Title of Invention	PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE
Abstract	A process for the preparation of Gemcitabine Hydrochloride (I) comprising: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary (1) by Evans and Crimmins asymmetric aldol reaction to obtain (2); ii) protecting hydroxyl group at 3’-position in compound (2) to give (3); iii) hydrolsing acetonide moiety of (3) to give (4); iv) protecting the primary hydroxyl group of (4); v) reducing the carbonyl group of (5) by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate (6); vi) sulfonylizing compound (6); vii) condensing sulfonylated ß-D-ribofuranose (7) with Cytimidine to give protected Gemcitabine, viii) followed by deprotecting and converting it to Gemcitabine.HCI.

Title of Invention

PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE

Abstract

A process for the preparation of Gemcitabine Hydrochloride (I) comprising: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary (1) by Evans and Crimmins asymmetric aldol reaction to obtain (2); ii) protecting hydroxyl group at 3’-position in compound (2) to give (3); iii) hydrolsing acetonide moiety of (3) to give (4); iv) protecting the primary hydroxyl group of (4); v) reducing the carbonyl group of (5) by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate (6); vi) sulfonylizing compound (6); vii) condensing sulfonylated ß-D-ribofuranose (7) with Cytimidine to give protected Gemcitabine, viii) followed by deprotecting and converting it to Gemcitabine.HCI.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Process for the preparation of Gemcitabine Hydrochloride" 2. APPLICANTS: (a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E), Mumbai-400059, Maharashtra, India. (a) NAME: SHANGHAI PARLING PHARMA TECH CO., LTD. (b) NATIONALITY: China Company incorporated under the Chinese Companies Law (c) ADDRESS: Suite 2, No. 868 Zhenchen Road, Baoshan District, Shanghai, 200 444, China. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical Field of Invention: The present invention relates to a new improved process for the preparation of Gemcitabine Hydrochloride (2'-deoxy-2’, 2'-difluorocytidine hydrochloride). Background and prior art of Invention: Gemcitabine Hydrochloride is a nucleoside analogue that exhibits anti-tumor activity and belongs to a general group of chemotherapy drug known as anti-metabolites. 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-b-D-ribofuranosyl)-pyrimidin-2(lH)-one or 2’-deoxy-2’2’-difluorocytidine (b isomer). The key intermediate of Gemcitabine is 3,5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose and has the following structure (II) P = protecting group There are generally, two synthetic routes of Gemcitabine. US Pat. No.4526988, 4808614, 5223608 and J.Org.Chem. (1988, 2406) describes successful process using Reformatsky Reaction (between ethyl 2-bromide-2, 2-difluoro acetate and 2,3-O-isopropylidene-D-glyceraldehyde) as key step. The process described as follows: US Pat. No. 6001994 describes another process as the aldol reaction (between t-butyl 2-bromide-2,2-difluoro thioacetate and 2,3-O-isopropylidene-D-glycer-aldehyde) as key step. The process illustrated as follows: The above mentioned processes involve condensation reaction which result in a mixture of isomers and further gives low yield of desired key intermediate of Gemcitabine i.e. 3, 5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose (II). So, there is a need to develop a new process for preparation of key intermediate i.e. 3, 5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose (II) and Gemcitabine. HC1 which, is simple, high yielding, and can be carried out at industrial scale by using mild reaction conditions. Summary of the Invention: In an aspect, the present invention discloses a new improved process for the preparation of Gemcitabine Hydrochloride (I) comprising: reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of compound of formula (1) by Evans and Crimmins asymmetric aldol reaction to obtain compound of formula (2); protecting the new hydroxyl group formed at 3'-position in compound of formula (2) to give compound of formula (3); hydrolysing acetonide moiety of compound of formula (3) to give compound of formula (4); protecting the primary hydroxyl group obtained in ring opening to give compound (5); reducing the carbonyl group of compound of formula (5) followed by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate, diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose of formula (6); sulfonylizing of diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose; condensing sulfonylated b-D-ribofuranose with Cytimidine to give protected Gemcitabine followed by deprotection and converting it to hydrochloride salt. Detailed Description Of the Invention: In accordance of the present invention the novel process for preparation of Gemcitabine Hydrochloride (I) comprises: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of formula 1 by Evans and Crimmins asymmetric aldol reaction to give compound of formula 2 in the presence of base and catalyst; Wherein, X=Y=0; X=Y=S and X=S, Y=0 Rl= Benzyl (Bn), Phenyl (Ph), iso-propyl (i-Pr) ii) protecting the new hydroxyl group formed at 3'-position of compound of formula 2 to give compound of formula (3); iii) hydrolyzing acetonide group of compound of formula 3 to give compound of formula 4; v) reducing carbonyl group of compound of formula (5) by simultaneous elimination of iv) protecting primary hydroxyl group of compound of formula 4 to give compound of formula 5; the chiral auxiliary using a base followed by cyclization by treating with mineral acid to give product of formula (6); vi) sulfonylization of compound of formula (6) in the presence of base and using solvent such as methylene chloride at a temperature range 25 - 40°C by stirring overnight; vii) reacting compound of formula (7) with a solution of Cytimidine in hexamethyldisilizane (HMDS) under reflux to give protected Gemcitabine (8); viii) deprotecting of