Indian Patents. 198372:A PROCESS FOR THE PREPARATION OF 10-HYDROXY-9-N,N-DIMETHYLAMINOMETHYL-5-(2'-FLUOROETHOXY)-20(S)-CAMPTOTHECIN HYDROCHLORIDE

Title of Invention	A PROCESS FOR THE PREPARATION OF 10-HYDROXY-9-N,N-DIMETHYLAMINOMETHYL-5-(2'-FLUOROETHOXY)-20(S)-CAMPTOTHECIN HYDROCHLORIDE
Abstract	The present invention relates to a process for the preparation of 10-hydroxy-9- N,N-dimethylaminomethyl- 5-(2'-fluoroethoxy)-20(S)-camptothecin hydrochloride having formula (I). The compounds of formula (I) is useful for the treatment of melanoma, prostate leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancer.

Full Text	Field of the Invention The present invention relates to a process for the preparation of lO-hydroxy-9- N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin hydrochloride having the formula (I). wherein R", R1, R2 and R4 independently represent hydrogen or represent a group selected from hydroxy, lower alkoxy, lower alkanoyl, nitro, cyano, halo, carboxy, amino, substituted amino wherein the amino group is mono or disubstituted and the substituents are selected from lower alkyl, lower haloalkyl, benzyl, benzoyl, carboxyl, amido or lower alkylamino; lower alkyl, or substituted lower alkyl wherein the substituents are selected from hydroxy, lower haloalkyl, benzyl, lower alkoxy, benzyloxy, cyano, nitro, amino or lower alkylamino; or R^ and R^ together represent 0-(CH2)n-0- where n=l or 2, each of R", R^, R^ and R"^ are not the same except where each of R", R^, R^ and R"* are hydrogen; R^ represents hydrogen, lower alkyl, substituted lower alkyl, wherein the substituents are selected from hydroxy, halogen, lower alkoxy, benzyloxy, carboxy, amido, or amino where the amino group is mono or disubstituted and the substituents are selected from lower alkyl, lower haloalkyl, benzyl, or benzoyl, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic ring of formula (A); where Y represents O, S, NH or CH2 when formula (A) is a 5-membered ring and Y represents CH2 when formula (A) is a 6-membered ring; or R^ represents lower aralkyl, where the aryl group is selected from phenyl, biphenyl or naphthyl; and R* represents phenyl or benzyl where the phenyl group may be unsubstituted or substituted with mono, di or trisubstituents selected from halogen, lower alkoxy, cyano, nitro, lower alkyl, amino, or substituted amino wherein the amino group is mono or disubstituted with lower alkyl groups; cycloalkyl or cycloalkyl lower alkyl where the cyclic ring has 3 to 7 ring atoms all of the said ring atoms being carbon; lower alkyl groups substituted with saturated 5 or 6 membered heterocyclic ring of formula (B), when formula (B) is a 5-membered ring X represents CH or N and Y represents O, S, NH or CH2 when formula (B) is a 6-membered ring, X represents CH or N and Y represents CH2; substituted benzoyl wherein the substituents are selected from lower alkyl, lower haloalkyl, halogen, lower alkoxy, thioalkoxy, cyano, nitro, amido, amino, or lower alkylamino; lower alkenyl; substituted lower alkyl, or substituted lower alkenyl, wherein the substituents are selected from halogen, hydroxy, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, wherein the aryl group is selected from phenyl, biphenyl, or naphthyl; heteroaryl wherein the heteroaryl is selected from pyridyl, quinoline, isoquinoline, indole, pyrrole, furan, benzofiiran, thiophene, thiazolidine or imidazole; carboxy, cyano, nitro amido or amino in which the amino group can be unsubstituted or mono or disubstituted , wherein the substituents are selected from hydroxy, lower alkyl, lower haloalkyl, benzyl, benzoyl, lower alkoxy, carboxy, amido or lower alkylamino, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic group of formula (A), when formula (A) is a 5-membered ring, Y represents O, S, NH or CH2, when formula (A) is a 6-membered ring, Y represents CH2; or R^ represents substituted lower alkanoyl wherein the substituents are selected from halogen, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, wherein the aryl group is selected from phenyl, biphenyl, or naphthyl; heteroaryl wherein the heteroaryl is selected from pyridyl, quinoline, isoquinoline, indole, pyrrole, ftiran, benzofuran, thiophene, thiazolidine or imidazole; carboxy, cyano, nitro, amido or amino in which the amino group can be unsubstituted or mono, or disubstituted wherein the substituents are selected from hydroxy, lower alkyl, lower haloalkyl, benzyl, benzoyl, lower alkoxy, carboxy, amido, amino or lower alkylamino, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic group of formula (A), when formula (A) is a 5-membered ring, Y represents O, S, NH or CH2; when formula (A) represents a 6-membered ring Y represents CH2; and when R" represents hydroxy, amino or nitro, R^, R^ R"* and R^ represent hydrogen and R^ represents hydrogen, lower alkyl, alkanoyl