WO2006053116A2

WO2006053116A2 - Rizatriptan process

Info

Publication number: WO2006053116A2
Application number: PCT/US2005/040718
Authority: WO
Inventors: Padi Pratap Reddy; Sonny Sebastian; Saurabh Shashikant Chitre; Peri Seetha Rama Sarma; Bhimavarapu Srinivasa Reddy; Sankineni Sampath Kumar
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2004-11-10
Filing date: 2005-11-09
Publication date: 2006-05-18
Also published as: WO2006053116A3

Abstract

Rizatriptan is prepared by reacting 4-hydrazinophenylmethyl-1,2,4-triazole dihydrochloride with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid.

Description

RIZATRIPTAN PROCESS

INTRODUCTION TO THE INVENTION

The present invention relates to the preparation of rizatriptan. More particularly, the invention relates to a process that provides rizatriptan having high purity.

Rizatriptan base has the chemical name Λ/,Λ/-dimethyl-5-(1 /-/-1 ,2,4-triazol- 1-ylmethyl)-1H-indole-3-ethanamine and is represented structurally by Formula I.

Formula 1

Rizatriptan is a selective 5-hydroxytryptamineiB/iD (5-HT-I_B/ID ) receptor agonist and is of particular use in the treatment of migraine and associated conditions. Products containing rizatriptan monobenzoate as the active ingredient are commercially available under the trademarks MAXALT and MAXALT-MLT. U.S. Patent Nos. 5,298,520 and 5,602,162 describe derivatives of imidazole, triazole and tetrazole, including rizatriptan, and the synthesis and purification of such compounds and their salts, pharmaceutical compositions containing them, and their use.

These patents describe the preparation of rizatriptan by Fischer indole synthesis, using the corresponding phenylhydrazine and an aldehyde. Rizatriptan and rizatriptan benzoate are prepared as depicted in Schemes 1 and 2 below. In brief, rizatriptan base can be obtained starting from 1-(4-hydrazinophenyl)methyl- 1 ,2,4-triazole dihydrochloride of Formula III by reacting with 4-N,N- dimethylaminobutanal dimethylacetal in the presence of sulphuric acid as given in Scheme 1 , or by reacting with 4-chlorobutanal dimethylacetal in the presence of - -

hydrochloric acid, followed by reaction of the ethylamine derivative of formula IV with sodium cyanoborohydride in the presence of formaldehyde and acetic acid, as depicted in Scheme 2.

; acetal \ /

Scheme 1

Scheme 2

These methods demonstrate poor yield and the purity of the product is low. The product requires several steps of column purification to yield pure rizatriptan and is obtained in an overall yield of only about 11 %. PCT publication No. WO 94/02476 describes the preparation of the intermediate 1-(4-hydrazinophenyl)methyl-1 ,2,4-triazole of Formula V.

Formula V

Conversion of this intermediate into rizatriptan is carried out by Fischer indole synthesis in the same way as in the above-discussed patents. The yield of this intermediate of Formula V is improved by this process. The end product nevertheless continues to require a column purification step, using a relatively large quantity of solid support and a complex elution using an eluent that is a 30:8:1 mixture of dichloromethane:ethanol:ammonia, and hence the process is not cost effective for operation on an industrial scale.

The processes in Scheme 1 and Scheme 2 as described above involve the Fischer indole reaction wherein an acid catalyst is involved. The indole derivative is susceptible to degradation in the presence of acidic species which results in the formation of a closely related dimeric impurity 3-[2-(N,N-dimethylamino) ethyl-2- [[3-[2-(N,N-dimethylamino)ethyl]-1 H-indol-5-yl]methyl]-1 H-indol-5-yl]methyl-1 H- 1 ,2,4-triazole, having the structural Formula II, and comprising about 11% of the isolated products. Thus repeated purifications are required to provide a material having a desired low level of this impurity, making the processes uneconomical.