compound (8) using a base by stirring in a solvent such as alcohol and converting the gemcitabine formed to Gemcitabine.HC1 of formula (I). According to the present invention the process for preparation of Gemcitabine hydrochloride comprises condensation of 2,3-0 (l-ethylpropylidene)-D-glyceraldehyde with chiral auxiliary of formula (1) as a key step followed by cyclization to give 2-deoxy-2,2-difluoro-D-furanose -3,5-dibenzoate of formula 6. The process is schematically represented as follows: Wherein, X=Y=O; X=Y=S and X=S, Y=O Rl= Benzyl (Bn), Phenyl (Ph), iso-propyl (i-Pr) R2= Benzoyl (Bz), Triethylsilyl (TES), Tertbutylsilyl (TBS) R3= Benzoyl (Bz), Triethylsilyl (TES), Tertbutylsilyl (TBS) R4= Tosyl (Ts) or Mesyl (Ms) Preferably, in accordance of the present invention the aldol condensation as described in of step i) is carried out by stirring the solution of chiral auxiliary of formula (1) for two hours in the presence of base and catalyst such as titanium tetrachloride. To this mixture, solution of 2, 3-0-isopropylidene-D-glyceraldehyde in dimethyl carbitol (DMC) is added and the reaction mixture is stirred to get compound of formula 2. Wherein, the chiral auxiliary is oxazolidinone (X=Y=O), oxazolidinethione (X=S, Y=O) or thiazolidinonethione (X=Y=S) and Rl=phenyl, benzyl or isopropyl. The base is selected from tetramethylethylenediamine, tetramethylpropenediamine, triethylamine, diisopropylamine or sparteine. The catalyst used is selected from titanium tetrachloride, stannous chloride or magnesium chloride. The solvent used for the aldol reaction is dimethylsulfoxide, dimethylformamide, acetone, methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol or propanol. In step ii) the protection of hydroxyl group at 3'-position is carried out by cooling a mixture of base and compound of formula (2) to 0°C in a solvent and adding protecting reagent at room temperature followed by stirring overnight to give compound of formula (3). The protecting reagent is selected from benzoyl chloride, triethylsilyl chloride (TES-Cl), tertbutylsilyl chloride (TBS-C1), methoxymethyl chloride or benzyl chloride. In step iii) acetonide group of compound of formula (3) is hydrolysed by refluxing the mixture of compound (3) in solvent such as alcohol and p-toluenesulphonic acid (TsOH) followed by adding a base to separate the organic phase. The solvent used is alcohol, preferably primary, secondary alcohol and is selected from methanol, ethanol, isopropanol etc. The base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate etc. In step iv) primary hydroxyl group is protected by acyl group using acyl halide in the presence of base such as triethylamine by stirring overnight at room temperature. The solvent used for the reaction is methylene chloride. In step v) the chiral auxiliary is eliminated by reducing compound of formula (5) in a alcoholic solvent by using a base such as sodium borohydride at a temperature of 10-20 °C. The alcoholic solvent used is selected from methanol, ethanol, isopropanol, n-butanol etc. The base used is sodium borohydride, potassium borohydride, lithium borohydride, calcium hydride, red-Al or DIBAL. In step vi) sulfonylization of compound 6 is carried out by adding sulfonylating agent to the reaction mixture of compound (6) and base such as triethylamine at room temperature and stirring the mixture overnight at room temperature. The sulfonylating agent is preferably p-toluenesulfonyl chloride or methylsulfonyl chloride. The solvent used is methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or toluene. In step vii) compound of formula (7) is condensed with cymitidine by stirring the mixture overnight to give compound of formula (8). The reaction is carried out in a solvent such as hexamethyldisilizane (HMDS) and anisole. The compound of formula (8) is deprotected by using a base such as sodium alkoxide preferably sodium ethoxide, sodium methoxide. The mixture of alcohol such as ethanol, methanol, isopropanol and hydrochloric acid is added to the deprotected Gemcitabine to give Gemcitabine HC1 of formula (I). Recrystallization of Gemcitabine HC1 is carried out using acetone and water. The advantages of the process of preparation of the reaction are as follows: 1. Reaction is simple, high yielding, and is carried out at industrial scale by using mild reaction conditions. 3. The intermediates formed is used in the subsequent step without any further Purification. 2. The new chiral center is introduced by asymmetric aldol reaction, thereby avoiding the separation of unwanted isomer. 3. There is no isomer of pyranose as the primary OH is already protected 4. The auxiliary is removed easily and at the same time, the imide is reduced to aldehyde directly and the ribofuranosyl is formed. The following examples of the present invention are only for illustration purpose and limit the scope of invention. To a solution of la (55g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added successively. After addition the mixture was stirred for two hours. Solution of 2,3-O-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material was not identified by TLC. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 2a (~64g). Compound 2a was used in the next step without any further purification. To a solution of 2a (64g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (28g) was added drop-wise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 3a (~72g). Compound 3a was used in the next step without any further purification. To a solution of 3a (~72g) in methanol (250ml), TsOH (5g) was added. The mixture was refluxed until the reaction was complete. Sodium bicarbonate solution was added and the organic phase was separated to obtain compound 4a (~64g). Compound 4a was used in the next step without any further purification. To a solution of 4a (64g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (25g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4CI (aq.) was added and organic phase was separated to obtain compound 5a (~72g). No further purification of compound 5a was required and to be used in the next step. To a solution of 5a (~72g) in ethanol (250ml) cooled to 10°C, sodium borohydride (10g) was added in portions. The temperature was controlled below 20°C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. Methanol (20ml) was added to the reaction mixture to remove excess sodium borohydride. Ethanol was concentrated in vacuum. Water and dilute hydrochloric acid is added to the reaction mixture and was extracted with ethyl acetate. The residue was dissolved in acetic acid and was stirred at room temperature. Acetic acid was removed by vacuum to obtain compound 6a (~44g). No further purification of compound 6a required and to be 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 (12g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was removed to room temperature and was stirred overnight. Add 5% ammonium chloride solution and separate the organic phase to obtain compound 7a (~48g). No further purification of compound 7a required and to be used in the next step. The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and the excess HMDS was removed. To the residual, solution of compound 7a (~48g) in Anisole was added and the mixture was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated 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, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was completed, the mixture was cooled in ice-water bath .The mixture of methanol (100ml) and HC1 (8.2g) was added to the reaction mixture. After stirring for 30 minutes, sodium chloride was filtered off. The mixture of methanol (50ml) and HCI (4.1g) was added again and was stirred for 30 minutes. The residual was concentrated and was recrystallized from acetone and water to obtain Gemcitabine Hydrochloride (20g). To a solution of lb (55g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added successively. After addition the mixture was stirred for two hours. Solution of 2,3-O-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material was not identified by TLC. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 2b (~64g). Compound 2b was used in the next step without any further purification. To a solution of 2b (54g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (28g) was added drop-wise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 3b (~65g). Compound 3a was used in the next step without any further purification. To a solution of 3b (~65g) in methanol (250ml), TsOH (5g) was added. The mixture was refluxed until the reaction was completed. Sodium bicarbonate solution was added and the organic phase was separated to obtain compound 4b (~54g). No further purification of compound 4b required and to be used in the next step. To a solution of 4b (54g) and triethylamine (40ml) in methylene dichloride (250ml), was cooled in ice-water bath. Benzoyl chloride was added dropwise (25g). After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% NH4CI (aq.) was added and organic phase was separated to obtain compound 5b (~56g). No further purification of compound 5b was required and to be used in the next step. To a solution of 5b (~56g) in ethanol (250ml) cooled to 10°C, sodium borohydride (l0g) was added in portions. The temperature was controlled below 20°C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. Methanol (20ml) was added to remove to remove excess sodium borohydride. Ethanol was concentrated in vacuum. Water and dilute hydrochloric acid were added to the reaction mixture and was extracted with ethyl acetate. The residue was dissolved in acetic acid and stirred at room temperature. The acetic acid was removed by vacuum to obtain compound 6b (~35g). No further purification of compound 6b was required and to be 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, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. The 5% ammonium chloride solution was added to the reaction mixture and the organic phase was separated to obtain compound 7b (~40g). No further purification of compound 7b was required and to be used in the next step. The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and was removed the excess HMDS. To the residual, solution of compound 7b (~40g) was added in Anisole and was the mixture was stirred overnight. 5% NH4CI (aq.) was added to the reaction mixture and the organic phase was separated to obtain compound 8b (~36g). No further purification of compound 8b required and to be 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, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was complete, the mixture was cooled in ice-water bath .To this reaction mixture, mixture of methanol (100ml) and HCI (8.2g) was added, was stirred for 30 minutes and sodium chloride formed was filtered off. Again, mixture of methanol (50ml) and HCI (4.1 g) was added and was stirred for 30 minutes. The residual obtained was concentrated and was recrystallised from acetone and water to obtain Gemcitabine Hydrochloride (18g). Example 3: To a solution of l c (48g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added dropwise successively, After addition, the mixture was stirred for two hours. Soution of 2,3-0-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material not identified by TLC. 5% NH4C1 (aq.) was added and the organic phase was separated 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, benzoyl chloride (28g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was removed to room temperature and was stirred overnight. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 3c (~61g). No further purification of compound 3c required and to be used in the next step. To a solution of 3c (~61g) in methanol (250ml), TsOH (5g) was added. The mixture was refiuxed until the reaction was complete. Sodium bicarbonate solution was added and was the organic phase was separated to obtain compound 4c (~51 g). No further purification of compound 4c required and to be used in the next step. To a solution of 4c (51g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (25g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 5c (~52g). No further purification of compound 5c was required and to be used in the next step. To a solution of 5c (~52g) in ethanol (250ml) cooled to 10°C, add sodium borohydride (l0g) in portions. The temperature was controlled below 20°C. After the addition, cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. Methanol was added (20ml) to remove excess sodium borohydride. Concentrate ethanol in vacuum. Water and dilute hydrochloric acid was added and was extracted with ethyl acetate. The residue was dissolved in acetic acid and was stirred at room temperature. Acetic acid was removed by vacuum to obtain compound 6c (~31g). No further purification of compound 6c required and to be used in the next step. To a solution of 6c (31g) and triethylamine (30ml) in methylene dichloride (250ml), cooled in ice-water bath, methylsulfonyl chloride (12g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% ammonium chloride solution was added and the organic phase was separated to obtain compound 7c (~36g). No further purification of compound 7c required and to be used in the next step. The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and the excess HMDS was removed. To the residual, solution of compound 7c (~36g) was added in Anisole and the mixture was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 8c (~32g). No further purification of compound 8c required and to be used in the next step. To a solution of 8c (~32g) in methanol (250ml), cooled in ice-water bath, solid sodium methoxide (12g) was added in portions. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was complete, the mixture was cooled in ice-water bath. To this, the mixture of methanol (100ml) and HCl (8.2g) was added. After stirring for 30 minutes, the sodium chloride formed was filtered off. Again mixture of methanol (50ml) and HCl (4.1g) was added and was stirred for 30 minutes. The residual obtained was concentrated and was recrystallized from acetone and water to obtain Gemcitabine Hydrochloride (15g). We claim: 1. A process for preparation of Gemcitabine Hydrochloride (I) comprises: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of formula 1 to give compound of formula 2 under Evans and Crimmins asymmetric aldol reaction of the presence of base and catalyst Wherein, X=Y=0; X=Y=S; X=S, Y=0; and Rl=Bn, Ph, i-Pr; ii) protecting the new hydroxyl group formed at 3'-position of compound of formula 2 to give compound of formula 3; wherein, R2= Bz, TES, TBS, MOM or Bn; iii) hydrolyzing acetonide moiety of compound of formula 3 by refluxing in the presence of organic acid to give compound of formula 4; iv) protecting primary hydroxyl group of compound of formula 4 by acyl chloride to give compound of formula 5; Wherein, R3=Bz, TES, TBS, MOM or Bn; v) reducing compound of formula (5) by simultaneous elimination of the chiral auxiliary using a base in the presence of solvent followed by treatment with mineral acid to give cyclised product of formula (6) i.e. diprotected-2-deoxy-2,2-difluoro-P-D-ribofuranose; vi) sulfonylizng compound of formula (6) in the presence of base and using solvent such as methylene chloride at a temperature 25 - 40°C by stirring overnight; Wherein, R4=Ts or Ms vii) condensing sulfonylated 2,2-difluoro-\|3-D-ribofuranose derivative (7) with Cytimidine under reflux conditions to give protected Gemcitabine Hydrochloride (8); and viii) deprotecting compound of formula (8) followed by reacting with hydrochloric acid to give Gemcitabine.HCl (I). 2. The process as claimed in claim 1, wherein the chiral auxiliary is oxazolidinone (X=Y=0), oxazolidine-thione (X=S,Y=0) or thiazolidinethione (X=Y=S); R1 is phenyl, benzyl or isopropyl. 3. The process as claimed in claim 1, wherein the solvent used in step i) (aldol reaction) is selected from the group comprising of dimethylsulfoxide, dimethylformamide, acetone, methylene dichloride, chloroform, tetrahydrofuran, methanol, ethanol or propanol. 4. The process as claimed in claim 1 wherein in step i), the catalyst used is selected from titanium tetrachloride, stannous chloride or magnesium chloride. 5. The process as claimed in claim 1 wherein in step i), the base used is selected from tetramethylethylenediamine, tetramethylpropene-diamine, triethylamine, diisopropylethylamine or sparteine. 6. The process as claimed claim 1, wherein the protecting group used in step ii) for protection of hydroxyl group is benzoyl, subsitituted benzoyl, TES, TBS, MOM or benzyl. 7. The process as claimed in claim 1, wherein the mineral acid used in step (v) is hydrochloric acid or sulphuric acid. 8. The process as claimed in claim 1 wherein the organic acid used in step iii) is selected from p-toluenesulfonic acid (TsOH), trifluoroacetic acid, methanesulfonic acid or trifluoromethane sulfonic acid. 9. The process as claimed in claim 1, wherein the reagent used for reduction to remove the auxiliary in step v) is selected from sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, red-Al, DIBAL. 10. The process as claimed in claim 1, wherein the reagent used for sulfonylization in step vi) is selected from p-toluenesulfonyl chloride (TsCl) or methylsulfonyl chloride and the solvent used is methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or toluene. Abstract: A process for the preparation of Gemcitabine Hydrochloride (I) comprising: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary (1) by Evans and Crimmins asymmetric aldol reaction to obtain (2); ii) protecting hydroxyl group at 3'-position in compound (2) to give (3); iii) hydrolysing acetonide moiety of (3) to give (4); iv) protecting the primary hydroxyl group of (4); v) reducing the carbonyl group of (5) by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate (6) ; vi) sulfonylizing compound (6); vii) condensing sulfonylated P-D-ribofuranose (7) with Cytimidine to give protected Gemcitabine, viii) followed by deprotecting and converting it to Gemcitabine.HC1.

