WO2003068778A1

WO2003068778A1 - A process for the preparation of 10-hydroxy-9-n,n-dimethylaminomethyl-5-(2'-fluoroethoxy)-20(s)-camptothecin hydrochloride

Info

Publication number: WO2003068778A1
Application number: PCT/IB2003/000547
Authority: WO
Inventors: Sairam Pothukuchi; Rajender Kumar Potlapally; Sreenivasa Rao Bhatraju; Narsimha Murthy Kotra; Raju Sirisilla; Venkata Rama Murali Krishna Reddy Velagala; Lingam Yedugani
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2002-02-18
Filing date: 2003-02-18
Publication date: 2003-08-21
Also published as: AU2003207369A1

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.

Description

A PROCESS FOR THE PREPARATION OF 10-HYDROXY-9-N,N-

DIMETHYLAMINOMETHYL-5-(2 -FLUOROETHOXY)-20(S)-

CAMPTOTHECIN HYDROCHLORTOE

Field of the Invention

The present invention relates to a process for the preparation of 10-hydroxy-9-

having the formula (I).

The compound 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.

The compound of formula (I) has significant formulation and bulk handling advantages in view of the their stability and solubility.

Background of Invention

(a) In our recently granted US patent no. 6,177,439 Bl, we have disclosed and described the process for the preparation of novel compounds of the formula (II),

wherein R , R , R and R 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 R² and R³ together represent O-(CH₂)_n-0- where n=l or 2, each of R¹, R², R³ and R⁴ are not the same except where each of R¹, R², R³ and R⁴ are hydrogen; R⁵ 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);

N (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 R⁵ represents lower aralkyl, where the aryl group is selected from phenyl, biphenyl or naphthyl; and R⁶ 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),

X (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, 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 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), N Y (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 R⁶ 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, furan, 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),

Y (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 R¹ represents hydroxy, amino or nitro, R², R³, R⁴ and R⁵ represent hydrogen and R⁶ represents hydrogen, lower alkyl, alkanoyl or benzoyl groups, which comprises : (i) reacting the compounds of formula (III)

where R¹ to R⁵ 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),

wherein R - R⁵ have the meaning given above,

(ii) separating the compounds of formulae (IV) and (V) prepared in step (i) by conventional methods,

(iii) hydrolysing the compounds of formula (IV) by conventional methods to obtain amounts of the compounds of formula (V),

(iv) reacting the compound of formula (V) in the presence of an acid with a compound having the formula R⁶-OH to obtain compounds of formula (II).

(b) Our co-pending WTO application no. 798/MAS/2001 dated September 25, 2001 discloses the process for the preparation of compound of formula (I).

This process is as shown in scheme-I below:

Scheme-I

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 10^th 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 treataent 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.

Summary of the Invention

The present invention relates to a process for the preparation of 10-hydroxy-9- N,N-dimethylaminomethyl-5-(2^Λ -fluoroethoxy)-20(S)-camptothecin hydrochloride of formula (I)

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 a 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, Lewis acid, in the presence of a solvent, at a temprature in the range of 100 tol30 °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, in the presence of hydrogen pressure in the range of 40 to 65 PSI, a solvent and oxidizing agent, 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^- N-dimethylaminometliyl-S-^ -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-hydro y-9-N,N-dimethylaminomethyl-5-(2^, -fluoroethoxy)-

20(S)-camptothecin of formula (He) to 10-hydroxy-9-N,N- dimethylaminomethyl-5-(2^,-fluoroethoxy)-20(S)-camptothecin hydrochloride of formula (I) by using hydrochloric acid and (vi) isolating the compound of formula (I) by using conventional isolation methods. This process is as shown in scheme-II below:

Scheme-II 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 a solvent such as dimethyl formamide (DMF), 1-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 such as sodium carbonate, potassium carbonate and the like. 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 Lewis acid such as titanium tetrachloride, zinc chloride, borontrifluoride ethereate, aluminium chloride and the like. The solvent 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 (He) with acetic acid and platinum oxide in the presence of hydrogen pressure in the range of 40 to 65 PSI, preferably in the range of 50 to 55 PSI. The solvent used in the reaction may be selected from dimethyl sulphoxide, acetic acid, methanol, ethanol, isopropyl alcohol or mixtures thereof. The oxidizing agent used in the reaction may be iodosobenzene diacetate in aqueous acetic acid, hydrogen peroxide and the like. 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. The 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 (1) is obtained by treating compound of formula (He) with hydrochloric acid. The temperature of the reaction may be in the range of 25 to 45 °C, preferably in the range of 25 to 40 °C.

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

10-hydroxy-9- N,N-dimethyIaminomethyl-5-(2^,-fluoroethoxy)-20(S)-camptothecin hydrochloride

Step (i):

Preparation of 5-hydroxy-20(S)-camptothecin

In a 3.0 L round-bottomed flask 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.

After completion of the reaction, 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 lh, filtered and dried at 60 °C under vacuum (217 g).

