Field of the invention:

The present invention relates to a process for preparing 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI) which is key intermediate in the preparation of Rizatriptan benzoate.

Background of the invention:

The chemical name of Rizatriptan is N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3yl]ethylamine and formula is C15H19N5 and molecular weight is 269.34.

Rizatriptan is antimigraine agent. It is Selective serotonin 5-HT1D receptor agonist. It is used in treatment of migraine. The marketed form of Rizatriptan is Rizatriptan benzoate salt. The current pharmaceutical product containing this drug is being sold by Merck using tradename Maxalt and Maxalt-Mlt, in the form of tablets oral and orally disintegrating tablets.

Rizatriptan was first disclosed and claimed in US patent no. 5,298,520. It discloses a process for preparation of Rizatriptan benzoate as shown in given below scheme-II

Scheme-II

The process involves reacting 4-nitrobenzyl bromide (II) with sodium salt of 1,2,4-triazole (III) in DMF to give 1-(4-nitrophenyl)methyl-1,2,4-triazole (IV) which is reduced to give hydrochloride salt of 1-(4-aminophenyl)methyl-1,2,4-triazole (V). Compound (V) is diazotized and subsequently reduced to give 1-(4-hydrazinophenyl)methyl-1,2,4-triazole (VI). The compound (VI) is condensed with 4-chlorobutanal dimethylacetal to give 2-[5-(1,2,4-triazol-1-yl-methyl)-1H-indol-3-yl]ethylamine (VII) which is fischer indole reaction. Compound (VII) is then reacted with formaldehyde in the presence of sodiumcyanoborohydride to give Rizatriptan (VIII). In another approach the compound (VI) is condensed with 4-N,N-dimethylaminobutanal dimethylacetal in aq. Sulfuric acid to give Rizatriptan (VIII). Rizatriptan benzoate (I) is obtained by reacting Rizatriptan with benzoic acid in diethyl ether/ethanol.

1-(4-hydrazinophenyl)methyl-1,2,4-triazole (VI) is key intermediate in fischer indole reaction which is used to prepare Rizatriptan benzoate.

There are various routes reported in the literature to prepare this intermediate. The widely used route is to prepare amine from corresponding nitro compound and then diazotize the amine using NaNO2/HCl and reduce it using SnCl2/HCl or alkali metal sulphite to give hydrazone intermediate. Preparation of 1-(4-hydrazinophenyl) methyl-1,2,4-triazole (VI) by this route requires low temperature for diazotization step and costly metal reagents such as SnCl2 for reduction steps. The process involves four steps. Further, the diazo compound which is generated is genotoxic and hazardous to the environment.

It is therefore, a need to develop a process which not only overcomes the disadvantages of prior art but also be economical, industrially applicable and environmentally friendly.

Present inventors have directed their research work towards developing a process for the preparation of 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI) which is devoid of the above mentioned disadvantages. Further, the process is one step only compared to prior art process. The present inventor developed a novel process which reduces cost of production by reducing number of steps. The process is environmentally friendly avoiding use of toxic metal reagents. The process is also viable at industrial scale and need not require stringent condition like low temperature or any specialized skill to handle the reagents.

Summary of the invention:

It is therefore an object of the present invention to provide a process for the preparation of 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI)

Another object of the present invention is to provide a process for the preparation of 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI) which is simple and easy to handle at an industrial scale.

Yet another object of the present invention is to provide a process for the preparation of Rizatriptan benzoate using 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI) prepared by the present invention.

Accordingly, present invention provides a process for the preparation of 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI)

comprising a step of reacting 1H-1, 2, 4-triazole (III)

with formaldehyde and 4-hydrazinophenyl boronic acid (IX)

to give 1-(4-hydrazinophenyl)methyl-1, 2, 4-triazole (VI)

Detailed description of the invention:

Present invention provides a process for the preparation of 1-(4-hydrazinophenyl) methyl-1, 2, 4-triazole (VI)

comprising a step of reacting 1H-1, 2, 4-triazole (III)

with formaldehyde and 4-hydrazinophenyl boronic acid (IX)

to give 1-(4-hydrazinophenyl)methyl-1, 2, 4-triazole (VI)

In another aspect present invention provides a process for the preparation of Rizatriptan benzoate (I)

comprising a step of reacting 1H-1, 2, 4-triazole (III)

with formaldehyde and 4-hydrazinophenyl boronic acid (IX)

to give 1-(4-hydrazinophenyl)methyl-1, 2, 4-triazole (VI)

The synthetic reaction scheme of the present invention is as shown below in scheme-I

Scheme-I

The process of the present invention has following advantages:
(i) It reduces the number of steps and thereby reducing the cost of production.
(ii) It eliminates the use of costly metal catalyst.
(iii) It eliminates diazotization reaction which generate genotoxic diazo compound.
(iv) It eliminates the use of reducing agents like SnCl2. The disposal of toxic tin salt is environmentally hazardous.