or benzoyl groups, which comprises : where R" to R^ have the meaning described above, in the presence of an acid and oxidising agent which is a ferric salt, with a compound having the formula R*-OH where R represents lower alkyl, lower alkenyl, (C3-C7)cycloalkyl, haloalkyl or hydroxyalkyl to obtain the compounds of formula (IV) and compounds of formula (V), In the above process, the compound of formula (Ic) was prepared by the etherification of compound of formula (lb) by using borontrifluoride etherate. As a result of etherification there was a possibility of reaction of hydroxy group at lO"" position apart from 5"" position. Thereby, reduction in the yield of the final product. Objective of the Invention The main objective of the present invention is therefore to provide a simple and economical process for the preparation of pharmaceutically acceptable salt of novel 20(S)-camptothecin derivative having the formula (I), which can be used for the treatment of melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancers with better efficacy, potency and lower toxicity. Accordingly, the present invention provides a process for the preparation of 10-hydroxy-9-N,N-dimethylaminomethyl-5 -(2" -fluoroethoxy)-20(S)-camptothecin hydrochloride, which comprises: (i) converting 20(S)-camptothecin of formula (Ila) to 5-hydroxy-20(S)-camptothecin of formula (lib) by using base and reagent in the presence of a solvent, at a temperature in the range of 20 to 70 °C in the duration 25 to 50 h, (ii) converting 5-hydroxy-20(S)-camptothecin of formula (lib) to 5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lie) by using 2-fluoroethanol, borontrifluoride ethereate in the presence of a solvent, at a temprature in the range of 100 to 130 °C in the duration of 24 to 48 h, (iii) converting 5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lie) to 10-hydroxy-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lid) by using acetic acid. platinum oxide and oxidizing agent, in the presence of hydrogen pressure and solvent, at a temperature in the range of 0 to 45 °C in the duration of 2 to 14 h, (iv) converting 10-hydroxy-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lid) to 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (He) by using acetic acid, formaldehyde and dimethylamine, in the presence of a solvent, at a temperature in the range of 20 to 45 °C in the duration of 10 to 16 h, (v) converting 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (He) to 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluorpethoxy)-20(S)-camptothecin hydrochloride of formula (I) by using hydrochloric acid and Detailed Description of the Invention The conversion of compound of formula (Ila) to a compound of formula (lib) may be carried out in the presence of solvents such as dimethyl formamide (DMF), l-methyl-2-pyrrolidinone (NMP), N, N-diethyl formamide (DEF) and the like. The base used in the reaction may be selected form anhydrous alkali metal carbonates. The reagent used in the reaction may be selected from iodine, potassium iodide and the like. The temperature of the reaction is maintained in the range of 20 to 70 °C, preferably at room temperature. The reaction may be carried out in the presence of nitrogen atmosphere. The time of the reaction may range from 25 to 50 h, preferably in the range of 40 to 45 h. The conversion of compound of formula (lib) to a compound of formula (lie) may be carried out in the presence of 2-fluoroethanol and borontrifluoride ethereate. The solvents used in the reaction are selected from dimethylsulfoxide, toluene, DMF, NMP and the like. The temperature of the reaction is maintained in the range of 100 to 130 °C, preferably in the range of 110 to 115 "C. The duration of the reaction is 24 to 48 h, preferably 40 h. The compound of formula (lid) may be obtained by treating compound of formula (lie) with acetic acid and platinum oxide in the presence of hydrogen pressure. The solvent used in the reaction may be selected from dimethyl sulphoxide, AcOH, methanol, ethanol, isopropyl alcohol or mixtures thereof The oxidizing agent used in the reaction may be iodosobenzene diacetate in aqueous acetic acid, hydrogen peroxide. The temperature of the reaction is maintained in the range of 0 to 45 °C, preferably in the range of 10 to 20 °C. The duration of the reaction is maintained in the range of 2 to 14 h. The compound of formula (He) may be obtained by treating compound of formula (lid) with acetic acid, formaldehyde and dimethylamine. Tlie temperature of the reaction is maintained in the range of 20 to 45 "C, preferably at room temperature. The duration of the reaction is maintained in the range of 10 to 16 h, preferably 14 h. The compound of formula (I) is obtained by treating compound of formula (He) with hydrochloric acid. The present invention is described