compound of formula XV;

- compound of formula XV is treated with a reducing agent preferably a hydride base to g\ve a compound oformula II:

R2=Bz,TES,TBS,ect. R3=Bz,TES,TBS,ect.

- compound of formula II is treated with an -O salt forming compound to activate the —OH group in an organic solvent to obtain a compound of formula XVI

K2=BZ, I bS, I bS.ect. R3=Bz,TES,TBS,ect. R4=Ts or Ms
- compound of formula XVI is reacted with cytimidine to give a compound of formula XVII;

- compound of formula XVII is treated with a base to give gemcitabine base and isolated as hydrochloride of formula I

2. Chiral auxiliary as claimed in claim 1 is selected from the group comprising

compounds of the formulae

Wherein Rl= Benzyl., Phenyl, isopropyl 3. Solvents used for the process for the preparation of compound of formula XII as
claimed in claim 1 is selected from the group of solvents of dimethylsulfoxide,
dimethylformamide, acetone, methylene dichloride, chloroform,
tetrahydrofuran, methanol, ethanol or propanol or mixture thereof. 4.. The catalyst or metal halide used in the process as claimed in claim 1 is selected
from the group of titanium tetrachloride, stannous chloride or magnesium
chloride. 5. The base used in the process as claimed in claim 1 is selected from the group of
tetramethy leth y lenediam ine, tetrameth ylpropene-d iamine, tri ethy Iamine,
diisopropylethylamine or sparteine. 5. Protective group used in the process as claimed in claim 1 is selected from the
group of benzoyl, subsitituted benzoyl, trialkyl silyl preferably triethyl silyl
(TES), tert butyldimethyl silyl (TBS), methoxy methyl(MOM) or benzyl. 7. The acid used in the hydrolysis to convert compound of formula XIII to

compound of formula XV as claimed in claim 1 is selected from hydrochloride or sulphuric acid,TsOH, trifluoroacetic acid, methanesulfonic acid or trifluoromethane sulfonic acid.
8. The reagent used for reduction and removing the auxiliary as claimed in claim 1
is selected from the group of hydrides preferably sodium borohydride,
potassium borohydride, lithium borohydride, calcium borohydride, or red-Al,
DIBAL.
9. The reagent used for O salt formation to activate -OH Gp as claimed in claim 1 is selected from p-toluene sulphonyl chloride or methylsulfonyl chloride or dicresyl phosphonate and the solvent is selected from methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or toluene.
10. Compound of the formula

11. Compound of the formula


12. Compound of the formula

13. Compound of the formula

Abbreviation used is as:
Bn-Benzyl
Ph- Phenyl
1-Pr-Isopropyl
Bz- Benzoyl
TES- Triethyl silyl
TBS-Tert butyl dimethyl silyl
Ts- Tosyl
Ms- Mesyl