^!H-NMR (DMSO-d₆): δ 8.50 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.85 (s, J=6.8 Hz, 1H), 7.64 (s, J=6.8 Hz, 1H), 7.58 (s, 0.5H), 7.56 (s, 0.5H), 7.06 (s, 0.5H), 7.01 (s, 0.5H), 6.95 (br d, 1H, D₂O exchangeable), 5.67 (d, J=16.5 Hz, 1H), 5.25 (d, J=16.5 Hz, 1H), 5.05 (br d, 1H, 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), 2-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.

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.

1H-NMR (CDCl₃+DMSO-d₆): 6 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):

Preparation of 10-hydroxy-5- (2'-fluoroethoxy)camptothecin

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.

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 (CDCl₃+DMSO-d₆): δ 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 10-hydroxy-9- N,N-dimethylaminomethyl-5-(2^,-fluoroethoxy)-20(S)- camptothecin

10-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.

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): δ 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 10-hydroxy-9- N,N-dimethylaminomethyl-5-(2"-fluoroethoxy)-20(S)- camptothecϊn hydrochloride

10-hydroxy-9- N,N-dimethylaminomethyl-5-(2^λ -fluoroethoxy)-20(S)-camptothecin hydrochloride (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 tarry 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). Η-NMR (DMSO, 200MHz): δ 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 10-hydroxy-9- N,N-dimethylaminomethyl-5-(2^,-fluoroethoxy)-20(S)- camptothecin 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.

Claims

We claim:

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

which comprises:

(i) converting compound of formula (Ila)

to a compound of formula (lib)

by using a base and a reagent in the presence of a solvent, 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 (lib) to a compound of formula (lie)

by using 2-fluoroethanol, Lewis acid, in the presence of a solvent, at a temprature in the range of 100 tol30 °C in the duration of 24 to 48 h, (iii) converting a compound of formula (lie) to a compound of formula (lid)

by using acetic acid, platinum oxide and an oxidizing agent, in the presence of hydrogen pressure in the range of 30 to 75 PSI and a solvent, at a temperature in the range of 0 to 45 °C in the duration of 2 to 14 h, (iv) converting a comound of formula (lid) to a compound of formula (He)

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 (Ie) to a compound of formula (I) by using hydrochloric acid at a temperature in the range of 25 to 45 °C and

(vi) isolating the compound of formula (I) by using conventional isolation methods.

2. The process as claimed in claim 1, wherein the base used in step (i) of the reaction is selected from alkali metal carbonates.

3. The process as claimed in claim 1, wherein the reagent used in step (i) of the reaction is selected from iodine or potassium iodide.

4. The process as claimed in claim 1, wherein the solvent used in step (i) of the reaction is selected from dimethyl formamide, l-methyl-2-pyrrolidinone or N, N-diethyl formamide.

5. The process as claimed in claim 1, wherein the temperature and duration in step (i) of the reaction are maintained at room temperature and 40 to 45 h respectively

6. The process as claimed in claim 1, wherein the Lewis acid used in step (ii) of the reaction is selected from titanium tetrachloride, zinc chloride, borontrifluoride ethereate or aluminium chloride.

7. The process as claimed in claim 1, wherein the Lewis acid used in step (ii) of the reaction is selected from borontrifluoride ethereate.

8. The process as claimed in claim 1, wherein the Lewis acid used in step (ii) of the reaction is selected from titanium tetrachloride.

9. The process as claimed in claim 1, wherein the Lewis acid used in step (ii) of the reaction is selected from zinc chloride. 10. The process as claimed in claim 1, wherein the Lewis acid used in step (ii) of the reaction is selected from aluminium chloride.

1,1. The process as claimed in claim 1, wherein the solvent used in step (ii) of the reaction is selected from dimethylsulfoxide, toluene, dimethylformamide or l-methyl-2- pyrrolidinone. 12. The process as claimed in claim 1, wherein the temperature and duration in step (ii) of the reaction are maintained at 110 to 115 °C and 40 h respectively.

13. The process as claimed in claim 1, wherein the solvent used in step (iii) of the reaction is selected from dimethyl sulphoxide, acetic acid, methanol, ethanol, isopropyl alcohol or mixtures thereof. 14. The process as claimed in claim 1, wherein the hydrogen pressure in step (iii) of the reaction is maintained in the range of 50 to 55 PSI.

15. The process as claimed in claim 1, wherein the oxidizing agent used in step (iii) of the reaction is selected from iodosobenzene diacetate in aqueous acetic acid or hydrogen peroxide. 16. The process as claimed in claim 1, wherein the temperature in step (iii) of the reaction is maintained at 10 to 20 °C.

17. The process as claimed in claim 1, wherein the temperature and duration in step (iv) of the reaction are maintained at room temperature and 14 h respectively.

18. The process as claimed in claim 1 , wherein the temperature of the reaction in step (v) is maintained in the range of 25 to 40 °C.

19. The process for the preparation of compound of the formula ( 1 ) substantially as herein described with reference to example 1.