in detail with examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 9-Mimethylaminomethyl-5-[(RS)-2"-fluoroethoxy]-10-hydroxy-20(S)-camptothecin hydrochloride Step (i): Preparation of 5-hvdroxv-20(S)-camptothecin In a 3.0 L round-bottomed tlask equipped with nitrogen gas flow was placed camptothecin (200 g) and dimethylformamide (1.0 L) were added and stirred for 5 min. Potassium carbonate (86 g) and iodine (160 g) were added to reaction mixture and stirred vigorously at room temperature for 40-45 h. Completion of the reaction was checked with thin layer chromatography (TLC). After completion of thereaction, hypo solution and water were added to reaction mixture and neutralized with concentrated hydrochloric acid. Then the reaction mass was stirred at room temperature for Ih, filtered and dried at 60 °C under vacuum (217 g). "H-NMR (DMSO-de): 8 8.50 (s, IH), 8.20 (d, J=8.0 Hz, IH), 7.94 (d, J=8.0 Hz, IH), 7.85 (s, J=6.8 Hz, IH), 7.64 (s, J=6.8 Hz, IH), 7.58 (s, 0.5H), 7.56 (s, 0.5H), 7.06 (s, 0.5H), 7.01 (s, 0.5H), 6.95 (br d, IH, D2O exchangeable), 5.67 (d, J=16.5 Hz, IH), 5.25 (d, J=16.5 Hz, IH), 5.05 (br d, IH, D2O exchangeable), 2.05-1.86 (m, 2H), 1.06 (t, J=7 Hz, 3H). Step (ii): Preparation of 5-(2"-fluoroethoxY)-20(S)-camptothecin Method 1: 5-Hydroxy-20(S)-camptothecin (125 g) (obtained in step (i)), dimethylsulphoxide (375 ml), fluoroethanol (625 ml) were placed in a 2 L four necked round-bottomed flask and stirred for 5 to 10 min. Borontrifluoride etherate (189 ml) was added slowly drop wise at room temperature to the reaction mass. After completion of addition, temperature was raised to 110-115 °C and maintained for approximately 40 h. Reaction was monitored by TLC. After completion, reaction mass was concentrated at 100 °C. Residue was dissolved in 10% methanol in ethylacetate. Organic layer was washed with bicarbonate solution, water and brine solution. Organic layer was then concentrated and triturated with pet-ether. The precipitated compound was filtered and dried (84.5 g). Crude product (250 g) was purified with column chromatography. Column was eluted with acetone and dichloromethane mixtures to get the compound 70 g. "H-NMR (CDCla+DMSO-ds): 5 8.46 (s, IH), 8.20 (d, J=8.0 Hz, IH), 7.95 (d, J=8.0 Hz, IH), 7.83 (s, J=6.8 Hz, IH), 7.65-7.55 (m, 2H), 6.86 (s, 0.5H), 6.78 (s, 0.5H), 5.68 (d, J=16.5 Hz, IH), 5.26 (d, J=16.5 Hz, IH), 4.90-4.20 (m, 4H), 4.44 (s, IH, D2O exchangeable), 2.05-1.85 (m,2H), 1.12-095 (m,3H). Method 2: 5-Hydroxy-20(S)-camptothecin (10 g) (obtained in step (i)), fluoroethanol (50 ml), toluene (50 ml), dimethylsulfoxide (10 ml), and borontrifluoride etherate (13.0 ml) were placed in a 250 ml three necked round-bottomed flask provided with Dean-Stark apparatus and stirred at reflux temperature for about 48 h. Completion of the reaction was monitored by TLC. After completion, reaction mass was diluted with ethylacetate and washed with 5% bicarbonate solution and water. Organic layer was evaporated and precipitated with n-hexane. Compound was filtered and dried to get the solid (7.6 g). Step (iii): Platinum oxide (4.5 g) and acetic acid (50 ml) were transferred in to a 1 L parr-hydrogenation flask. Then 5-(2"-Fluoro ethoxy)-20(S)-camptothecin (16 g) (obtained in step (ii)) dissolved in acetic acid (400 ml) and DMSO (1.35 ml) were added and hydrogenated at 50 to 55 PSI hydrogen pressure for 3 h. Completion of reaction monitored with TLC. Catalyst was filtered on a celite bed and reaction mixture was concentrated to approximately 100 ml under reduced pressure. The residue was transferred in to 500 ml round bottomed flask. DM water (100 ml) and iodosobenzene diacetate (27 g) were added and stirred for 10 to 12 h. Completion of reaction was monitored by TLC. After completion, reaction mixture was concentrated to approximately 30 ml and water (350 ml) was added and stirred for 2 h. Compound precipitated was filtered and dried (14.8 g). "H-NMR (CDCb+DMSO-dfi): 5 10.0 (br s, IH, D2O exchangeable), 8.31 (s, IH), 8.00 (d, J=8.0 Hz, IH), 7.80 (s, IH), 7.45 (d, J=6.0 Hz, IH), 7.40 (s, IH), 6.85 (s, 0.5H), 6.80 (s, 0.5H), 6.15 (s, IH, D2O exchangeable), 5.55 (d, J=16.0 Hz, IH), 5.23 (d, J=16.0 Hz, IH), 4.85-4.20 (m, 4H), 2.05-1.81 (m, 2H), 1.00 (t, J=7.0 Hz, 3H). Step (iv): Preparation of 9-dimethyl aminomethyl-5-[(RS)-2"-fluoroethoxyl-10-hydroxy-20(S)- camptothecin lO-Hydroxy-5- (2"-fluoroethoxy)camptothecin (55g) (obtained in step (iii)) and acetic acid (1.2 L) were placed in round bottomed flask and stirred at room temperature to get clear solution. Formaldehyde solution (30%, 70 ml) and dimethyl amine (40%, 68.7 ml) were added and stirred at room temperature for 14 h. Completion of reaction was monitored by TLC. After completion, acetic acid was removed under reduced pressure. Residue thus obtained was stirred with n-hexane and decanted to get the dark