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process for the preparation of Gemcitabine Hydrochloride"
2. APPLICANTS:
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
(a) NAME: SHANGHAI PARLING PHARMA TECH CO., LTD.
(b) NATIONALITY: China Company incorporated under the Chinese
Companies Law
(c) ADDRESS: Suite 2, No. 868 Zhenchen Road, Baoshan District, Shanghai,
200 444, China.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed.

Technical Field of Invention:
The present invention relates to a new improved process for the preparation of Gemcitabine Hydrochloride (2'-deoxy-2’, 2'-difluorocytidine hydrochloride).
Background and prior art of Invention:
Gemcitabine Hydrochloride is a nucleoside analogue that exhibits anti-tumor activity and belongs to a general group of chemotherapy drug known as anti-metabolites. 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-b-D-ribofuranosyl)-pyrimidin-2(lH)-one or 2’-deoxy-2’2’-difluorocytidine (b isomer). The key intermediate of Gemcitabine is 3,5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose and has the following structure (II)

P = protecting group
There are generally, two synthetic routes of Gemcitabine. US Pat. No.4526988, 4808614, 5223608 and J.Org.Chem. (1988, 2406) describes successful process using Reformatsky Reaction (between ethyl 2-bromide-2, 2-difluoro acetate and 2,3-O-isopropylidene-D-glyceraldehyde) as key step. The process described as follows:

US Pat. No. 6001994 describes another process as the aldol reaction (between t-butyl 2-bromide-2,2-difluoro thioacetate and 2,3-O-isopropylidene-D-glycer-aldehyde) as key step. The process illustrated as follows:

The above mentioned processes involve condensation reaction which result in a mixture of isomers and further gives low yield of desired key intermediate of Gemcitabine i.e. 3, 5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose (II). So, there is a need to develop a new process for preparation of key intermediate i.e. 3, 5-diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose (II) and Gemcitabine. HC1 which, is simple, high yielding, and can be carried out at industrial scale by using mild reaction conditions.
Summary of the Invention:
In an aspect, the present invention discloses a new improved process for the preparation of Gemcitabine Hydrochloride (I) comprising: reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of compound of formula (1) by Evans and Crimmins asymmetric aldol reaction to obtain compound of formula (2); protecting the new hydroxyl group formed at 3'-position in compound of formula (2) to give compound of formula (3); hydrolysing acetonide moiety of compound of formula (3) to give compound of formula (4); protecting the primary hydroxyl group obtained in ring opening to give compound (5); reducing the carbonyl group of compound of formula (5) followed by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate, diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose of formula (6); sulfonylizing of diprotected-2-deoxy-2,2-difluoro-b-D-ribofuranose; condensing sulfonylated b-D-ribofuranose with Cytimidine to give protected Gemcitabine followed by deprotection and converting it to hydrochloride salt.
Detailed Description Of the Invention:
In accordance of the present invention the novel process for preparation of Gemcitabine Hydrochloride (I) comprises:
i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of formula 1 by Evans and Crimmins asymmetric aldol reaction to give compound of formula 2 in the presence of base and catalyst;

Wherein, X=Y=0; X=Y=S and X=S, Y=0
Rl= Benzyl (Bn), Phenyl (Ph), iso-propyl (i-Pr) ii) protecting the new hydroxyl group formed at 3'-position of compound of formula 2 to give compound of formula (3);

iii) hydrolyzing acetonide group of compound of formula 3 to give compound of formula 4;

v) reducing carbonyl group of compound of formula (5) by simultaneous elimination of
iv) protecting primary hydroxyl group of compound of formula 4 to give compound of formula 5;

the chiral auxiliary using a base followed by cyclization by treating with mineral acid to give product of formula (6);

vi) sulfonylization of compound of formula (6) in the presence of base and using solvent such as methylene chloride at a temperature range 25 - 40°C by stirring overnight;

vii) reacting compound of formula (7) with a solution of Cytimidine in hexamethyldisilizane (HMDS) under reflux to give protected Gemcitabine (8);

viii) deprotecting of compound (8) using a base by stirring in a solvent such as alcohol and converting the gemcitabine formed to Gemcitabine.HC1 of formula (I).

According to the present invention the process for preparation of Gemcitabine hydrochloride comprises condensation of 2,3-0 (l-ethylpropylidene)-D-glyceraldehyde with chiral auxiliary of formula (1) as a key step followed by cyclization to give 2-deoxy-2,2-difluoro-D-furanose -3,5-dibenzoate of formula 6.
The process is schematically represented as follows:

Wherein, X=Y=O; X=Y=S and X=S, Y=O
Rl= Benzyl (Bn), Phenyl (Ph), iso-propyl (i-Pr)
R2= Benzoyl (Bz), Triethylsilyl (TES), Tertbutylsilyl (TBS)
R3= Benzoyl (Bz), Triethylsilyl (TES), Tertbutylsilyl (TBS)
R4= Tosyl (Ts) or Mesyl (Ms)
Preferably, in accordance of the present invention the aldol condensation as described in of step i) is carried out by stirring the solution of chiral auxiliary of formula (1) for two hours in the presence of base and catalyst such as titanium tetrachloride. To this mixture, solution of 2, 3-0-isopropylidene-D-glyceraldehyde in dimethyl carbitol (DMC) is added and the reaction mixture is stirred to get compound of formula 2.