Formula Il

It is difficult to reduce the dimer impurity of rizatriptan to less than 0.15 %, which is the maximum level for any impurity allowed by the regulatory authorities in a pharmaceutical product. _ _

There remains a need for a simple, efficient and ecofriendly process resulting in rizatriptan substantially free of the dimer impurity.

SUMMARY OF THE INVENTION

In an aspect, the invention provides a process for preparing rizatriptan, comprising: a) reacting 4-hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid to form crude rizatriptan base; b) adsorbing crude rizatriptan base onto silica gel; and c) eluting purified rizatriptan base from the silica gel with a solvent.

In another aspect, the invention provides a process for preparing rizatriptan benzoate, comprising: a) reacting 4-hydrazinophenyl methyl- 1 ,2,4-triazole dihydrochloride with

4-N₁N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid to form crude rizatriptan base; b) adsorbing crude rizatriptan base onto silica gel; c) eluting purified rizatriptan base from the silica gel with a solvent; d) reacting purified rizatriptan base with benzoic acid to form rizatriptan benzoate; and e) recrystallizing rizatriptan benzoate from n-butanol. In an embodiment of the invention, rizatriptan is eluted from silica gel using a solvent comprising an ester, an alcohol, or a mixture of an ester and an alcohol.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an X-ray powder diffraction ("XRPD") pattern of crystalline rizatriptan base. Fig. 2 is an infrared absorption spectrum of crystalline rizatriptan base.

Fig. 3 is a differential scanning calorimetry curve of crystalline rizatriptan base. DETAILED DESCRIPTION

The present invention relates to rizatriptan substantially free of the dimer impurity of rizatriptan having Formula II. More specifically, the present invention relates to rizatriptan that comprises not greater than about 1500 ppm of the dimer impurity, as determined by high performance liquid chromatography ("HPLC"), and a process for its preparation.

The invention provides a process which allows the preparation of rizatriptan of high purity free from the dimer and other related impurities. The process utilizes apparatus commonly available in the laboratory, and involves easy adsorption and elution operations without the need for any additional pre-purification. The process is readily scalable to industrial requirements and is economically viable.

As used herein, the term rizatriptan includes rizatriptan free base and pharmaceutically acceptable salts of rizatriptan. In one embodiment, the rizatriptan is rizatriptan free base. In another embodiment, the rizatriptan is rizatriptan benzoate.

In an aspect, the present invention provides rizatriptan containing less than about 1500 ppm, or less than about 1000 ppm, or less than about 500 ppm of the dimer impurity. These amounts can be expressed, respectively, as less than about 0.15 area-%, less than about 0.1 area-%, and less than about 0.05 area-% in an analysis by HPLC.

In an embodiment, the invention provides a method of synthesizing rizatriptan that comprises an amount of dimer impurity of not greater than about 1500 ppm, comprising the steps of: a) reacting 4-hydrazino-phenyl-methyl 1 ,2,4-triazole dihydrochloride

(III) with 4-N,N dimethylaminobutanal dimethylacetal in the presence of an acid to form crude rizatriptan base containing the rizatriptan dimer impurity; b) reducing the rizatriptan dimer impurity content of the crude rizatriptan base by adsorption on silica gel followed by elution with a suitable solvent to get purified rizatriptan base of Formula I; and c) optionally reacting purified rizatriptan base with benzoic acid in a suitable solvent, optionally followed by purification to afford a purified rizatriptan benzoate of Formula Vl. - -

An embodiment of a process for the preparation of rizatriptan benzoate is described in reaction Scheme 3.

₃

Scheme 3

Step a) involves reacting 4-hydrazino-phenyl-methyl-1 ,2,4-triazole dihydrochloride (111) with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of an acid catalyst, such as, for example, aqueous hydrochloric acid, to obtain rizatriptan base. Suitable acid catalysts useful for the preparation of rizatriptan base of Formula I include hydrochloric acid under aqueous or non¬ aqueous conditions. The concentration of the catalyst can be determined based on the type of catalyst and the medium in which it is to be provided. When aqueous hydrochloric acid is used as a catalyst, it can be present in amount of about 5-20% of the amount of the starting material 4-hydrazinophenylmethyl- 1 ,2,4-triazole dihydrochloride. The HCI concentration in the aqueous hydrochloric acid can range from about 1 to 37 percent by weight.

The reaction for the preparation of rizatriptan base of Formula I can be carried out at a temperature of about 65-85° C, or about 70-75° C, until the reaction is complete, over a sufficient period of time to complete the reaction, such as, for example, up to about 4 hours. Longer times could be necessary if the reaction is conducted at lower temperatures. Upon completion, the reaction mass can be brought down to a lower temperature, such as, for example, about ambient temperature, and the reaction can be quenched by the addition of an appropriate basic substance. The basic substance to be used can be any organic or inorganic _ _

base such as, for example: alkali metal hydroxides, carbonates and bicarbonates like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and the like; and organic bases such as primary, secondary and tertiary amines, and the like. The basic substance can be in the form of a solution in a suitable solvent such as, for example: alcohols such as methanol, ethanol, and propanol; ketones such as acetone and tertiary-butyl ketone; hydrocarbons such as Cβ to Cg alkanes, and the like; and water; and mixtures thereof.

The amount and concentration of the base required for quenching the reaction will depend on the size of the batch being synthesized, the quantity of acidic catalyst being used and such other parameters known to a person skilled in the art of chemical synthesis.

The quenched mass comprising rizatriptan base along with other reactants and impurities can be further extracted with an organic solvent to recover rizatriptan base. The organic solvents which are useful in this extraction include, but are not limited to: hydrocarbons such as C₅ to C₉ alkanes; esters such as ethyl acetate, propyl acetate, and tertiary-butyl acetate; ethers such as diethyl ether and diisopropyl ether; and mixtures thereof.

Step b) involves reducing the dimer impurity content by adsorbing the crude rizatriptan base contained in the organic layer obtained after extraction from the reaction mass in step a on silica gel followed by elution with solvent to get pure rizatriptan base. This crude rizatriptan base may contain, in addition to the rizatriptan base, quantities of the dimer impurity of rizatriptan, unreacted catalyst, and other impurities. The crude rizatriptan obtained after extraction of the reaction mass into the organic layer is adsorbed on the silica gel. The concentration of rizatriptan base in the solution that is loaded onto the silica gel can vary widely. In an embodiment, the concentration of rizatriptan is in the range of about 0.01 to 25% w/v or about 2 to 15% w/v. The silica gel which can be used for the purposes of this invention can have a particle size range such as for example 240-400 mesh, 100-200 mesh, or 60-120 mesh. The quantity of silica gel used can range from about 4 to 10 times, or about 4 to 6 times, with respect to the weight of the starting material having Formula III. _ _

The adsorbent silica gel may be filled into any suitable container or reaction vessel such as for example a filtration funnel or a cylindrical vessel or the like. The size of the container may be chosen based on the amount of the silica gel to be contained therein and the batch size of rizatriptan to be purified. Rizatriptan and its impurities are adsorbed onto the silica gel from the process solution, which solution passes through the silica gel bed or column. The silica gel loaded with the rizatriptan base and impurities is then eluted using a suitable solvent or a mixture of solvents and the eluted solvent containing the purified rizatriptan is collected. It has been surprisingly found that the dimer impurity is extensively bound to the silica gel, while rizatriptan can be substantially completely eluted with a solvent, thereby avoiding the need to change the polarity of the solvents used for elution.

Suitable solvents for elution include, without limitation thereto: esters such as ethyl acetate and n-butyl acetate; ketones such as acetone; alcohols such as isopropanol, methanol, and ethanol; hydrocarbons such as cyclohexane; and the like. Mixtures of such solvents, in various proportions, are useful. The temperature of the solvent used for elution can range from about 5 to 80° C. The appropriate temperature to be used will be determined based on the solvent or solvent mixture that is used to achieve optimal separation. The flow of the solvent can be continuous or in lots and the quantity of solvent can range from about 2 to 20 times the volume of the solution containing the crude rizatriptan.

The rizatriptan base of Formula I obtained after removing solvent from the eluate is a crystalline solid and is characterized by an XRPD pattern, using Cu Ka radiation (1.541 A wavelength), substantially in accordance with Fig. 1. It is also characterized by XRPD peaks at 20.6, 6.0, 13.6, 15.7, 18.0, 19.5, 22.2, and 23.4,

± 0.2 degrees 20. It may be characterized further by XRPD peaks at 18.7, 23.9,

24.1 , 26.2, and 29.8, ± 0.2 degrees 20.

Crystalline rizatriptan base Formula I is further characterized by an infrared absorption spectrum in potassium bromide substantially in accordance with Fig. 2. The rizatriptan base is also characterized by its infrared absorption spectrum comprising peaks at about 3069, 2852, 2762, 1508, 1273, 1136, 814, and 741 , ± 5 cm^"1. - -

Crystalline rizatriptan base of Formula I is further characterized by a differential scanning calorimetry curve substantially in accordance with Fig 3.

Rizatriptan prepared according to the process has a low level of impurities, generally totaling less than about 1 area-%, or less than about 0.75 area-%, or less than about 0.5 area-%, as determined by HPLC. In particular, the dimer impurity is generally present in amounts less than about 0.15 area-% by HPLC. An N-oxide impurity N,N-dimethyl-5-(1 H-1 ,2,4-triazol-1-yl-methyl)-1 H-indole-3- ethanamine N-oxide having the structure below is generally present in amounts less than about 0.15 area-% by HPLC.

A 4-hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride impurity having the structure below is generally present in amounts less than about 0.15 area-%.

A hydrazone impurity 1-(4-(2-(4-(dimethylamino)butylidene)hydrazino)phenyl) methyl-1 ,2,4-triazole having the structure below is generally present in amounts less than about 0.15 area-%.

All other individual impurities are generally present in amounts less than about 0.1 area-%.

Step c) involves reacting rizatriptan base with benzoic acid in a suitable solvent, optionally followed by purification, to afford rizatriptan benzoate of Formula Vl.

Suitable solvents that can be used for the preparation of a solution of benzoic acid include, without limitation, acetone, ethanol, isopropanol, n-propanol, and n-butanol. Suitable solvents for recrystallisation of the crude benzoate salt include, without limitation, acetone, ethanol, isopropanol, n-propanol, and n-butanol. n- Butanol has shown improved results when compared to other solvents, for purification of rizatriptan benzoate. The rizatriptan benzoate of the invention is substantially free of the dimer impurity of rizatriptan and is manufactured by a economical process. The substantially pure rizatriptan benzoate prepared by the process of the invention is useful in the preparation of pharmaceutical compositions for the treatment of the disease conditions mentioned above. Certain aspects and embodiments of the invention will now be more fully described with reference to the following examples which are only illustrative and are not to be construed as limiting the scope of the invention.

EXAMPLE 1

PREPARATION OF RIZATRIPTAN BASE

To a solution of 200 g of 1-(4-aminophenyl) methyl-1 ,-2,4 triazole dihydrochloride in 2000 ml water was added 158 ml concentrated hydrochloric acid and 180.4 g of 4-dimethyl-amino-butanal-dimethyl-acetal, and the mixture was maintained for 1 hour at 4-5° C. Another 158 ml of concentrated hydrochloric acid was added to the mixture and the mixture was heated to 70-75° C for 2 hours. The mixture was cooled to 25-30° C, quenched by adding 260 ml of 40% aqueous sodium hydroxide solution, and the mixture was extracted with 3000 ml of ethyl acetate three times. The combined organic layer was passed through 840 g of silica gel (100-200 mesh) packed in a glass column. The silica gel was eluted with 8000 ml of isopropanol. Solvent was evaporated from the eluate to yield 108 g of the desired purified rizatriptan base having a dimer impurity content of 0.095 area-% as measured by HPLC. -

EXAMPLE 2

PREPARATION OF RIZATRIPTAN BASE

To a solution of 200 g of 1-(4-aminophenyl)-methyl-1 ,2,4 triazole dihydrochloride in 2000 ml water was added 158 ml of concentrated hydrochloric acid and 180 g of 4-dimethyl-amino-butanal-dimethyl-acetal, and the mixture was maintained for 1-2 hours at 0-5° C. Another 158 ml of concentrated hydrochloric acid was added to the mixture and the mixture was heated to 70-75° C for 2 hours. The mixture was cooled to 25-30° C, quenched by adding 265 ml of 40% aqueous sodium hydroxide solution, and the product was extracted with 3000 ml of ethyl acetate three times. Combined organic layer was passed through 950 g of silica gel (60-120 mesh) packed in a glass column, and the clear solvent was collected and discarded. The silica gel was eluted with 8000 ml of isopropanol. Solvent was evaporated from the eluate to yield 101 g of the desired purified rizatriptan base having a dimer impurity content of 0.055 area-% as measured by HPLC.

EXAMPLE 3

PREPARATION OF RIZATRIPTAN BENZOATE

To a solution of 99 g of rizatriptan base, as obtained above, in 495 ml isopropanol, a solution of 45 g benzoic acid in isopropanol was added. The precipitated salt was filtered and washed with 99 ml isopropanol. The wet product was dried at 50-60° C for 4-5 hours to get 80 g of the desired rizatriptan benzoate having a dimer impurity content of 0.045 area-% as measured by HPLC.

EXAMPLE 4

PURIFICATION OF RIZATRIPTAN BENZOATE 80 g of crude rizatriptan benzoate obtained in Example 3 was suspended in

400 ml of n-butanol. The suspension was heated to 115-120° C to get a clear solution. The hot solution was filtered through a perlite bed and the filtrate was cooled to 25-30° C and maintained for 2-3 hours. The precipitated product was filtered and washed with 80 ml of n-butanol. The product was finally dried at 50- 60° C for 4-5 hours to yield 68.7 g of rizatriptan benzoate with an HPLC purity of 99.7 area-% and a dimer impurity content of 0.036 area-%.

EXAMPLE 5

Experiments were carried out using the general procedure of Example 1 , with different acid catalysts under aqueous and nonaqueous conditions, to determine influences on the yield and quality of the rizatriptan base product. As the dimer impurity was a major potential impurity formed during the process, quality of product was monitored with respect to the percentage of dimer impurity in the product. The results of the experiments are tabulated below:

The results from the above experiments reveal that hydrochloric acid is the most suitable acid catalyst for producing rizatriptan according to Scheme 3. EXAMPLE 6

The crude rizatriptan base obtained by the process using hydrochloric acid as the catalyst contained the dimer impurity in the range of 4 to 8 area-% by HPLC. Various purification processes were attempted for reducing this impurity to acceptable levels. The results of the experiments are tabulated below:

- -

MeOH = methanol IPA = isopropanol EA = ethyl acetate

Recrystallizations from solvents were not effective in reducing the dimer impurity to the desired levels. Purification by adsorbing the compound onto silica gel can be used to reduce the impurity levels to below 0.15 area-% by HPLC, which is the maximum level for any impurity allowed by the regulatory authorities in a pharmaceutical product.

EXAMPLE 7

The rizatriptan benzoate obtained from the purified rizatriptan base contains various impurities formed as by-products in the process, other than the dimer impurity. These impurities have to be eliminated from the final product to meet quality guidelines for purity of the pharmaceutical product. Various recrystallization solvents have been used to purify rizatriptan benzoate. The results of the experiments are tabulated below:

_ _

In the experiments, rizatriptan benzoate was dissolved in a minimum quantity of solvent at an elevated temperature, then the temperature was reduced to ambient and crystals were allowed to form. The crystals were isolated by filtration and dried to remove residual solvent.

The results obtained above indicate that purification in n-butanol gives rizatriptan benzoate having an enhanced purity.

Claims

_ _CLAIMS:

1. A process for preparing rizatriptan, comprising: a) reacting 4-hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid to form crude rizatriptan base; b) adsorbing crude rizatriptan base onto silica gel; and c) eluting purified rizatriptan base from the silica gel with a solvent.

2. The process of claim 1, wherein hydrochloric acid is present in an aqueous solution.

3. The process of claim 1 , wherein hydrochloric acid is present in an aqueous solution and comprises about 5-20 percent of an amount of 4- hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride.

4. The process of claim 1 , wherein silica gel is in an amount about 4 to 10 times a weight of crude rizatriptan base.

5. The process of claim 1 , wherein silica gel is in an amount about 4 to 6 times a weight of crude rizatriptan base.

6. The process of claim 1 , wherein rizatriptan base is eluted with a solvent comprising an ester, a ketone, an alcohol, or a hydrocarbon.

7. The process of claim 1 , wherein rizatriptan base is eluted with a solvent comprising an alcohol.

8. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.15 area-percent of 3-[2-(N,N-dimethylamino) ethyl-2-[[3-[2-(N,N- dimethylamino)ethyl]-1 H-indol-5-yl]methyl]-1 H-indol-5-yl]methyl-1 H-1 ,2,4-triazole impurity, as determined by high performance^' liquid chromatography. _ _

9. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.1 area-percent of 3-[2-(N,N-dimethylamino) ethyl-2-[[3-[2-(N,N- dimethylamino)ethyl]-1 H-indol-5-yl]methyl]-1 H-indol-5-yl]methyl-1 H-1 ,2,4-triazole impurity, as determined by high performance liquid chromatography.

10. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.05 area-percent of 3-[2-(N,N-dimethylamino) ethy)-2-[[3-[2-(N,N- dimethylamino)ethyl]-1 H-indol-5-yl]methyl]-1 H-indol-5-yl]methyl-1 H-1 ,2,4-triazole impurity, as determined by high performance liquid chromatography.

11. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.15 area-percent of N,N-dimethyl-5-(1 H-1 ,2,4-triazol-1-yl-methyl)- 1 H-indole-3-ethanamine N-oxide impurity, as determined by high performance liquid chromatography.

12. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.15 area-percent of 4-hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride impurity, as determined by high performance liquid chromatography.

13. The process of claim 1 , wherein a purified rizatriptan base product contains less than about 0.15 area-percent of 1-(4-(2-(4-(dimethylamino)butylidene) hydrazino)phenyl)methyl-1 ,2,4-triazole impurity, as determined by high performance liquid chromatography.

14. The process of claim 1 , further comprising: d) reacting purified rizatriptan base with benzoic acid to form rizatriptan benzoate; and e) recrystallizing rizatriptan benzoate.

15. The process of claim 11 , wherein recrystallization is from n-butanol. _ _

16. A process for preparing rizatriptan benzoate, comprising: a) reacting 4-hydrazinophenylmethyl-1 ,2,4-triazole dihydrochloride with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of hydrochloric acid to form crude rizatriptan base; b) adsorbing crude rizatriptan base onto silica gel; c) eluting purified rizatriptan base from the silica gel with a solvent; d) reacting purified rizatriptan base with benzoic acid to form rizatriptan benzoate; and e) recrystallizing rizatriptan benzoate from n-butanol.

17. The process of claim 17, wherein the solvent comprises ethyl acetate.

18. The process of claim 17, wherein the solvent comprises an alcohol.

19. The process of claim 17, wherein the solvent comprises ethyl acetate and an alcohol.