brown colored syrupy liquid (150 g) The above dark brown colored gummy mass (25 g) was purified by column chromatography. Column was eluted with dichloromethane and acetone mixtures. The pure fractions were collected and concentrated yield pure compound (9.8 g). "H-NMR (DMSO): 5 8.97 (s, IH), 8.18 (d, J=9.4 Hz, IH), 7.78 (d, J=9.4 Hz, IH), 7.19-7.17 (s, IH), 6.94 (s, IH), 6.88 (s, IH), 5.40 (br, s, 2H), 4.80 (br, s, 2H), 4.70 (m, 2H), 4.20 (m, 2H), 2.80 (br, s, 3H), 1.87 (br, m, 2H), 0.88 (br, m, 3H). Step(v): Preparation of 9-dimethylaminomethyl-5-r(RS)-2"-fluoroethoxy1-10-hvdroxy-20(S)- camptothecin hydrochloride 9-Dimethyl aminomethyl-5- [(RS)-2" -fluoroethoxy]-10-hydroxy-20(S)-camptothecin (31 g) (obtained in step (iv)) dissolved in aqueous hydrochloric acid solution (0.2 N, 300 ml) and warmed to 40 to 45 °C. Undissolved tariy material was filtered. The residue was washed with 0.2 N HCl (50 ml). Aqueous layer was washed with ethyl acetate. The organic layer was discarded and the aqueous layer was concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml) and triturated with n-hexane (500 ml), the precipitated compound was stirred at room temperature for 1 h and filtered. The yellow solid obtained was dried under vacuum to yield the title compound (18.2 g). "H-NMR (DMSO, 200MHz): 5 8.97 (s, IH), 8.18 (d, J=9.4 Hz, IH), 7.78 (d, J=9.4 Hz, IH), 7.19-7.17 (s, IH), 6.94 (s, IH), 6.88 (s, IH), 5.40 (br, s, 2H), 4.80 (br, s, 2H), 4.70 (m, 2H), 4.20 (m. 2H). 2.80 (br, s, 3H), 1.87 (br, m. 2H), 0.88 (br, m, 3H). Advantages of the Invention 1. The present invention provides commercially viable and easily scalable process for the preparation of 9-dimethylaminomethyl-5-[(RS)-2 "-fluoroethoxy]-10-hydroxy-20(S)-campto thecin hydrochloride of formula (1). 2. The present process employs simple and economical reagents, which are easy to handle in scale-up operations. 3. The yields of the compounds obtained through the present process are high compared to that of the existing process. We claim 1. The process for the preparation of compound of formula (I) which comprises: (i) converting compound of formula (Ila) by using a base such as alkali metal carbonates, and a reagent selected from iodine or potassium iodide in the presence of a solvent such as dimethyl formamide, l-methyl-2-pyrrolidinone or N, N-diethyl formamide, at a temperature in the range of 20 to 70 "C in the duration of 25 to 50 h, (ii) converting a compound of formula (IIb) to a compound of formula (IIc) by using 2-fluoroethanol, borontrifluoride ethereate in the presence of dimethylsulfoxide, toluene, dimethylformamide or 1-methyl-2-pyrrolidinone, at a temprature in the range of 100 to 130 °C in the duration of 24 to 48 h, (iii) converting a compound of formula (IIc) to a compound of formula (IId) by using acetic acid, formaldehyde and dimethylamine, at a temperature in the range of 20 to 45 "C in the duration of 10 to 16 h, (v) converting a compound of formula (He) to a compound of formula (I) by using hydrochloric acid and (vi) isolating the compound of formula (I) by using conventional isolation methods. 2. The process as claimed in claim 1, wherein the alkalimetalcarbonates used in step (i) of the reaction is selected from potassium carbonate or sodium carbonate. 3. The process as claimed in claims 1-2, wherein the reagent used in step (i) of the reaction is selected from iodine. 4. The process as claimed in claims 1-3, wherein the solvent used in step (i) of the reaction is selected from dimethyl formamide or N, N-diethyl formamide. 5. The process as claimed in claims 1-4, wherein the temperature and duration in step (i) of the reaction are maintained at 20 to 40 "C and 40 to 45 h respectively. 6. The process as claimed in claims 1-5, wherein the solvent used in step (ii) of the reaction is selected from dimethylsulfoxide, dimethylformamide or l-methyl-2-pyrrolidinone. 7. The process as claimed in claims 1-6, wherein the temperature and duration in step (ii) of the reaction are maintained at 110 to 115 °C and 40 h respectively. 8. The process as claimed in claims 1-7, wherein the solvent used in step (iii) of the reaction is selected from dimethyl sulphoxide, AcOH, methanol, ethanol, isopropyl alcohol or mixtures thereof. 9. The process as claimed in claims 1-8, wherein the oxidizing agent used in step (iii) of the reaction is selected from iodosobenzene diacetate in aqueous acetic acid or hydrogen peroxide. 10. The process as claimed in claims 1-9, wherein the temperature in step (iii) of the reaction is maintained at 10 to 20 °C. 11. The process as claimed in claims 1-10, wherein the temperature and duration in step (iv) of the reaction are maintained at room temperature and 14 h respectively. 12. The process for the preparation of compound of the formula (1) substantially as herein described with reference to example 1.

Full Text

Field of the Invention
The present invention relates to a process for the preparation of lO-hydroxy-9- N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin hydrochloride having the formula (I).

wherein R", R1, R2 and R4 independently represent hydrogen or represent a group selected from hydroxy, lower alkoxy, lower alkanoyl, nitro, cyano, halo, carboxy, amino, substituted amino wherein the amino group is mono or disubstituted and the substituents are selected from lower alkyl, lower haloalkyl, benzyl, benzoyl, carboxyl, amido or lower alkylamino; lower alkyl, or substituted lower alkyl wherein the substituents are selected from hydroxy, lower haloalkyl, benzyl, lower alkoxy, benzyloxy, cyano, nitro, amino or lower alkylamino; or R^ and R^ together represent 0-(CH2)n-0- where n=l or 2, each of R", R^, R^ and R"^ are not the same except where each of R", R^, R^ and R"* are hydrogen; R^ represents hydrogen, lower alkyl, substituted lower alkyl, wherein the substituents are selected from hydroxy, halogen, lower alkoxy, benzyloxy, carboxy, amido, or amino where the amino group is mono or disubstituted

and the substituents are selected from lower alkyl, lower haloalkyl, benzyl, or benzoyl, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic ring of formula (A);

where Y represents O, S, NH or CH2 when formula (A) is a 5-membered ring and Y represents CH2 when formula (A) is a 6-membered ring; or R^ represents lower aralkyl, where the aryl group is selected from phenyl, biphenyl or naphthyl; and
R* represents phenyl or benzyl where the phenyl group may be unsubstituted or substituted with mono, di or trisubstituents selected from halogen, lower alkoxy, cyano, nitro, lower alkyl, amino, or substituted amino wherein the amino group is mono or disubstituted with lower alkyl groups; cycloalkyl or cycloalkyl lower alkyl where the cyclic ring has 3 to 7 ring atoms all of the said ring atoms being carbon; lower alkyl groups substituted with saturated 5 or 6 membered heterocyclic ring of formula (B),

when formula (B) is a 5-membered ring X represents CH or N and Y represents O, S, NH or CH2 when formula (B) is a 6-membered ring, X represents CH or N and Y represents CH2; substituted benzoyl wherein the substituents are selected from lower alkyl, lower haloalkyl, halogen, lower alkoxy, thioalkoxy, cyano, nitro, amido, amino, or lower alkylamino; lower alkenyl; substituted lower alkyl, or substituted lower alkenyl, wherein the substituents are selected from halogen, hydroxy, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, wherein the aryl group is selected from phenyl, biphenyl, or naphthyl; heteroaryl wherein the heteroaryl is selected from pyridyl, quinoline, isoquinoline, indole, pyrrole, furan, benzofiiran, thiophene, thiazolidine or imidazole; carboxy, cyano, nitro amido or amino in which the amino group can be unsubstituted or mono or disubstituted , wherein the substituents are selected from hydroxy, lower alkyl, lower haloalkyl, benzyl, benzoyl, lower alkoxy, carboxy, amido or lower alkylamino, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic group of formula (A),

when formula (A) is a 5-membered ring, Y represents O, S, NH or CH2, when formula (A) is a 6-membered ring, Y represents CH2;
or R^ represents substituted lower alkanoyl wherein the substituents are selected from halogen, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, wherein the aryl group is selected from phenyl, biphenyl, or naphthyl; heteroaryl wherein the heteroaryl is selected from pyridyl, quinoline, isoquinoline, indole, pyrrole, ftiran, benzofuran, thiophene, thiazolidine or imidazole; carboxy, cyano, nitro, amido or amino in which the amino group can be unsubstituted or mono, or disubstituted wherein the substituents are selected from hydroxy, lower alkyl, lower haloalkyl, benzyl, benzoyl, lower alkoxy, carboxy, amido, amino or lower alkylamino, when the amino group is disubstituted the substituents are independent or together with the linking nitrogen atom form a saturated 5 or 6 membered heterocyclic group of formula (A),
when formula (A) is a 5-membered ring, Y represents O, S, NH or CH2; when formula (A) represents a 6-membered ring Y represents CH2; and when R" represents hydroxy, amino or nitro, R^, R^ R"* and R^ represent hydrogen and R^ represents hydrogen, lower alkyl, alkanoyl or benzoyl groups, which comprises :

where R" to R^ have the meaning described above, in the presence of an acid and oxidising agent which is a ferric salt, with a compound having the formula R*-OH where R represents lower alkyl, lower alkenyl, (C3-C7)cycloalkyl, haloalkyl or hydroxyalkyl to obtain the compounds of formula (IV) and compounds of formula (V),

In the above process, the compound of formula (Ic) was prepared by the etherification of compound of formula (lb) by using borontrifluoride etherate. As a result of etherification there was a

possibility of reaction of hydroxy group at lO"" position apart from 5"" position. Thereby, reduction in the yield of the final product.
Objective of the Invention
The main objective of the present invention is therefore to provide a simple and economical process for the preparation of pharmaceutically acceptable salt of novel 20(S)-camptothecin derivative having the formula (I), which can be used for the treatment of melanoma, prostate, leukemia, lymphoma, non-small lung cancers, cancer of the central nervous system, breast, colon, ovarian or renal cancers with better efficacy, potency and lower toxicity.