Wherein, the chiral auxiliary is oxazolidinone (X=Y=O), oxazolidinethione (X=S, Y=O) or thiazolidinonethione (X=Y=S) and Rl=phenyl, benzyl or isopropyl.
The base is selected from tetramethylethylenediamine, tetramethylpropenediamine,
triethylamine, diisopropylamine or sparteine.
The catalyst used is selected from titanium tetrachloride, stannous chloride or magnesium
chloride.
The solvent used for the aldol reaction is dimethylsulfoxide, dimethylformamide, acetone,
methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol or propanol.
In step ii) the protection of hydroxyl group at 3'-position is carried out by cooling a mixture of base and compound of formula (2) to 0°C in a solvent and adding protecting reagent at room temperature followed by stirring overnight to give compound of formula (3). The protecting reagent is selected from benzoyl chloride, triethylsilyl chloride (TES-Cl), tertbutylsilyl chloride (TBS-C1), methoxymethyl chloride or benzyl chloride.
In step iii) acetonide group of compound of formula (3) is hydrolysed by refluxing the mixture of compound (3) in solvent such as alcohol and p-toluenesulphonic acid (TsOH) followed by adding a base to separate the organic phase. The solvent used is alcohol, preferably primary, secondary alcohol and is selected from methanol, ethanol, isopropanol etc.
The base is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate
etc.
In step iv) primary hydroxyl group is protected by acyl group using acyl halide in the
presence of base such as triethylamine by stirring overnight at room temperature. The
solvent used for the reaction is methylene chloride.
In step v) the chiral auxiliary is eliminated by reducing compound of formula (5) in a alcoholic solvent by using a base such as sodium borohydride at a temperature of 10-20 °C. The alcoholic solvent used is selected from methanol, ethanol, isopropanol, n-butanol etc.

The base used is sodium borohydride, potassium borohydride, lithium borohydride, calcium hydride, red-Al or DIBAL.
In step vi) sulfonylization of compound 6 is carried out by adding sulfonylating agent to the reaction mixture of compound (6) and base such as triethylamine at room temperature and stirring the mixture overnight at room temperature. The sulfonylating agent is preferably p-toluenesulfonyl chloride or methylsulfonyl chloride. The solvent used is methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or toluene.
In step vii) compound of formula (7) is condensed with cymitidine by stirring the mixture
overnight to give compound of formula (8). The reaction is carried out in a solvent such
as hexamethyldisilizane (HMDS) and anisole.
The compound of formula (8) is deprotected by using a base such as sodium alkoxide
preferably sodium ethoxide, sodium methoxide. The mixture of alcohol such as ethanol,
methanol, isopropanol and hydrochloric acid is added to the deprotected Gemcitabine to
give Gemcitabine HC1 of formula (I).
Recrystallization of Gemcitabine HC1 is carried out using acetone and water.
The advantages of the process of preparation of the reaction are as follows:
1. Reaction is simple, high yielding, and is carried out at industrial scale by using
mild reaction conditions.
3. The intermediates formed is used in the subsequent step without any further Purification.
2. The new chiral center is introduced by asymmetric aldol reaction, thereby avoiding the separation of unwanted isomer.
3. There is no isomer of pyranose as the primary OH is already protected
4. The auxiliary is removed easily and at the same time, the imide is reduced to aldehyde directly and the ribofuranosyl is formed.
The following examples of the present invention are only for illustration purpose and limit the scope of invention.

To a solution of la (55g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added successively. After addition the mixture was stirred for two hours. Solution of 2,3-O-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material was not identified by TLC. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 2a (~64g). Compound 2a was used in the next step without any further purification.
To a solution of 2a (64g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (28g) was added drop-wise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 3a (~72g). Compound 3a was used in the next step without any further purification.
To a solution of 3a (~72g) in methanol (250ml), TsOH (5g) was added. The mixture was refluxed until the reaction was complete. Sodium bicarbonate solution was added and the organic phase was separated to obtain compound 4a (~64g). Compound 4a was used in the next step without any further purification.
To a solution of 4a (64g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (25g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4CI (aq.) was added and organic phase was separated to

obtain compound 5a (~72g). No further purification of compound 5a was required and to be used in the next step.
To a solution of 5a (~72g) in ethanol (250ml) cooled to 10°C, sodium borohydride (10g) was added in portions. The temperature was controlled below 20°C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. Methanol (20ml) was added to the reaction mixture to remove excess sodium borohydride. Ethanol was concentrated in vacuum. Water and dilute hydrochloric acid is added to the reaction mixture and was extracted with ethyl acetate. The residue was dissolved in acetic acid and was stirred at room temperature. Acetic acid was removed by vacuum to obtain compound 6a (~44g). No further purification of compound 6a required and to be 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 (12g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was removed to room temperature and was stirred overnight. Add 5% ammonium chloride solution and separate the organic phase to obtain compound 7a (~48g). No further purification of compound 7a required and to be used in the next step.
The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and the excess HMDS was removed. To the residual, solution of compound 7a (~48g) in Anisole was added and the mixture was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated 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, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was completed, the mixture was cooled in ice-water bath .The mixture of methanol (100ml) and HC1 (8.2g) was added to the reaction mixture. After stirring for 30 minutes, sodium chloride was filtered off. The mixture of methanol (50ml) and HCI (4.1g) was added again and was stirred for 30 minutes. The residual was concentrated and was

recrystallized from acetone and water to obtain Gemcitabine Hydrochloride (20g).

To a solution of lb (55g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added successively. After addition the mixture was stirred for two hours. Solution of 2,3-O-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material was not identified by TLC. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 2b (~64g). Compound 2b was used in the next step without any further purification.
To a solution of 2b (54g) and triethylamine (50ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (28g) was added drop-wise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 3b (~65g). Compound 3a was used in the next step without any further purification.
To a solution of 3b (~65g) in methanol (250ml), TsOH (5g) was added. The mixture was refluxed until the reaction was completed. Sodium bicarbonate solution was added and the organic phase was separated to obtain compound 4b (~54g). No further purification of compound 4b required and to be used in the next step.
To a solution of 4b (54g) and triethylamine (40ml) in methylene dichloride (250ml), was

cooled in ice-water bath. Benzoyl chloride was added dropwise (25g). After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% NH4CI (aq.) was added and organic phase was separated to obtain compound 5b (~56g). No further purification of compound 5b was required and to be used in the next step.
To a solution of 5b (~56g) in ethanol (250ml) cooled to 10°C, sodium borohydride (l0g) was added in portions. The temperature was controlled below 20°C. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. Methanol (20ml) was added to remove to remove excess sodium borohydride. Ethanol was concentrated in vacuum. Water and dilute hydrochloric acid were added to the reaction mixture and was extracted with ethyl acetate. The residue was dissolved in acetic acid and stirred at room temperature. The acetic acid was removed by vacuum to obtain compound 6b (~35g). No further purification of compound 6b was required and to be 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, the cooling bath was removed and the reaction mixture was warmed to room temperature and stirred overnight. The 5% ammonium chloride solution was added to the reaction mixture and the organic phase was separated to obtain compound 7b (~40g). No further purification of compound 7b was required and to be used in the next step.
The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and was removed the excess HMDS. To the residual, solution of compound 7b (~40g) was added in Anisole and was the mixture was stirred overnight. 5% NH4CI (aq.) was added to the reaction mixture and the organic phase was separated to obtain compound 8b (~36g). No further purification of compound 8b required and to be 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, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was complete, the mixture was cooled in ice-water bath .To this reaction mixture, mixture of

methanol (100ml) and HCI (8.2g) was added, was stirred for 30 minutes and sodium chloride formed was filtered off. Again, mixture of methanol (50ml) and HCI (4.1 g) was added and was stirred for 30 minutes. The residual obtained was concentrated and was recrystallised from acetone and water to obtain Gemcitabine Hydrochloride (18g).
Example 3:

To a solution of l c (48g) in methylene dichloride (250ml), cooled in ice-water bath, fresh distilled titanium tetrachloride (40g) and TMEDA (30g) were added dropwise successively, After addition, the mixture was stirred for two hours. Soution of 2,3-0-isopropylidene-D-glyceraldehyde (27g) in DMC was added dropwise. The reaction mixture was stirred till starting material not identified by TLC. 5% NH4C1 (aq.) was added and the organic phase was separated 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, benzoyl chloride (28g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was removed to room temperature and was stirred overnight. 5% NH4C1 (aq.) was added and the organic phase was separated to obtain compound 3c (~61g). No further purification of compound 3c required and to be used in the next step.
To a solution of 3c (~61g) in methanol (250ml), TsOH (5g) was added. The mixture was refiuxed until the reaction was complete. Sodium bicarbonate solution was added and was the organic phase was separated to obtain compound 4c (~51 g). No further purification of

compound 4c required and to be used in the next step.
To a solution of 4c (51g) and triethylamine (40ml) in methylene dichloride (250ml), cooled in ice-water bath, benzoyl chloride (25g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 5c (~52g). No further purification of compound 5c was required and to be used in the next step.
To a solution of 5c (~52g) in ethanol (250ml) cooled to 10°C, add sodium borohydride (l0g) in portions. The temperature was controlled below 20°C. After the addition, cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. Methanol was added (20ml) to remove excess sodium borohydride. Concentrate ethanol in vacuum. Water and dilute hydrochloric acid was added and was extracted with ethyl acetate. The residue was dissolved in acetic acid and was stirred at room temperature. Acetic acid was removed by vacuum to obtain compound 6c (~31g). No further purification of compound 6c required and to be used in the next step.
To a solution of 6c (31g) and triethylamine (30ml) in methylene dichloride (250ml), cooled in ice-water bath, methylsulfonyl chloride (12g) was added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature and was stirred overnight. 5% ammonium chloride solution was added and the organic phase was separated to obtain compound 7c (~36g). No further purification of compound 7c required and to be used in the next step.
The solution of Cytimidine (12g) in HMDS (50ml) was heated under reflux for 4 hours and the excess HMDS was removed. To the residual, solution of compound 7c (~36g) was added in Anisole and the mixture was stirred overnight. 5% NH4CI (aq.) was added and the organic phase was separated to obtain compound 8c (~32g). No further purification of compound 8c required and to be used in the next step.
To a solution of 8c (~32g) in methanol (250ml), cooled in ice-water bath, solid sodium methoxide (12g) was added in portions. After the addition, the cooling bath was removed and the reaction mixture was warmed to room temperature. After the reaction was

complete, the mixture was cooled in ice-water bath. To this, the mixture of methanol (100ml) and HCl (8.2g) was added. After stirring for 30 minutes, the sodium chloride formed was filtered off. Again mixture of methanol (50ml) and HCl (4.1g) was added and was stirred for 30 minutes. The residual obtained was concentrated and was recrystallized from acetone and water to obtain Gemcitabine Hydrochloride (15g).

We claim:
1. A process for preparation of Gemcitabine Hydrochloride (I) comprises:
i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary of formula 1 to give compound of formula 2 under Evans and Crimmins asymmetric aldol reaction of the presence of base and catalyst

Wherein, X=Y=0; X=Y=S; X=S, Y=0; and Rl=Bn, Ph, i-Pr;
ii) protecting the new hydroxyl group formed at 3'-position of compound of formula 2 to give compound of formula 3;

wherein, R2= Bz, TES, TBS, MOM or Bn;
iii) hydrolyzing acetonide moiety of compound of formula 3 by refluxing in the presence of organic acid to give compound of formula 4;

iv) protecting primary hydroxyl group of compound of formula 4 by acyl chloride to give compound of formula 5;

Wherein, R3=Bz, TES, TBS, MOM or Bn;
v) reducing compound of formula (5) by simultaneous elimination of the chiral auxiliary using a base in the presence of solvent followed by treatment with mineral acid to give cyclised product of formula (6) i.e. diprotected-2-deoxy-2,2-difluoro-P-D-ribofuranose;

vi) sulfonylizng compound of formula (6) in the presence of base and using solvent such as methylene chloride at a temperature 25 - 40°C by stirring overnight;

Wherein, R4=Ts or Ms
vii) condensing sulfonylated 2,2-difluoro-|3-D-ribofuranose derivative (7) with Cytimidine under reflux conditions to give protected Gemcitabine Hydrochloride (8); and

viii) deprotecting compound of formula (8) followed by reacting with hydrochloric acid to give Gemcitabine.HCl (I).

2. The process as claimed in claim 1, wherein the chiral auxiliary is oxazolidinone
(X=Y=0), oxazolidine-thione (X=S,Y=0) or thiazolidinethione (X=Y=S); R1 is phenyl,
benzyl or isopropyl.
3. The process as claimed in claim 1, wherein the solvent used in step i) (aldol reaction) is selected from the group comprising of dimethylsulfoxide, dimethylformamide, acetone, methylene dichloride, chloroform, tetrahydrofuran, methanol, ethanol or propanol.
4. The process as claimed in claim 1 wherein in step i), the catalyst used is selected from titanium tetrachloride, stannous chloride or magnesium chloride.
5. The process as claimed in claim 1 wherein in step i), the base used is selected from tetramethylethylenediamine, tetramethylpropene-diamine, triethylamine, diisopropylethylamine or sparteine.
6. The process as claimed claim 1, wherein the protecting group used in step ii) for protection of hydroxyl group is benzoyl, subsitituted benzoyl, TES, TBS, MOM or

benzyl.
7. The process as claimed in claim 1, wherein the mineral acid used in step (v) is hydrochloric acid or sulphuric acid.
8. The process as claimed in claim 1 wherein the organic acid used in step iii) is selected from p-toluenesulfonic acid (TsOH), trifluoroacetic acid, methanesulfonic acid or trifluoromethane sulfonic acid.
9. The process as claimed in claim 1, wherein the reagent used for reduction to remove the auxiliary in step v) is selected from sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride, red-Al, DIBAL.
10. The process as claimed in claim 1, wherein the reagent used for sulfonylization in step
vi) is selected from p-toluenesulfonyl chloride (TsCl) or methylsulfonyl chloride and the
solvent used is methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane or
toluene.

Abstract:
A process for the preparation of Gemcitabine Hydrochloride (I) comprising: i) reacting 2,3-O-isopropylidene-D-glyceraldehyde and chiral auxiliary (1) by Evans and Crimmins asymmetric aldol reaction to obtain (2); ii) protecting hydroxyl group at 3'-position in compound (2) to give (3); iii) hydrolysing acetonide moiety of (3) to give (4); iv) protecting the primary hydroxyl group of (4); v) reducing the carbonyl group of (5) by simultaneous elimination of chiral auxiliary and cyclization to give key intermediate (6) ; vi) sulfonylizing compound (6); vii) condensing sulfonylated P-D-ribofuranose (7) with Cytimidine to give protected Gemcitabine, viii) followed by deprotecting and converting it to Gemcitabine.HC1.

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Patent Number

270778

Indian Patent Application Number

450/MUM/2008

PG Journal Number

04/2016

Publication Date

22-Jan-2016

Grant Date

19-Jan-2016

Date of Filing

04-Mar-2008

Name of Patentee

MAC CHEM PRODUCTS INDIA PVT. LTD.

Applicant Address

304, TOWN CENTRE, ANDHERI-KURLA ROAD, ANDHERI(EAST), MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	HE XIAO	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444
2	LIAO LIXIN	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444
3	YANG JIDONG	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444
4	JAIN MOHAN BABULAL	MAC CHEM PRODUCTS INDIA PVT. LTD. 304, TOWN CENTRE, ANDHERI-KURLA ROAD, ANDHERI(EAST), MUMBAI-400059.
5	SHEN XIN	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444
6	ZHAN HUAXING	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444
7	LIN FUXING	SHANGHAI PARLING PHARMA TECH CO.,LTD, SHANGHAI 200444

PCT International Classification Number

G01N33/577

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA