Patent Application
20090062550
The present invention relates to an improved process for the large scale production of Rizatriptan benzoate in high yield with dimer impurity less than 0.1% and purity more than 99.5% with out involving hazardous reactions or reagents
N,N-Dimethyl-2[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine (Rizatriptan) has the formula as given below (Formula-I).
Rizatriptan and the physiologically acceptable salts are useful as 5-HT1B1D receptor agonist, and is marketed as an oral formulation for acute treatment of migraine.
U.S. Pat. No. 5,298,520 and J. S. Leslie et al., J. Med. Chem., 1995, 38, and 1799 discloses Rizatriptan, methods for its preparation and pharmaceutical formulations using the same. The process disclosed in U.S. Pat. No. 5,298,520 involves the preparation of Rizatriptan by Fisher indole synthesis using the corresponding phenyl hydrazine and an aldehyde. The method described in that patent involves multi step synthesis accompanied by of column purifications. It also involves hazardous reagents such as NaH which results in the formation of more unwanted regioisomer of 1,2,4-Triazol-4-yl and stillbene derivative impurity. Again using this prior art process in Fisher indolization, which invariably results in the formation of a polar dimer impurity (Formula-II) to a large extent. Isolation of desired product without this dimer impurity is very cumbersome and expensive.
U.S. Pat. No. 5,567,819 discloses the preparation of 1-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride (Formula-III) which comprises reacting 4-amino-1,2,4-triazol with a nitrobenzene derivative containing a readily displaceable group. Subsequently conversion of this intermediate into Rizatriptan is carried out by Fisher indole synthesis. The end product nevertheless continues to have the disadvantages on quality of product even a column purification step is involved, so that it is not cost-effective to carry out the process in industrial scale.
U.S. Pat. No. 5,567,824 also discloses a process for preparing Rizatriptan, by palladium-catalyzed coupling ring closure of 3-Iodine-4-aminobenzyl-triazol with a suitably protected butynol derivative to corresponding tryptophol followed by conversion of the hydroxyethyl moiety to dimethylaminoethyl moiety (Rizatriptan). Although this process does not require column purification, it has the disadvantage of using a palladium catalyst which makes the process more expensive, while also using highly toxic reagents such as iodine chloride and highly flammable reagents such as n-butyl lithium.
However, the above discussed processes have one major drawback in common in that the removal of polar dimer impurity of Formula-II using conventional techniques.
EP 0,925,302 discloses the preparation of 2-silyl protected indoles, by palladium-catalyzed cross-coupling reaction of halo anilines with acylsilanes, and preparation of product sought by deprotection of these intermediates so obtained.
U.S. Pat. Appl. No. 2005/0148778 discloses the synthesis of the Rizatriptan using hydrazine hydrochloride derivative of Formula-VI with α-keto-δ-valreolactone with low overall yield due to the lengthy process.
In the all above discussed prior art processes there are significant draw backs for commercial process with yield, quality and cost effective which are as.
Hence there is a need for a simple and commercially viable process for the preparation of Rizatriptan benzoate without involving the hazardous chemicals and it is also necessary to minimize the undesired regioisomer and stillbene derivative impurity at the early stages of the synthesis, which subsequently carried over to finished stage along with dimer impurity in the finished product.
Thus the present invention is provided with a commercially viable process which does not require hazardous & expensive catalyst like sodium hydride, palladium and the final product with dimer impurity less than 0.1%.
Unless other wise defined, all technical and synthetic terms used herein have the same ordinary meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and not intended to be limiting.
The main object of the present invention is to provide an improved process for the preparation of Rizatriptan and its pharmaceutically acceptable salts.
Another object of the invention is to provide a process for preparation of Rizatriptan benzoate with purity more than 99.5%.
Another object of the invention is to provide a process for preparation of Rizatriptan benzoate with dimer impurity less than 0.1%.
Another object of the invention is to provide a process for preparation of Rizatriptan benzoate with out involving expensive hydrogenation catalysts or highly toxic and hazardous or highly flammable reagents.
Accordingly in the present invention Rizatriptan and its pharmaceutically acceptable salts are prepared by; i) Condensation of triazole with 4-nitro benzyl bromide to yield 1-(4-nitrophenyl) methyl-1,2,4-triazole ii) Reduction of 1-(4-nitrophenyl) methyl-1,2,4-triazole to 1-(4-aminophenyl) methyl-1,2,4-triazole iii) Converting 1-(4-nitrophenyl)methyl-1,2,4-triazole to 1-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride iv) condensing the hydrazine derivative with 4-(Dimethylamino) butanal diethylacetal to get Rizatriptan and v) Saltification of Rizatriptan to Rizatriptan benzoate.
Thus in accordance with the present invention preparation of Rizatriptan benzoate comprises the following steps;
In a specific embodiment, the present invention provides a process for the preparation of Rizatriptan benzoate, which involves
Further reduction of the resulting 1-(4-nitrophenyl) methyl-1,2,4-triazole is carried out by
Conversion of the 1-(4-aminophenyl) methyl-1,2,4-triazole to 1-(4-hydrazino phenyl)methyl-1,2,4-triazole hydrochloride is carried out by
Further condensation of 1-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride with 4-(Dimethylamino) butanal dimethylacetal is carried out by
The conversion of Rizatriptan to Rizatriptan benzoate is carried out by
Methods known in the art may be used with the process of this invention to enhance any aspect of this process. For example the product obtained may be further purified by crystallization from solvent(s). The present invention is further illustrated by the following examples, which are provided nearly to the exemplary of the inventions and is not intended to limit the scope of invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included with in the scope of the present invention in any way.
1,2,4-Triazole (25 kg.) and potassium carbonate (53 kg.) are added to anhydrous DMF (125 lt.) at room temperature. The reaction mixture is heated to 90-95° C. and maintained for about 5 hrs. The reaction mixture is cooled to 0° C. and 4-nitro benzyl bromide (75 kg.) is added below 10° C. Reaction is maintained at 25-30° C. for 14-16 hrs. Finally the reaction mixture is poured into water (245 lt.) below 25° C. and maintained at 20-25° C. for 2-3 hrs. The product is filtered and slurry washed with water (100 lt) to yield 1-(4-nitrophenyl) methyl-1,2,4-triazole (49 kg)
1-(4-Nitrophenyl) methyl-1,2,4-triazole (35 kg.), methanol (350 lt.) and water (35 lt.) are suspended in a hydrogenator. To the suspension Raney Nickel (approx. 7.0 kg) is added and mixture is hydrogenated at 40-45° C. maintaining at 5-6 kg pressure. After the reaction completion, the catalyst is filtered through hyflo bed and washed the hyflo bed with methanol (15 lt.). Methanol is distilled off and IPA (35 lit.) is charged. Reaction mass is cooled to 20-25° C. and maintained at 20-25° C. for 1 hrs. The precipitated product is filtered and washed the product with IPA (17 lt.) to yield 1-(4-aminophenyl) methyl-1,2,4-triazole (25 kg)
A solution of 1,4-aminophenyl methyl-1,2,4 triazole (23 kg.) in concentrated HCl (28 lt.) is added to sodium nitrite solution (10.6 kg. in 13 lt of water) in such a rate the temp. does not exceed −10° C. The reaction mixture is maintained for 60 min. at about −2° C. and added slowly to a precooled (−10° C.) sodium sulphite (41.4 kg.) and water (50 lt.) solution at 15° C. The reaction mixture is maintained at −10 to −15° C. for 30 min. Reaction mass is raised to 25-30° C. and HCl (35 lt.) is added at 25-30° C. and maintained for 2 hrs. The product is filtered, washed the product with water (90 lt.) followed by IPA (23 lt.) to yield 1-(4-hydrazinophenyl) methyl-1,2,4-triazole hydrochloride (33 Kg).
1-(4-Hydrazinophenyl)methyl-1,2,4-triazole hydrochloride (7.0 kg.) in Conc. HCl (35.0 lt.) is stirred for 30 min at 20-25° C., to that water (140.0 lt.) is added and stirred for another 30 min at 20-25° C. 4-(Dimethylamino) butanal diethylacetal (7.10 kg.) is added slowly at 20-25° C. and stirred for 60 min. The reaction mixture is hated to 70-75° C. and maintained for 60 min. After completion of reaction, cooled the mass to 30° C., adjusted the pH to 6.0-6.5 and extracted with methylene chloride (2×35 lt.). Aq. layer is separated and adjusted the pH to 10-11 and extracted with ethyl acetate (3×55 lt.). Ethyl acetate is removed under vacuum and the residue is chromatographed on silica gel (55 kg.) and eluted with ethyl acetate (25 lt.) followed by methanol (30 lt.) to give Rizatriptan as residue. The obtained residue is dissolved in ethanol (15 lt.) and pH is adjusted to 6.0-6.5 with benzoic acid (1.8 kg.) in ethanol (3.5 lt) at 30-35° C. The reaction mass is cooled to 0° C. and stirred for 1 hr. The product is centrifuged and washed with ethanol (3 lt) to yield Rizatriptan benzoate (3.0 kg.) with purity >99.0%.
Crude Rizatriptan benzoate (7 Kg) obtained in example-2 is dissolved in ethanol (60 lt.) at 78-80° C. to give a clear colorless solution. The solution is slowly cooled to room temperature and allowed it to crystallize and finally cooled to 5-8° C. and stirred for 1 hr. The purified product is then centrifuged, washed with chilled ethanol (7 lt.) and dried to give 6.25 kg pure Rizatriptan benzoate with dimer impurity <0.1%.
The mother liquors from the benzoate formation could be further processed by a combination of fractional crystallization and column chromatography to yield the dimer impurity of formula-II
1H NMR [300 MHz 1H NMR (DMSO-d6, δ)]: 2.28 [S, 12H, 2×-N(CH3)2]; 2.35-2.90 (m, 8H, 4×-CH2); 4.10 (s, 2H, —CH2 at C-14); 5.41 (s, 2H, —CH2 at C-11); 6.94-7.44 (m, 7H, Aromatic U); 7.93 (s, 1H, CH at C-13); 8.59 (s, 1H, —CH at C-12); 10.86 (s, 1H, —NH exchangeable) &10.72 (s, 1H, —NH exchangeable)
13C NMR [300 MHz 13C NMR (DMSO-d6, δ)]: 21.49 (C-8) 22.50 (C-22); 32.06 (C-14); 44.43 (C-10); 53.15 (C-11); 59.29 (C-23); 59.46 (C-9); 107.79 (C-7); 110.82 (C-17); 111.23 (C-20); 111.64 (C-3); 117.63 (C-6); 117.74 (C-16); 120.47 (C-4); 121.81 (C-21); 122.84 (C-19); 125.77 (C-5); 127.26 (C-15); 128.05 (C-3a); 129.21 (C-20a); 134.90 (C-7a); 135.02 (C-17a); 136.91 (C-2); 143.63 (C-12) & 151.30 (C-13)
Mass (N+H): 470.3
| Number | Date | Country | Kind |
|---|---|---|---|
| 1657/CHE/2005 | Nov 2005 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN06/00450 | 11/14/2006 | WO | 00 | 5/14/2008 |