Accordingly, the present invention provides a process for the preparation of 10-hydroxy-9-N,N-dimethylaminomethyl-5 -(2" -fluoroethoxy)-20(S)-camptothecin hydrochloride, which comprises:
(i) converting 20(S)-camptothecin of formula (Ila) to 5-hydroxy-20(S)-camptothecin of formula (lib) by using base and reagent in the presence of a solvent, at a temperature in the range of 20 to 70 °C in the duration 25 to 50 h, (ii) converting 5-hydroxy-20(S)-camptothecin of formula (lib) to 5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lie) by using 2-fluoroethanol, borontrifluoride ethereate in the presence of a solvent, at a temprature in the range of 100 to 130 °C in the duration of 24 to 48 h, (iii) converting 5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lie) to 10-hydroxy-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lid) by using acetic acid.

platinum oxide and oxidizing agent, in the presence of hydrogen pressure and solvent, at a temperature in the range of 0 to 45 °C in the duration of 2 to 14 h,
(iv) converting 10-hydroxy-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (lid) to 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (He) by using acetic acid, formaldehyde and dimethylamine, in the presence of a solvent, at a temperature in the range of 20 to 45 °C in the duration of 10 to 16 h,
(v) converting 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)-camptothecin of formula (He) to 10-hydroxy-9-N,N-dimethylaminomethyl-5-(2"-fluorpethoxy)-20(S)-camptothecin hydrochloride of formula (I) by using hydrochloric acid and

Detailed Description of the Invention
The conversion of compound of formula (Ila) to a compound of formula (lib) may be carried out in the presence of solvents such as dimethyl formamide (DMF), l-methyl-2-pyrrolidinone (NMP), N, N-diethyl formamide (DEF) and the like. The base used in the reaction may be selected form anhydrous alkali metal carbonates. The reagent used in the reaction may be selected from iodine, potassium iodide and the like. The temperature of the reaction is maintained in the range of 20 to 70 °C, preferably at room temperature. The reaction may be carried out in the presence of nitrogen atmosphere. The time of the reaction may range from 25 to 50 h, preferably in the range of 40 to 45 h.
The conversion of compound of formula (lib) to a compound of formula (lie) may be carried out in the presence of 2-fluoroethanol and borontrifluoride ethereate. The solvents used in the reaction are selected from dimethylsulfoxide, toluene, DMF, NMP and the like. The temperature of the reaction is maintained in the range of 100 to 130 °C, preferably in the range of 110 to 115 "C. The duration of the reaction is 24 to 48 h, preferably 40 h.
The compound of formula (lid) may be obtained by treating compound of formula (lie) with acetic acid and platinum oxide in the presence of hydrogen pressure. The solvent used in the reaction may be selected from dimethyl sulphoxide, AcOH, methanol, ethanol, isopropyl alcohol or mixtures thereof The oxidizing agent used in the reaction may be iodosobenzene diacetate in aqueous acetic acid, hydrogen peroxide. The temperature of the reaction is maintained in the range of 0 to 45 °C, preferably in the range of 10 to 20 °C. The duration of the reaction is maintained in the range of 2 to 14 h.
The compound of formula (He) may be obtained by treating compound of formula (lid) with acetic acid, formaldehyde and dimethylamine. Tlie temperature of the reaction is maintained in the range of 20 to 45 "C, preferably at room temperature. The duration of the reaction is maintained in the range of 10 to 16 h, preferably 14 h.
The compound of formula (I) is obtained by treating compound of formula (He) with hydrochloric acid.
The present invention is described in detail with examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1
9-Mimethylaminomethyl-5-[(RS)-2"-fluoroethoxy]-10-hydroxy-20(S)-camptothecin hydrochloride
Step (i):
Preparation of 5-hvdroxv-20(S)-camptothecin
In a 3.0 L round-bottomed tlask equipped with nitrogen gas flow was placed camptothecin (200 g) and dimethylformamide (1.0 L) were added and stirred for 5 min. Potassium carbonate (86 g) and iodine (160 g) were added to reaction mixture and stirred vigorously at room temperature for 40-45 h. Completion of the reaction was checked with thin layer chromatography (TLC).
After completion of thereaction, hypo solution and water were added to reaction mixture and neutralized with concentrated hydrochloric acid. Then the reaction mass was stirred at room temperature for Ih, filtered and dried at 60 °C under vacuum (217 g). "H-NMR (DMSO-de): 8 8.50 (s, IH), 8.20 (d, J=8.0 Hz, IH), 7.94 (d, J=8.0 Hz, IH), 7.85 (s, J=6.8 Hz, IH), 7.64 (s, J=6.8 Hz, IH), 7.58 (s, 0.5H), 7.56 (s, 0.5H), 7.06 (s, 0.5H), 7.01 (s, 0.5H), 6.95 (br d, IH, D2O exchangeable), 5.67 (d, J=16.5 Hz, IH), 5.25 (d, J=16.5 Hz, IH), 5.05 (br d, IH, D2O exchangeable), 2.05-1.86 (m, 2H), 1.06 (t, J=7 Hz, 3H).
Step (ii):
Preparation of 5-(2"-fluoroethoxY)-20(S)-camptothecin

Method 1:
5-Hydroxy-20(S)-camptothecin (125 g) (obtained in step (i)), dimethylsulphoxide (375 ml), fluoroethanol (625 ml) were placed in a 2 L four necked round-bottomed flask and stirred for 5 to 10 min. Borontrifluoride etherate (189 ml) was added slowly drop wise at room temperature to the reaction mass. After completion of addition, temperature was raised to 110-115 °C and maintained for approximately 40 h. Reaction was monitored by TLC.
After completion, reaction mass was concentrated at 100 °C. Residue was dissolved in 10% methanol in ethylacetate. Organic layer was washed with bicarbonate solution, water and brine solution. Organic layer was then concentrated and triturated with pet-ether. The precipitated compound was filtered and dried (84.5 g). Crude product (250 g) was purified with column chromatography. Column was eluted with acetone and dichloromethane mixtures to get the compound 70 g.
"H-NMR (CDCla+DMSO-ds): 5 8.46 (s, IH), 8.20 (d, J=8.0 Hz, IH), 7.95 (d, J=8.0 Hz, IH), 7.83 (s, J=6.8 Hz, IH), 7.65-7.55 (m, 2H), 6.86 (s, 0.5H), 6.78 (s, 0.5H), 5.68 (d, J=16.5 Hz, IH), 5.26 (d, J=16.5 Hz, IH), 4.90-4.20 (m, 4H), 4.44 (s, IH, D2O exchangeable), 2.05-1.85 (m,2H), 1.12-095 (m,3H). Method 2:
5-Hydroxy-20(S)-camptothecin (10 g) (obtained in step (i)), fluoroethanol (50 ml), toluene (50 ml), dimethylsulfoxide (10 ml), and borontrifluoride etherate (13.0 ml) were placed in a 250 ml three necked round-bottomed flask provided with Dean-Stark apparatus and stirred at reflux temperature for about 48 h. Completion of the reaction was monitored by TLC. After completion, reaction mass was diluted with ethylacetate and washed with 5% bicarbonate solution and water. Organic layer was evaporated and precipitated with n-hexane. Compound was filtered and dried to get the solid (7.6 g).
Step (iii):

Platinum oxide (4.5 g) and acetic acid (50 ml) were transferred in to a 1 L parr-hydrogenation flask. Then 5-(2"-Fluoro ethoxy)-20(S)-camptothecin (16 g) (obtained in step (ii)) dissolved in acetic acid (400 ml) and DMSO (1.35 ml) were added and hydrogenated at 50 to 55 PSI hydrogen pressure for 3 h. Completion of reaction monitored with TLC.
Catalyst was filtered on a celite bed and reaction mixture was concentrated to approximately 100 ml under reduced pressure. The residue was transferred in to 500 ml round bottomed flask. DM water (100 ml) and iodosobenzene diacetate (27 g) were added and stirred for 10 to 12 h. Completion of reaction was monitored by TLC.
After completion, reaction mixture was concentrated to approximately 30 ml and water (350 ml) was added and stirred for 2 h. Compound precipitated was filtered and dried (14.8 g). "H-NMR (CDCb+DMSO-dfi): 5 10.0 (br s, IH, D2O exchangeable), 8.31 (s, IH), 8.00 (d, J=8.0 Hz, IH), 7.80 (s, IH), 7.45 (d, J=6.0 Hz, IH), 7.40 (s, IH), 6.85 (s, 0.5H), 6.80 (s, 0.5H), 6.15 (s, IH, D2O exchangeable), 5.55 (d, J=16.0 Hz, IH), 5.23 (d, J=16.0 Hz, IH), 4.85-4.20 (m, 4H), 2.05-1.81 (m, 2H), 1.00 (t, J=7.0 Hz, 3H).
Step (iv):
Preparation of 9-dimethyl aminomethyl-5-[(RS)-2"-fluoroethoxyl-10-hydroxy-20(S)-
camptothecin
lO-Hydroxy-5- (2"-fluoroethoxy)camptothecin (55g) (obtained in step (iii)) and acetic acid (1.2 L) were placed in round bottomed flask and stirred at room temperature to get clear solution. Formaldehyde solution (30%, 70 ml) and dimethyl amine (40%, 68.7 ml) were added and stirred at room temperature for 14 h. Completion of reaction was monitored by TLC.
After completion, acetic acid was removed under reduced pressure. Residue thus obtained was stirred with n-hexane and decanted to get the dark brown colored syrupy liquid (150 g)

The above dark brown colored gummy mass (25 g) was purified by column chromatography. Column was eluted with dichloromethane and acetone mixtures. The pure fractions were collected and concentrated yield pure compound (9.8 g). "H-NMR (DMSO): 5 8.97 (s, IH), 8.18 (d, J=9.4 Hz, IH), 7.78 (d, J=9.4 Hz, IH), 7.19-7.17 (s, IH), 6.94 (s, IH), 6.88 (s, IH), 5.40 (br, s, 2H), 4.80 (br, s, 2H), 4.70 (m, 2H), 4.20 (m, 2H), 2.80 (br, s, 3H), 1.87 (br, m, 2H), 0.88 (br, m, 3H).
Step(v):
Preparation of 9-dimethylaminomethyl-5-r(RS)-2"-fluoroethoxy1-10-hvdroxy-20(S)-
camptothecin hydrochloride

9-Dimethyl aminomethyl-5- [(RS)-2" -fluoroethoxy]-10-hydroxy-20(S)-camptothecin (31 g) (obtained in step (iv)) dissolved in aqueous hydrochloric acid solution (0.2 N, 300 ml) and warmed to 40 to 45 °C. Undissolved tariy material was filtered. The residue was washed with 0.2 N HCl (50 ml). Aqueous layer was washed with ethyl acetate. The organic layer was discarded and the aqueous layer was concentrated under reduced pressure.
The residue was dissolved in ethanol (200 ml) and triturated with n-hexane (500 ml), the precipitated compound was stirred at room temperature for 1 h and filtered. The yellow solid obtained was dried under vacuum to yield the title compound (18.2 g). "H-NMR (DMSO, 200MHz): 5 8.97 (s, IH), 8.18 (d, J=9.4 Hz, IH), 7.78 (d, J=9.4 Hz, IH), 7.19-7.17 (s, IH), 6.94 (s, IH), 6.88 (s, IH), 5.40 (br, s, 2H), 4.80 (br, s, 2H), 4.70 (m, 2H), 4.20 (m. 2H). 2.80 (br, s, 3H), 1.87 (br, m. 2H), 0.88 (br, m, 3H).

Advantages of the Invention
1. The present invention provides commercially viable and easily scalable process for the preparation of 9-dimethylaminomethyl-5-[(RS)-2 "-fluoroethoxy]-10-hydroxy-20(S)-campto thecin hydrochloride of formula (1).
2. The present process employs simple and economical reagents, which are easy to handle in scale-up operations.
3. The yields of the compounds obtained through the present process are high compared to that of the existing process.

We claim
1. The process for the preparation of compound of formula (I)

which comprises:
(i) converting compound of formula (Ila)

by using a base such as alkali metal carbonates, and a reagent selected from iodine or potassium iodide in the presence of a solvent such as dimethyl formamide, l-methyl-2-pyrrolidinone or N, N-diethyl formamide, at a temperature in the range of 20 to 70 "C in the duration of 25 to 50 h, (ii) converting a compound of formula (IIb) to a compound of formula (IIc)

by using 2-fluoroethanol, borontrifluoride ethereate in the presence of dimethylsulfoxide, toluene, dimethylformamide or 1-methyl-2-pyrrolidinone, at a temprature in the range of 100 to 130 °C in the duration of 24 to 48 h, (iii) converting a compound of formula (IIc) to a compound of formula (IId)

by using acetic acid, formaldehyde and dimethylamine, at a temperature in the range of 20 to
45 "C in the duration of 10 to 16 h,
(v) converting a compound of formula (He) to a compound of formula (I) by using
hydrochloric acid and
(vi) isolating the compound of formula (I) by using conventional isolation methods.
2. The process as claimed in claim 1, wherein the alkalimetalcarbonates used in step (i) of the reaction is selected from potassium carbonate or sodium carbonate.
3. The process as claimed in claims 1-2, wherein the reagent used in step (i) of the reaction is selected from iodine.
4. The process as claimed in claims 1-3, wherein the solvent used in step (i) of the reaction
is selected from dimethyl formamide or N, N-diethyl formamide.
5. The process as claimed in claims 1-4, wherein the temperature and duration in step (i)
of the reaction are maintained at 20 to 40 "C and 40 to 45 h respectively.
6. The process as claimed in claims 1-5, wherein the solvent used in step (ii) of the
reaction is selected from dimethylsulfoxide, dimethylformamide or l-methyl-2-pyrrolidinone.
7. The process as claimed in claims 1-6, wherein the temperature and duration in step (ii)
of the reaction are maintained at 110 to 115 °C and 40 h respectively.

8. The process as claimed in claims 1-7, wherein the solvent used in step (iii) of the reaction is selected from dimethyl sulphoxide, AcOH, methanol, ethanol, isopropyl alcohol or mixtures thereof.
9. The process as claimed in claims 1-8, wherein the oxidizing agent used in step (iii) of the reaction is selected from iodosobenzene diacetate in aqueous acetic acid or hydrogen peroxide.
10. The process as claimed in claims 1-9, wherein the temperature in step (iii) of the reaction is maintained at 10 to 20 °C.
11. The process as claimed in claims 1-10, wherein the temperature and duration in step (iv) of the reaction are maintained at room temperature and 14 h respectively.
12. The process for the preparation of compound of the formula (1) substantially as herein described with reference to example 1.

Documents:

127-mas-2002 abstract duplicate.pdf

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127-mas-2002 abstract.pdf

127-mas-2002 claims duplicate.pdf

127-mas-2002 claims.pdf

127-mas-2002 correspondence-others.pdf

127-mas-2002 correspondence-po.pdf

127-mas-2002 description (complete) duplicate.pdf

127-mas-2002 description (complete).pdf

127-mas-2002 form-13.pdf

127-mas-2002 form-19.pdf

127-mas-2002 form-3.pdf

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Patent Number

198372

Indian Patent Application Number

127/MAS/2002

PG Journal Number

08/2007

Publication Date

23-Feb-2007

Grant Date

20-Jan-2006

Date of Filing

18-Feb-2002

Name of Patentee

DR. REDDY'S LABORATORIES LIMITED

Applicant Address

7-1-27, Ameerpet, Hyderabad - 500 016

Inventors:

#	Inventor's Name	Inventor's Address
1	SAIRAM POTHUKUCHI	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, Hyderabad - 500 016
2	POTLAPALLY, RAJENDER KUMAR	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad
3	BHATRAJU, SREENIVASA RAO	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad
4	KOTRA NARASIMHA MURTHY	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad, Andhra Pradesh
5	SIRISILLA, RAJU	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad,
6	VELAGALA, VENKATA RAMA MURALI KRISHNA REDDY	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad,
7	YEDUGANI, LINGAM	Dr. Reddy's Laboratories Limited, 7-1-27, Ameerpet, 500016 Hyderabad,

PCT International Classification Number

C07D 491/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA