Title of Invention

PROCESS FOR THE PREPARATION OF IRBESARTAN HYDROCHLORIDE

Abstract

The present invention is concerned with a process for the preparation of 2n-butyl-4-spirocyclopentane-l-[(2'-(te, a-zol-5-yl)biphenyl-4-yl) methyl]-2-imidazolin-5-one hydrochloride, irbesartan hydrochloride, novel hydrated and anhydrous crystalline forms thereof, amorphous irbesartan hydrochloride, formulations containing the same, therapeutic uses thereof and methods of treatment employing the same. The process of the present invention is a one-pot process which comprise reacting intermediate compounds 2n-butyl-l, 3-diazaspiro [4,4] non-l-en-4-one and 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) PROCESS FOR THE PREPARATION OF IRBESARTAN HYDROCHLORIDE" CIPLA LIMITED, of 289 Bellasis Road, Mumbai Central, Mumbai - 400 008, India. The following specification particularly describes the invention and the manner in which it is to be performed. WO 2006/046043 PCT/GB2005/004151 PROCESS FOR THE PREPARATION OF IRBESARTAN HYDROCHLORIDE The present invention is concerned with a process for the preparation of 2n-butyl-4-spkocyclopentane-l-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-irnidazolin-5-one hydrochloride, irbesartan hydrochloride, novel crystalline forms thereof, formulations containing the same, therapeutic uses thereof and methods of treatment employing the same. Irbesartan, 2n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5yl)biphenyl-4-yl)methyl]-2-imidazolin-5 one, can be represented by the following structural formula Irbesartan is a non-peptide angiotensin-II antagonist. Irbesartan inhibits the action of angiotensin - II on its receptor and thus prevents the increase in b100d pressure produced by the hormone - receptor interaction. Irbesartan is, therefore, employed in the treatment of cardiovascular complaints, such as hypertension and heart failure. US Patent 5,270,317 discloses certain N-substituted heterocyclic derivatives, including 2n-butyl-4-spirocyclopentane-1 -[(2'-(tetrazol-5yl)biphenyl-4-yl)methyl]-2-imidazolin-5 one, and methods of making and using the same. WO 2006/046043 PCT/GB2005/004151 US Patent 5,629,331 discloses two polymorphic forms, Form A and Form B, of 2n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5yl)biphenyl-4-yl)methyl]-2-imidazolin-5 one, a process for the preparation thereof and uses of the same for the treatment of hypertension. WO 99/67236 discloses a new crystalline habit of Form A of 2n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5yl)biphenyl-4-yl)methyl3-2-imidazolin-5 one, a process for the preparation thereof and composition containing the same. WO 03/050110Ai discloses preparation of amorphous 2n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5yl)biphenyl-4-yl)methyl]-2-imidazolin-5 one from Form A and Form B. WO 04/007482A2 discloses a two phase preparation of irbesartan using a phase transfer catalyst at me trityl irbesartan stage. WO 04/072064A1 discloses a number of processes for preparing irb-Tr, including reaction of the following starting materials in the presence of a phase transfer catalyst, an inorganic base and a solvent. N=N Rs.N-CPh, The WO2004/072064 process involves isolation of irb-Tr (by separation, column chromatography and, optionally, distillation), before conversion to irbesartan. There is, however, a need for an improved process for the preparation of irbesartan for the following reasons. The synthesis of irbesartan as discussed in US Patent 5,270,317, US Patent 5,559,233 and EP 045451 IB involves a pre-penultimate reaction step (excluding workup and purification) WO 2006/046043 PCT/GB2005/004151 which comprises reaction of a cyano group on the biphenyl ring with an azide, for example, tributyl tin azide. Reaction times as long as 210 hours are required, see line 5, column 20 of US Patent 5,270,317 and it is recognized in the art that there are safety risks associated with the use of azides. US Patent 5,629,331 also discloses the reaction of an azide with a cyano group as above, the process being carried out in the presence of a dipolar aprotic solvent, for example, methyl pyrrolidone, which is relatively high boiling and can be difficult to remove. US Patent 5,629,331 acknowledges safety risks involved in use of azides at high temperature (see column 4, line 39). WO Patent 04/007482A2 discloses the preparation of irbesartan using trityl irbesartan in a two phase reaction. Trityl irbesartan is first prepared, isolated in residue form and then detritylated in an acetone - HC1 mixture, further basified, filtered with tritanol and reacidified to isolate irbesartan. The isolation of crude irbesartan involves basification, reacidification, toluene distillation and isolation, making the process tedious and unsuitable for use on an industrial scale. Furthermore, formulation of irbesartan prepared by the above-described prior art processes has required much care because the resulting irbesartan powder tends to stick to the walls of equipment, for example, to the sides of the punches or to the mixer walls, due to its high electrostaticity. There is, therefore, a need for an improved process for the preparation of irbesartan, in particular a process that can provide irbesartan which is non-static, has free flowing properties, shorter reaction time and workup operations, and involves a simplified finishing operation which will enhance productivity and better intrinsic dissolution. This is now essentially achieved by a one-pot process according to the present invention, which results in irbesartan hydrochloride which has excellent flow properties. According to the present invention, therefore, there is provided a one-pot process for the preparation of irbesartan hydrochloride of formula (I) WO 2006/046043 PCT/GB2005/004151 5 ^^ HC1 CD which one-pot process comprises reacting intermediate compounds 2n-butyl-l,3-diazaspiro [4,4] non-l-en-4-one of formula (IT), optionally in salt form, preferably hydrochloride, and 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl l-lH-tetrazole of formula (III) (II) where Hal represents bromo, chloro, fluoro or iodo, preferably bromo. Intermediate compounds of formulae (II) and (III) are known in the art. Reaction of intermediate compounds of formulae (II) and (III) results in formation of intermediate compound 2n-butyl-3-[2'(triphenyl methyl tetrazol-5yl)-biphenyl-4-yl-methyl]-' 1,3-diazaspiro [4,4] non-l-en-4-one of formula (IV) shown below, optionally in salt form, preferably hydrochloride, which is subsequently detritylated to yield irbesartan hydrochloride of formula (I) WO 2006/046043 PCT/GB2005/004151 6 A one-pot process for the preparation of irbesartan hydrochloride according to the present invention can thus be represented by the following reaction scheme WO 2006/046043 PCT/GB2005/004151 xrl where Hal represents bromo, chloro, fluoro or iodo, preferably bromo, and each of intermediate compounds (II) and (IV) can optionally be present in salt form, preferably the hydrochloride. WO 2006/046043 PCT/GB2005/004151 A one-pot process according to the present invention can provide irbesartan hydrochloride in crystalline hydrated or anhydrous form, or in amorphous form, with high purity and yield, and which is free flowing, non-sticky and non-electrostatic. Preferably a one-pot process according to the present invention provides irbesartan hydrochloride as the sesquihydrate, hemihydrate, anhydrous or amorphous form, and also the process can be used for preparation of irbesartan free base either as Form A or Form B. Typically an intermediate compound of formula (II) is employed in salt form, preferably the hydrochloride. A one-pot process according to the present invention is preferably carried out in the presence of a phase transfer catalyst in a reaction system optionally comprising first and second phases, and also in the presence of an inorganic base. Detritylation is preferably achieved by using a mineral acid. Use of phase transfer catalysts for a similar type of reaction has previously been described for preparation of angiotensin II receptor antagonist losartan. Phase transfer catalysts are of particular utility when at least first and second reactants have such different solubility characteristics that there is no practical common solvent 'therefor and accordingly combining a solvent for one with a solvent for the other results in a two phase system. Several classes of compounds are known to be capable of acting as phase transfer catalysts, for example, quaternary ammonium compounds, quaternary phosphonium compounds, crown ethers or the like. A process according to the present invention preferably employs an aromatic or aliphatic hydrocarbon as a solvent of the one-pot reaction system, with a preferred solvent being an aromatic hydrocarbon, such as benzene, toluene, o-xylene, m-xylene, or the like. Toluene is a particularly preferred such aromatic hydrocarbon for use in accordance with the present invention. Aliphatic ketones, such as acetone and MIBK, may also be used as the solvent of the reaction system. Other hydrocarbons useful in the practice of the present invention will be apparent to the skilled artisan. WO 2006/046043 PCT/GB2005/004151 The solvent employed in a one-pot reaction system in a process according to the present invention can consist essentially of a hydrocarbon solvent substantially as described above. Alternatively, it may be preferred that the reaction system comprises first and second solvent phases. Suitably, the first solvent phase comprises a hydrocarbon solvent substantially as described above, and the solvent of the second solvent phase is substantially immiscible therewith. Typically, the solvent of the second solvent phase comprises water, which can be used alone, or more preferably an inorganic base can be combined therewith. An inorganic base used in a reaction system according to the present invention can be selected from the group consisting of hydroxides, carbonates or alkoxides of alkali metals, such as for example KOH, NaOH, LiOH, K2CO3, Na2C03, CS2CO3, sodium methoxide, sodium t-butoxide, potassium t-butoxide and the like. An inorganic base for use in accordance with the present invention can be combined with water as the solvent of the second phase of the reaction system as described above or can be used as such in powdered form. The preferred base for use in a one-pot reaction according to the present invention is NaOH, potassium-t-butoxide or sodium-t-butoxide. A synthetic one-pot process as provided by the present invention preferably involves the preparation of 2n-butyl-3-[2'(triphenyl methyl tetrazol-5yl)-biphenyl-4-yl-methyl]-l,3-diazaspiro [4,4] non-l-en-4-one hydrochloride of formula (IV) as shown above by the reaction of 5-(4'-bromomethyl biphenyl-2-yl)-l-tri1yl-lH-tetrazole of formula (III) and 2n-butyl-l,3-diazaspiro [4,4]-nori-l-en-4-one of formula (II) as the HC1 in presence of a base, with a phase transfer catalyst, in the presence of a hydrocarbon solvent, preferably toluene, optionally in presence of water as a second phase of the one-pot reaction system. The condensation of intermediate compounds of formulae (II) and (EI) is preferably carried out at a temperature from about 20°C to about 95°C, preferably at about 85°C. The reaction is allowed to proceed for a time that the skilled artisan will know to adjust according to the reaction temperature. For example, when the reaction temperature is about 90°C, a reaction time of between about 1 and 2 hours is usually sufficient. The reaction can be easily monitored using Thin Layer Chromatography. After reaction completion, the reaction is cooled to about 25°C and the aqueous layer, if present, is separated, the reaction mass is washed with water and the layers are separated. A suitable acid, such as HC1 (4N) is added to WO 2006/046043 PCT/GB2005/004151 the reaction mass and stirred at about 55°C for 40 minutes to 1 hour. The reaction can again be easily monitored by Thin Layer Chromatography and after reaction completion, the product can be filtered. Upon filtration, the product is washed with water and dried to yield irbesartan hydrochloride m hydrated form. Optionally, the irbesartan hydrochloride according to the present invention can be purified further by dissolving in a solvent, such as methanol, at elevated temperatures and precipitated with a non-solvent, such as ethyl acetate. Irbesartan hydrochloride according to the present invention may also be purified by suspending in a solvent, such as ethyl acetate, isopropyl acetate or ethyl acetate-methanol mixture, at elevated temperatures and filtering the suspension at room temperature. The water of hydration is retained by the irbesartan hydrochloride in the above described processes of purification. A process according, to the present invention may further optionally comprise converting irbesartan hydrochloride prepared thereby to irbesartan free base, either Form A or Form B. Suitably the process can thus further comprise addition of a base, such as aqueous ammonia, to adjust the pH to about 6 to 7, followed by isolation of irbesartan free base either as Form A or Form B, The present invention further provides irbesartan free base, either Form A or Form B, prepared from a process as described herein. In a one-pot process according to the present invention, isolation of trityl irbesartan is avoided and tedious work-up procedures such as distillation, basifying the reaction mass, and acidifying, as mentioned in Patent WO 04/007482, are not involved. In accordance with an especially advantageous embodiment of the invention, the two steps of coupling and hydrolysis are done using the same solvent and as such there is no replacing of one solvent with another. The above feature of the present invention eliminates the tedious process of distillation and thus avoids formation of impurities that are a feature of prior art processes. In another embodiment of the present invention, tritanol, which is a by-product of the reaction, is dissolved in toluene after detritylation and hence irbesartan can be directly filtered in a pure hydrochloride form. The present invention thus avoids filtration of tritanol and the whole process is completed in a single pot, without the need to isolate trityl irbesartan. WO 2006/046043 PCT/GB2005/004151 11 Thus, advantageously, the step of forming the trityl irbesartan and the steps of converting the trityl irbesartan to irbesartan is carried out in the same solvent or solvents. Advantageously, the step of converting the irbesartan to irbesartan hydrochloride is carried out in the same solvent or, solvents as the earlier step(s). Moreover, in this one-pot reaction the total time required to isolate irbesartan is about 8-10 hours, compared to the prior art processes that require a much longer time thus leading to a huge gain in productivity in accordance with the present invention. Hydrated irbesartan hydrochloride or anhydrous irbesartan hydrochloride obtained by the present invention is free flowing, less electrostatic, non-sticky, non-hygroscopic, has better intrinsic dissolution and is obtained in increased yield and purity. According to the present invention, there is further provided crystalline hydrated and anhydrous irbesartan hydrochloride, which is substantially non-hygroscopic and has good flow characteristics as referred to above. There is further provided by the present invention crystalline irbesartan hydrochloride in hydrated form or anhydrous form as prepared by a process according to the present invention. Hydrates of irbesartan hydrochloride according to the present invention have a moisture content ranging from 1% to about 10% by weight and the anhydrous form of irbesartan hydrochloride has a moisture content ranging from 0.1 to 1.0% by weight. The present invention further provides irbesartan hydrochloride in amorphous form. Specifically, therefore, the present invention discloses the amorphous, anhydrous, hemihydrate and sesquihydrate forms of irbesartan hydrochloride. There is provided by the present invention, therefore, crystalline irbesartan hydrochloride sesquihydrate having an TR pattern, or substantially the same IR pattern, as shown in Figure 2. More particularly, irbesartan hydrochloride sesquihydrate has characteristic IR absorbance at about 3638, 3273, 2451, 1761, 1639, 1514, 1477, 1323 and 1302 cm"1. Crystalline irbesartan hydrochloride sesquihydrate according to the present invention is further characterised by having a water content from about 5.7% to 7.5%. WO 2006/046043 PCT/GB2005/004151 Crystalline irbesartan hydrochloride sesquihydiate according to the present invention is further characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 1. Crystalline irbesartan hydrochloride sesquihydrate according to the present invention is further characterised as having characteristic peaks (29): 7.49, 8.24, 11.01, 14.92, 15.32, 16.28, 17.38, 22.52, 22.98, 23.42, 24.68, 26.57, 27.00 and 28.47°. Further characterising data for crystalline irbesartan hydrochloride sesquihydrate according to the present invention as obtained by X^-ray diffraction is shown in following table 1. Table 1 Peak No. 26 (deg) d (A)- I/II FWHM (deg) Ltitensity (Counts) Integrated (Counts) 1 7.0000 12.61783 9 0.30340 119 2189 2 7.4856 11.80035 20 0.34170 280 5101 3 8.2450 10.71511 52 0.33340 722 13970 4 11.0069 8.03185 61 0.34710 846 17285 5 12.8800 6.86770 38 0.36720 519 8115■ 6 13.0800 6.76314 36 0.49080 499 8702 7 13.6800 6.46783 6 0.18460 79 871 8 13.9759 6.33155 29 0.33600 406 6511 9 14.9200 5.93296 65 . 0.44780 900 19460 10 15.3200 5.77894. 67 0.32920 932 15317 11 16.2802 . 5.44020 . 33 0.35440 460 8936 12 17.3802 5.09829 50 0.34860 696 11627 13 17.8000 4.97898 21 0.36500 296 5445 14 18.2883 4.84713 11 0.28330 152 2161 15 19.0548* 4.65384 15 0.28560 206 2893 16 20.0911 4.41607 24 0.33310 332 6756 WO 2006/046043 PCT/GB2005/004151 17 20.5400 4.32056 12 0.00000 160 0 18 21.0682 4.21342 40 0.35940 546 11154 19 21.5400 4.12218 10 0.40500 139 3220 20 22.0800 4.02258 21 0.17640 286 3200 21 22.5200 3.94497 79 0.40400 1096 30030 22 22.9800 3.86703 57 0.00000 788 0 23 - 23.4200 3.79536 100 0.65620 1381 42435 24 24.0200 3.70190 9 0.20720 128 2678 25 24.6797 3.60442 24 0.34520 325 6592 26 25.9000 3.43729 11 0.33600 • 156 3086 27. 26.5731 3.35173 50 0.44340 691 13760 28 27.0000 3.29970 29 0.41340 405 7929 29 27.5207 3.23844 15 0.33860 208 3561 30 28.0000 3.18409 5 0.32000 74 1574 31 28.4714 3.13243 35 0.35110 478 7632 32 28.9200 3.08485 15 0.52800 207 4757 33 29.4168 3.03387 17 0.36820 230 3931 34 30.1680 2.96002 9 0.51600 119 3108 35 30.8863 2.89280 11 0,36160 156 2887 36 32.1204 2.78441 28 0.57740 389 12206 • 37 33.4207 2.67899 12 0.38320 163 3701 38 35.0527 2.55791 15 0.45740 205 5737 - 39 36.9991 2.42769 6 0.27170 79 1083 There is further provided by the present invention, therefore, crystalline irbesartan hydrochloride hemihydrate having an IR pattern, or substantially the same IR pattern, as . shown in Figure 4. More particularly, irbesartan hydrochloride hemihydrate has characteristic IR absorbance at about 1772, 1627, 1519, 1476, 1226, 1070, 998, 959, 940, 708 and 645 cm"1. WO 2006/046043 PCT/GB2005/004151 Crystalline irbesartan hydrochloride hemihydrate according to the present invention is further characterised by having a water content from about 1.7% to 2.8%, and suitably a melting point of about 186°C. Crystalline irbesartan hydrochloride hemihydrate according to the present invention is further characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 3. Crystalline irbesartan hydrochloride hemihydrate according to the present invention is further characterised as having characteristic peaks (20): 8.2, 10.33,11.02, 12.42, 12.87, 15.32,15.76,16.25,17.46, 22.42, 22.98, 23.3,24.81, 25.75,26.53 and 27.06°. Further characterising data for crystalline irbesartan hemihydrate according to the present invention as obtained by X-ray diffraction is shown in following table 2. Table 2 Peak No. 29 (deg). d (A) I/II FWHM (deg) Intensity (Counts) Integrated (Counts) 1. 8.2060 10.76595 23 0.24610 348 4678 2 9.2000 9.60487 6 0.62760 86 2901 3 9.5800 9.22472 6 0.00000 93 0 4 10.3309 8.55584 • 51 0.44560 763 19058 5 11.0174 8.02422 27 0.23210 401 4923 6 11.6076 7.61751 32 0.24750 481 6343 \ 7 12.4194 7.12135 57 0.31450 850 14204 8 12.8665 6.8748'8 57 0.33300 849 13723 9 13.2200 6.69183 12 0.14580 186 2503 10 13.9662 6.33592 7 0.23240 112 1398 11 ' 14.9000 5.94088 19 0.41400 286 5925 12' 15.3238 5.77752 31 0.29240 467 6546 13 15.7624 ' 5.61773 30 0.28160 447 6613 WO 2006/046043 PCT/GB2005/004151 14 16.2552 5.44851 32 0.30500 482 7766 15 17.4652 5.07366 73 0.34960 1097 21929 .16 18.2600 4.85458 13 0.27160 194 3791 17 18.8000 4.71634 11 0.29100 164 2347 18 19.0600 4.65258 8 0.23460 126 1489 19 20.0200 4.43159 15 0.14620 219 2671 20 20.4206 4.34555 76 0.28510 1134 17600 21 21.0003 4.22689 12 . 0,24470 185 2766 22 21.5800 4.11463 6 0.14480 88 1019 23 21.8800 4.05889 32 0.23000 473 10189 24 22.1400 4.01181 43 0.00000 638 0 25 22.4200 3.96234 74 0.46460 1107 28888 26 22.9800 3.86703 35 0.00000 531 0 27 23.2962 3.81525 100 0.30100 1498 26406 28 23.8200 3.73253 20 0.20920 301 5578 29 24.3600 3.65099 6 0.13140 94 847 30 24.8143 3.58517 33 0.45850 501 12503 31 25.2400 3.52566 9 0.00000 136 0 32 25.7510 3.45684 34 0.38890 503 10874 33 26.5309 3.35697 17 0.25470 259 3517 34 27.0573 3.29284 18 0.25690 275 4108 35 28.5000 3.12935 11 0.24000 166 2819 36 28.8600 3.09113 22 0.43560 334 4972 37 29.1200 3.06412 17 0.26460 251 2907 38 29.4800 3.02751 5 0.16220 78 929 39 29.9653 2.97958 6 0.24530 87 1111 There is further provided by the present invention crystalline anhydrous irbesartan hydrochloride having an IR pattern, or substantially the same IR pattern, as shown in Figure 6. More particularly, anhydrous irbesartan hydrochloride has characteristic IR absorbance at about 3400, 2958, 1628,1515, 1475, and 846 cm"1. WO 2006/046043 PCT/GB2005/004151 Crystalline anhydrous irbesartan according to the present invention is further characterised by having a water content from about 0.2 to 0.9%. Crystalline anhydrous irbesartan hydrochloride according to the present invention is further characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 5. Crystalline anhydrous irbesartan hydrochloride according to the present invention is further characterised as having characteristic peaks (29): 8.0, 8.35, 8.70, 9.48, 10.05, 11.76, 15.00,15.48, 16.38, 16.79, 17.47,20.26,21.12,23.54,25.14,26.44, 26.78, 28.12, and 32.45°. Further characterising data for crystalline anhydrous irbesartan hydrochloride according to the present invention as obtained by X-ray diffraction is shown in following table 3. Table 3 Peak No. 26-(deg) d (A) I/II FWHM (deg) Intensity (Counts) Integrated (Counts) 1 8.0000 11.04270 12 0.18660 192 3184 2 8.3519 10.57820 100 0.27240 1614 21537 3 8.7000 10.15572 39 0.26320 630 10111 4 9.1000 9.71019 8 0.00000 134 0 5 9.4800 9.332180 15 0.00000 246 0 6 10.0523 8.79234 79 0.29900 1270 23649 7 11.7572 7.52092 ' ' 45 0.26360 719 10737 8 13.2750 6.66423 7 0.39000 118 3856 9 15.0000 5.90150 28 0.33340 446 8600 10 15.4862 5.71729 44 0.33170 710 12135 11 16.3854 5.40551 81 0.31500 1306 21489 12 16.7950 5.27459 57 0.26290 921 12247 13 17.4706 5.07211 62 0.36070 1006 19518 WO 2006/046043 PCT/GB2005/004151 14 18.2997 4.84413 21 0.28850 333 5096 15 19.0343 4.65881 13 0.28680 203 3007 16 19.7200 4.49833 5 0.25600 81 1377 17 20.2626 4.37908 51 0.27480 827 11941 18 21.1227 4.20267 41 0.47520 664 16494 19 21.7009 4.09198 36 0.30140 574 8490 20 22.3465 3.97520 6 0.22450 97 1101 2.1 23.2200 3.82760 43 0.32700 690 11466 22 23.5400 3.77629 67 0.36460 1083 17624 23 24.1758 3.67839 7 0.23170 109 1362 24 25.1400 3.53946 29 0.33900 464 7612 25 25.5200 3.48761 34 0.38540 553 10609 26 26.1200 3.40884 16 0.24940 256 3524 27 26.4400 .3.36830 45 0.40880 719 10846 28 26.7800 3.32631 42 0.39220 675 10378 29 27.1400 3.28300 22 0.27200 354 4680 30 28.1193 3.17085 34 0.35870 553 9910 31 28.5400 3.12506 9 0.29600 153 2817 32 29.0200 3.07445 18 0.26400 285 3927 33 . 29.3600 3.03961 17 0.24820 275 3768 34 30.0492 2.97145 7 0.27350 120 1817 35 30.9800 2.88426 9 0.28660 148 2179 36 31.3038 2.85516 16 0.38770 265 5328 37 • 32.1800 2.77939 6 0.19120 96 1267 38 32.4548 2.75648 20 0.30330 320 5504 39 32.8600 2.72341 9 0.00000 144 0 The present invention further provides amorphous irbesartan hydrochloride. Amorphous irbesartan hydrochloride as provided by the present invention can be characterised by an IR pattern, or substantially the same DR. pattern, as shown in Figure 8. More particularly, amorphous irbesartan hydrochloride has characteristic IR absorbance at about 3402, 1773, WO 2006/046043 PCT/GB2005/004151 1625, 666 and 624 cm"1: Amorphous irbesartan hydrochloride according to the present invention is further characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 7. Irbesartan hydrochloride, preferably irbesartan hydrochloride sesquihydrate according to the present invention, can be isolated directly from the final reaction mixture obtained as described above with reference to a process according to the present invention. More specifically, it is preferred that irbesartan hydrochloride, as the sesquihydrate, can be isolated directly from the final reaction mixture obtained further to detritylation of a compound of formula (IV). Irbesartan hydrochloride hemihydrate according to the present invention can be prepared by drying the sesquihydrate at higher temperatures, or by dissolving the sesquihydrate in a solvent, such as methanol, at elevated temperatures and concentrating to a residue and subsequent precipitating with a non-solvent, such as ethyl acetate. Alternatively, the hemihydrate may be prepared from amorphous irbesartan free base (known in the art, for example WO 03/050110) by dissolving the amorphous form in a solvent mixture of methanol and water at elevated temperatures and concentrating to a residue and subsequent precipitation with a non-solvent, such as ethyl acetate. Anhydrous irbesartan hydrochloride according to the present invention can be prepared by repeatedly stirring the sesquihydrate in a solvent, such as methanol, or a methanol-ethylacetate mixture at elevated temperatures and subsequently precipitating with a non-solvent, such as ethyl acetate. Alternatively, the anhydrous form may be prepared from irbesartan in sesquihydrate. form or hemihydrate form, by drying the product at elevated temperature (80-85°C). Amorphous irbesartan hydrochloride may be prepared from irbesartan in sesquihydrate form, hemihydrate form or anhydrous form by drying the product at elevated temperature (90-105°C). WO 2006/046043 PCT/GB2005/004151 Irbesartan as provided by the present invention is an angiotensin II antagonist and is thus useful in the treatment of various cardiovascular complaints, especially hypertension, heart failure and venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy and various complaints of the central nervous system, for example anxiety, depression, memory deficiencies or Alzheimer's disease. The present invention further provides, therefore, a pharmaceutical composition comprising a therapeutically effective dose of irbesartan according to the invention, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, irbesartan according to the present invention is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, irbesartan according to the present invention can be used in creams, ointments or lotions. To achieve the desired prophylactic or therapeutic effect, the dose of irbesartan according to the present invention can vary between 0.01 and 50 mg per kg of body weight per day. Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of irbesartan according to the present invention in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg. When a solid composition in the form of tablets is prepared, irbesartan according to the present invention is mixed with a pharmaceutical, vehicle such as gelatin, starch, lactose, WO 2006/046043 PCT/GB2005/004151 magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously. A preparation in the form of gelatin capsules can be obtained by mixing irbesartan according to the present invention with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. A preparation in the form of a syrup or elixir or for administration in the form of drops can contain irbesartan according to the present invention in conjunction with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring and an appropriate color. Water-dispersible granules or powders can contain irbesartan according to the present invention mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors. Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols. Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol. Irbesartan according to the present invention can also be formulated as microcapsules, with one or more carriers or additives if appropriate. There is. also provided by the present invention irbesartan substantially as hereinbefore described for use in therapy. WO 2006/046043 PCT/GB2005/004151 The present invention further provides irbesartan substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II antagonist as described herein. The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of irbesartan substantially as hereinbefore described. The present invention can be further illustrated by the following Figures and non-limiting Examples. With reference to the Figures, these are as follows: Fig 1: An XRPD of irbesartan hydrochloride sesquihydrate according to the present invention obtained by using a Rigaku Miniflex between 2° to 40°. Fig 2: An IR pattern of irbesartan hydrochloride sesquihydrate obtained by using a Parkin Elmer Paragon 500 Model. Fig 3: An XRPD of irbesartan hydrochloride hemihydrate obtained by using a Rigaku Miniflex between 2° to 40°. Fig 4: An IR pattern of irbesartan hydrochloride hemihydrate obtained by using Parkin Elmer Paragon 500 Model. Fig 5: An XRPD of anhydrous irbesartan hydrochloride according to the present invention obtained by using a Rigaku Miniflex between 2° to 40°. Fig 6: An IR pattern of anhydrous irbesartan hydrochloride obtained by using a Parkin Elmer Paragon 500 Model. WO 2006/046043 PCT/GB2005/004151 Fig 7: An XRPD of amorphous irbesartan hydrochloride according to the present invention obtained by using a Rigaku Miniflex between 2° to 40°. Fig 8: An IR pattern of amorphous irbesartan hydrochloride obtained by using a Parkin Elmer Paragon 500 Model. EXAMPLES Example 1 32.8g of powdered sodium hydroxide was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH4etrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HC1 (50g) in toluene (500ml) in the presence of tetra butyl ammonium bromide (4.3g). The mixture was heated to about 85°C for about 2 hours. Alter reaction completion, the reaction mass was cooled to about 25°C, washed with purified water (200ml x 2). The toluene layer was separated. To this 4N HC1 was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 -30°C. The wet cake was dried at about 60°C under vacuum to obtain 87.5g (94%) of the product characterised as irbesartan hydrochloride sesquihydrate by moisture content and powder x-ray diffraction. Example 2 32.8g of sodium hydroxide was dissolved in 480ml of purified water and added to the mixture of 5-(4'-bromomethyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro-(4,4)-non-l-en-4-one HC1 (50g) in toluene (500ml) in the presence of tetra butyl ammonium bromide (4.3g).. The mixture was heated to about 85°C for about 2 hours. After reaction completion, the reaction mass was cooled to about 25°C and the toluene layer separated. The toluene layer was washed with water (200ml x 2). The toluene layer was again separated. To this 4N HC1 was added (600ml). The contents were then heated to about 55° C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30° C. The wet cake was dried at about 60°C under vacuum to obtain 84.5g (91%) of WO 2006/046043 PCT/GB2005/004151 23 the product characterised as irbesartan hydrochloride sesquihydrate by moisture content and powder x-ray diffraction. Example 3 32.8g of powdered sodium hydroxide was added to the mixture of 5-(4'-bromomethyl biphenyl-2-yl)-l-trityl -IH-tetrazole (119g) and 2n-butyl-l, 3-diazaspiro (4,4)-non-l-en-4 one HC1 (50g) in toluene (500ml). The mixture was heated to about 85°C for about 2 to 4 hours. After reaction completion, the reaction mass was cooled to about 25°C, washed with purified water (200ml x 2). The toluene layer was separated and 4N HC1 was added (600ml). The contents were heated to about 55°C for about 75 minutes. After reaction completion, the product was isolated by filtration at about 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 60.5g (65%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 4 42.6g of powdered potassium hydroxide was added to the mixture of 5-(4Vbromomethyl biphenyl-2-yl)-l-trityl-IH-tetrazole (119 g) and 2n-butyl-l,3-diazaspiro (4,4)-non-l-en-4-one HC1 (50g) in toluene (500ml). The mixture was heated to about 85°C for about 2 hours.- After reaction completion, the reaction mass was cooled to about 25°C, washed with purified water (200 ml x 2). The toluene layer was separated. To this, 4N HC1 was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C and dried under vacuum at 80°C to give 62.5g (69%) of irbesartan hydrochloride hemihydrate. Example 5 32.8g of sodium hydroxide dissolved in 480ml of purified water was added to the mixture of 5-(4'-bromomethyl biphenyl-2-yl)-1 -trityl-IH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HC1 (50g) and terra butyl ammonium bromide (4.3g) in toluene (500ml). The mixture was heated to about 85°C for about 2 hours. After reaction WO 2006/046043 PCT/GB2005/004151 completion, the reaction mass was cooled to about,25°C and the toluene layer separated. The toluene layer was washed with water (200ml x 2). The toluene layer was again separated. To this, 4N HC1 was added (600ml). The contents were then heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 80°C under vacuum to obtain 85.5g (92%) of the product characterised as irbesartan hydrochloride hemihydrate. Example 5A Example 5 was repeated but with an added isolation step before the detritylation, so as to illustrate the difference between a one-pot process of the present invention (Example 5), and a non-one-pot process of the prior art (this Example). 16.4g of sodium hydroxide dissolved in 240ml of purified water was added to the mixture of 5-(4l-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole (59.5g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HC1 (25 g)" and terra butyl ammonium bromide (2.15g) in toluene (250ml). The mixture was heated to about 85°C for about 2 hours. After reaction completion, the reaction mass was cooled to about 25°C and the toluene layer separated. The aqueous phase was extracted with toluene (105ml). The combined organic layer was evaporated. The residue was dissolved in acetone (208ml) and 3N HC1 was added (600ml). The contents were stirred at room temperature until reaction completion (as monitored by TLC). After reaction completion, a solution of KOH (30.4 g) in water (208 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2 x 105 ml). The filtrate was washed with toluene and slowly acidified to pH 4 with 3 N HC1. The suspension was cooled to 0 - 4° C, stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2 x 50 ml) and dried under reduced pressure at 50 - 60° C to yield irbesartan free base (92.0%). Example 6 42.6g of potassium hydroxide was dissolved in 480ml of purified water which was added to a mixture of 5-(4'-bromo methyl biphenyl-2yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HC1 (50g) and. terra butyl ammonium bromide (4.3g) in toluene (500ml). The mixture was heated to about 85°C for about 2 hours. After reaction WO 2006/046043 PCT/GB2005/004151 completion, the reaction mass was cooled to about 25°C and the toluene layer separated. The toluene layer was washed with water (200 ml x 2). The toluene layer was again separated. To this 4N HCl was added (600ml). The contents were then heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by direct filtration at 25 -30°C. The wet cake was dried at about 60°C under vacuum to obtain 87.5g (94%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 7 About 32.8g of powdered sodium hydroxide was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HCl (50g) in xylene (500ml) in the presence of 18-Crown-6 (4.0g). The mixture was heated to about 85°C for about 2 to 4 hours. After reaction completion, the reaction mass was cooled to about 25°C, the xylene layer was washed with purified water (200ml x 2) and then separated. To this 4N HCl was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by direct filtration at 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 87.5g (94%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 8 42.6g of powdered potassium hydroxide was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HCl (50g) in xylene (500ml) along with tetra butyl ammonium bromide (4.3g). The mixture was heated to about 85°C for about 2 hours. After reaction completion, the reaction mass was cooled to about 25°C and the xylene layer was washed with water (200 ml x 2). The xylene layer was separated. To this 4N HCl was added (600ml). The contents were then heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 87.5g (94%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 9 WO 2006/046043 PCT/GB2005/004151 32.8g of potassium carbonate was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl) -1-trityl-lH-tetrazo.le (119g) and 2n-butyl-l,3-diazaspiro (4,4)non-l-en-4 one HCl (50g) in acetonitrile (500ml). The contents were heated to about 70°C to obtain a condensed product. The product was isolated upon filtration, with the product being in the filtrate. The filtrate was distilled under reduced pressure to a residue. To this mixture 4N HCl (400ml) and toluene (400ml) were added, heated to about 55°C, maintained for 1 hour and filtered at room temperature. The wet cake was dried at about 60°C under vacuum to obtain 80g (85%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 10 109.3g of potassium carbonate was added to the mixture of 5-(4'-bromo methyl biphenyi-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HCl (50g) and tetra butyl ammonium bromide (4.3g) in MIBK (500ml). The mixture was heated to about 85°C for about 2 hours. After reaction completion, the reaction mass was cooled to about 25°C, washed with purified water (200ml x 2). The MIBK layer was separated. To this 4N.HC1 was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 75g (80%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 11 109.3g of potassium carbonate dissolved in 480ml of purified water was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HCl (50g) in MTBK (500ml). The mixture was heated to about 85°C for about 2 hours. After reaction completion, the reaction mass was cooled to about 25 °C and the MIBK layer separated. The MOBK layer was washed with water (200ml x 2). The MIBK layer was again separated. To this, 4N HCl was added (600ml). The contents were then heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 80°C under vacuum to obtain 62.5g (69%) of the product characterised as irbesartan hydrochloride hemihydrate. WO 2006/046043 PCT/GB2005/004151 Example 12 109.3g of potassium carbonate was added to the mixture of 5-(4'-bromo methyl biphenyl -2yl)-l-trityl-lH tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4)non-l-en-4 one HCl (50g) in DMF (250ml). The contents were heated to about 85°C. The inorganics were filtered off. The filtrate was distilled under reduced pressure to residue. To this mixture aq. HCl' and toluene were added, heated to about 55°C and filtered at room temperature. The wet cake was dried at about 60°C under vacuum to obtain 80g (86%) of the product characterised as irbesartan hydrochloride sesquihydrate. Example 13 44.28g of sodium methoxide was added to a mixture of 5-(4'-bromomethyl biphenyl-2yl)-l-trityl-lH tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HCl in DMF (250ml). The contents were heated to about 85°C. The product was isolated upon filtration of inorganics, with the product being in the filtrate. The filtrate was distilled under reduced pressure to residue. To this a mixture of hydrochloric acid and toluene was added and heated to about 55°C for 1 hour and filtered at room temperature, dried under vacuum at 60°C to yield irbesartan hydrochloride sesquihydrate 80g (86%). Example 14 About 52.0g of sodium t-butoxide was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HCl (50g) in toluene (500ml) in the presence of tetra butyl ammonium bromide (4.3g). The mixture was stirred at about 25°C (20-30C) for about 4 hours. After reaction completion, the reaction mass was washed with purified water (200ml x 2). The toluene layer was separated. To this 4N HCl was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 80.5g (86%) of the product characterised as irbesartan hydrochloride sesquihydrate by moisture content and powder x-ray diffraction. .Example 15 WO 2006/046043 PCT/GB2005/004151 About 61.0g of potassium t-butoxide was added to the mixture of 5-(4'-bromo methyl biphenyl-2-yl)-l-trityl-lH-tetrazole (119g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HCl (50g) in toluene (500ml) in the presence of tetra butyl ammonium bromide (4.3g). The mixture was stirred at about 25°C (20-30°C) for about 4 hours. After reaction completion, the reaction mass was cooled to about 25 °C, washed with purified water (200ml x 2). The toluene layer was separated. To this 4N HCl was added (600ml). The contents were heated to about 55°C for about 45 minutes. After reaction completion, the product was isolated by filtration at 25 - 30°C. The wet cake was dried at about 60°C under vacuum to obtain 85.5g (91%) of the product characterised as irbesartan hydrochloride sesquihydrate by moisture content and powder x-ray diffraction. Example 16 83.0g of sodium methoxide powder was added to a mixture of 2n-butyl-l,3-diazaspiro (4,4)-non-lten-4-one hydrochloride (l00g), 5(4'-bromomethyl biphenyl-2yl)-l-trityl 1 H tetrazole (234g) and tetra butyl ammonium bromide (l0g) in Toluene (2.4L). The contents were heated to 80-90 C for 2 hours. After reaction completion, the reaction mass was cooled to 25 - 30°C, washed with water (1.0L x 3) to remove the excess alkalinity. Then to the toluene layer 4N HCl (1.2L) was added and the contents heated to about 50°C for about 2 hours. After reaction completion, the reaction mass was cooled to 25 - 30°C, product filtered and washed with water, dried under vacuum at 60°C to yield irbesartan hydrochloride sesquihydrate 140g (76%). Example 17 Trityl irbesartan (25g) was dissolved in 250ml of toluene and 4N HCl (125ml) was added and the contents heated to about 55°C and maintained for about 1 hour. After reaction completion, the reaction mass was cooled to about 25°C and filtered. The product was dried at about 60°C under vacuum to get 15g irbesartan hydrochloride sesquihydrate (95%). Example 18 100g of irbesartan hydrochloride obtained by any of the Examples 1 to 17 was dissolved in a mixture of ethyl acetate (350mi) and methanol (150ml). The mixture was distilled to 200ml. To this, 200ml of ethyl acetate was added to isolate pure irbesartan hydrochloride. The WO 2006/046043 PCT/GB2005/004151 ^product was dried at about 100°C under vacuum to get 94g of the amorphous irbesartan hydrochloride having purity by HPLC greater than 99.5%. Example 19 100g of irbesartan hydrochloride obtained by any of Examples 1 to 17 was stirred in a mixture of 360ml ethyl acetate, 40ml methanol and 25ml purified water at about 45°C, cooled to 25°C and filtered. The product was dried at about 60°C under vacuum to get 95g of irbesartan hydrochloride sesquihydrate having a purity by HPLC greater than 99.5%. Example 20 100g of irbesartan hydrochloride obtained by any of Examples 1 to 17 was stirred in a mixture of 360ml ethyl acetate and 40ml methanol at about 65°C, cooled to 25°C and filtered. The product was re-purified by repeating the same process and was dried at about 60°C under vacuum to get 96g of anhydrous irbesartan hydrochloride having a purity by HPLC greater than 99.5%. Example 21 100g of irbesartan hydrochloride obtained by any of Examples 1 to 17 was dissolved in methanol (250ml). The mixture was distilled to residue. To this, 200ml of ethyl acetate was added to isolate pure irbesartan hydrochloride. The product was dried at about 80°C under vacuum to get 94g of irbesartan hydrochloride hemihydrate having a purity by HPLC greater than 99.5%. Example 22 100g of irbesartan hydrochloride sesquihydrate was taken in a mixture of 250ml toluene and 250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia at 25-30°C and stirred for about 30 minutes and filtered. The product was dried at 60°C under vacuum to yield Form A of irbesartan free base. Example 23 100g of irbesartan hydrochloride hemihydrate was taken in a mixture of 250ml toluene and 250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia WO 2006/046043 PCT/GB2005/004151 at 25-30°C and stirred for about 30 minutes and filtered. The product was dried at 60°C under vacuum to yield Form A of irbesartan free base. Example 24 100g of anhydrous irbesartan hydrochloride was taken in a mixture of 250ml toluene and 250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia at 25-30°C and stirred for about 30 minutes and filtered. The product was dried at 60°C under vacuum to yield Form A of irbesartan free base. Example 25 100g of irbesartan free base (Form A) was taken in a mixture of 500ml toluene and 500ml 4N hydrochloric acid and heated to about 100°C for about 2 hours, cooled to 25-30°C and filtered. The product was dried at 60°C under vacuum to yield irbesartan hydrochloride sesquihydrate. Example 26 - Example 1 ofWO2004/007482 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole (24.6 g) was charged to toluene (240 ml). To this, a solution of KOH (10.4 g), 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HC1 (12.0 g) and BU4NHSO4 (1.8 g) in water (40 ml) was added. The two-phase mixture was men heated to 90° C for 90 minutes under vigorous stirring. The reaction mixture was cooled to room temperature. The toluene layer was separated and the aqueous phase was extracted with toluene (50 ml). The combined organic layer was evaporated. The residue was dissolved in acetone (100 ml) and 3N HC1 (52 ml) and stirred at room temperature (TLC monitoring). A solution of KOH (14.6 g) in water (100 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2 x 50 ml). The filtrate was washed with toluene and slowly acidified to pH 4.0 with 3 N HC1. The suspension was cooled to 0 - 4° C, stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2 x 25 ml) and dried under reduced pressure at 50 - 60° C to yield irbesartan free base (84%). HPLC Analysis WO 2006/046043 PCT/GB2005/004151 The products of Examples 5, 5A and 26 were analysed using HPLC. The parameters for the HPLC analysis were as follows: Injection volume: 20 microlitres Channel: UV_VIS_lRun time: 45 minutes Wavelength: 237 nm The results for the products of the three examples are as follows. Table 4 - HPLC of product of Example 5 process No. Peak Name Ret. Time Area Rel. Area nun mAU*min % 1 n.a. 5.47 53615.21 0.76 2 n.a. 8.97 7952.81 0.11 3 n.a. 10.78 5951.77 0.08 4 n.a. 17.47 15229.68 0.22 5 n.a. 18.01 110955.75 1.57 6 n.a. 18.84 5302.10 0.08 7 n.a. 19.10 7257.12 0.10 8 n.a. 19.84 8188.45 0.12 . 9 n.a. 20.16 6944.33 0.10 10 ISR-2 20.46 6717762.27 95.26 11 n.a. 21.52 5261.84 0.07 12 n.a. 24.67 10727.96 0.15 13 n.a. 27.26 5977.49 0.08 14 n.a. 34.64 66383.49 0.94 15 n.a. 35.62 24514.71 0.35 Table 5 - HPLC of product of Example 5A process No. Peak Name Ret. Time Area Rel. Area min mAU*mm % 1 n.a. 5.33 53246.31 1.04 2 n.a. 5.48 61723.88 1.21 3 n.a. 6.53 17947.74 0.35 4 n.a. 8.96 25037.14 0.49 5 n.a. 16.17 112660.36 2.21 6 n.a. 17.45 209546.25 4.11 7 n.a. 18.02 . 79076.72 1.55 WO 2006/046043 PCT/GB2005/004151 8 n.a. 18.87 108952.66 2.14 9 ISR-2 20.52 4286448.20 84.10 10 n.a. 21.52 38106.23 • 0.75 11 n.a. 24.67 65230.24 1,28 12 n.a. 27.26 30873.05 0.61 13 n.a. 36.06 8184.13 0.16 Table 6 - HPLC of product of Example 26 process No. Peak Name Ret. Time Area Rel. Area min mAU*min % 1 n.a. 5.34 44058.53 0.96 2 n.a. 5.48 46725.20 1.02 3 n.a. 6.52 8674.48 0.19 4 n.a. 8.96 11880.56 0.26 5 n.a. 16.16 121866.64 2.66 6 n.a. 17.45 192015.07 4.20 7 n.a. 18.01 59547.57 1.30 8 n.a. 18.87 52749.09 1.15 9 ISR-2 20.53 3988963.45 87.18 10 n.a. 24.66 8829.51 0.19 11 n.a. 26.56 8216.77 0.18 12 n.a. 27.26 5790.12 0.13 13 n.a. 34.64 26342.11 0.58 In summary, using identical HPLC conditions, irbesartan hydrochloride having a purity of 95.26% is produced according to the process of the present invention, irbesartan having a purity of. 87.18% is produced according to the WO2004/007482 process, and irbesartan having a purity of 84.10% is produced in a similar manner to the present invention, but with an added isolation step (i.e. a non-one-pot process). Thus, the process of the present invention represents a simple and highly effective method of producing irbesartan hydrochloride, and irbesartan free base, having a high yield and purity. It will be appreciated that the invention may be modified within the scope of the appended claims.. 33 CLAIMS 1. One-pot process for the preparation of irbesartan hydrochloride of formula (I) which one-pot process comprises reacting intermediate compounds 2n-butyl-l,3-diazaspiro [4,4] non-1-en-4-one of formula (II), optionally in salt form,, and 5-(4' -bromomethyl-biphenyl-2-yl)-1-trityl-lH-tetrazole of formula (III) CPh, (H) ^^ (III) where Hal represents bromo, chloro, fluoro or iodo, wherein reaction of intermediate compounds of formulae (II) and (III) results in formation of intermediate compound 2n-butyl-3-[2'(triphenyl methyl tetrazol-5yl)-biphenyl-4-yl-methyl]-l,3-diazaspiro [4.4] non-l-en-4-one (trityl irbesartan) of formula (IV), optionally in salt form, which is subsequently 34 detritylated, and, if necessary, converted to the hydrochloride salt, to yield irbesartan hydrochloride of formula (I) wherein the trityl irbesartan (IV) is not isolated before detritylation. 2. A process according to claim 1, wherein Hal represents bromo. 3. A process according to claim 1 or 2, wherein an intermediate compound of formula (II) is employed in salt form. 4. A process according to claim 3, wherein said intermediate compound of formula (II) is employed as the hydrochloride. 5. A process according to any of claims 1 to 4, wherein condensation of intermediate compounds of formulae (II) and (III) is carried out at a temperature from about 20°C to about 95°C. 6. A process according to claim 5, wherein condensation of intermediate compounds of formulae (II) and (III) is carried out at a temperature of about 85°C. 7. A process for the preparation of irbesartan hydrochloride of formula (I) 35 HCl (i) comprising forming an intermediate compound 2n-butyl-3-[2'(triphenyl methyl tetrazol-5yl)-biphenyl-4-yl-methyl]-l,3-diazaspiro [4,4] non-l-en-4-one (trityl irbesartan) of formula (IV), optionally in salt form, which is subsequently detritylated, and, if necessary, converted to the hydrochloride salt, to yield irbesartan hydrochloride of formula (I), wherein the trityl irbesartan (IV) is not isolated before detritylation. 8. A process according to any of claims I to 7, which yields irbesartan hydrochloride in one of the following forms: sesquihydrate, hemihydrate, anhydrous or amorphous. 36 A process according to any of claims 1 to 8, which is carried out in the presence of a phase transfer catalyst. 10. A process according to claim 9, wherein said phase transfer catalyst is selected from the group consisting of quaternary ammonium compounds, quaternary phosphonium compounds and crown ethers. 11. A process according to any of claims 1 to 10, which comprises an aromatic or aliphatic hydrocarbon as a solvent of the reaction system. 12. A process according to claim 11, wherein said solvent is an aromatic hydrocarbon. 13. A process according to claim 12, wherein said solvent is selected from the group consisting of benzene, toluene, o-xylene and m-xylene. 14. A process according to claim 13, wherein said solvent is toluene. 15. A process according to claim 11, wherein said solvent is an aliphatic hydrocarbon. 16. A process according to claim 15, wherein said solvent is acetone or MIBK. 17. A process according to any of claims 1 to 16, wherein said reaction system comprises first and second solvent phases. 18. A process according to claim 17, wherein said first solvent phase comprises a hydrocarbon solvent as defined in any of claims 11 to 16, and said solvent of said second solvent phase is substantially immiscible therewith. 19. A process according to claim 18, wherein said solvent of said second solvent phase comprises water. 20. A process according to any of claims 1 to 19, wherein an inorganic base is present in the reaction system. 21. A process according to claim 20, wherein said inorganic base is selected from the group consisting of hydroxides, carbonates and alkoxides of alkali metals. 22. A process according to claim 21, wherein said inorganic base is selected from the group consisting of KOH, NaOH, LiOH, K2CO3, Na2C03, Cs2C03, sodium methoxide, sodium t-butoxide and potassium t-butoxide. 23. A process according to claim 22, wherein said base is NaOH, sodium t-butoxide or potassium t-butoxide. 24. A process according to any of claims 20 to 23, wherein said base is employed in powder form. 25. A process according to any of claims 20 to 23, wherein said base is combined with the solvent of the second solvent phase of the reaction system as defined in any of claims 21 to 23. 26. A process according to claim 25, wherein said base is combined with water as the solvent of the second solvent phase of the reaction system as defined in claim 23. 27. A process according to any preceding claim, wherein detritylation is achieved by using a mineral acid. 28. A process according to any of claims 1 to 27, which comprises directly isolating irbesartan hydrochloride from a reaction mixture obtained further to a process as defined in any of claims 1 to 27. 38 29. A process according to any of claims. 1 to 27, wherein irbesartan hydrochloride prepared thereby is further purified by dissolving in a solvent at elevated temperature and precipitated with a non-solvent. 30. A process according to claim 29, wherein said solvent is methanol. 31. A process according to claim 29 or 30, wherein said non-solvent is ethyl acetate. 32. A process according to any of claims 1 to 27, wherein irbesartan hydrochloride prepared thereby is further purified by suspending in a solvent at elevated temperature and filtering the suspension at room temperature. 33. A process according to claim 32, wherein said solvent is ethyl acetate or isopropyl acetate. 34. A process according to any of claims 1 to 27, wherein the irbesartan hydrochloride is in the sesquihydrate form, and the sesquihydrate is subsequently repeatedly stirred in a solvent at elevated temperature and precipitated with a non-solvent to yield the anhydrous form of irbesartan hydrochloride. 35. A process according to claim 34, wherein the solvent is methanol or a methanol-ethylacetate mixture. 36. A process according to claim 34 or 35, wherein the non-solvent is ethyl acetate. 37. A process according to any of claims 1 to 33, further comprising drying the hydrated product at elevated temperature to yield the anhydrous form of irbesartan hydrochloride. 38. A process according to claim 37, wherein the elevated temperature is from 80 to 85°C. 39 39. A process according to any preceding claim, further comprising drying the irbesartan hydrochloride product at elevated temperature to yield amorphous irbesartan hydrochloride. 40. A process according to claim 39, wherein the elevated temperature is from 90 to 105°C. 41. A process according to any of claims 1 to 40, which further comprises converting irbesartan hydrochloride prepared thereby to irbesartan free base. 42. A process according to claim 38, which comprises addition of a base. 43. A process according to claim 39, wherein said base comprises aqueous ammonia. 44. Irbesartan hydrochloride directly isolated from a reaction mixture obtained further to a process as defined in any of claims I to 27. 45. Irbesartan hydrochloride according to claim 44, which is irbesartan hydrochloride sesquihydrate. 46. Irbesartan hydrochloride according to claim 44, which is irbesartan hydrochloride hemihydrate. 47. Irbesartan free base, either Form A or Form B, prepared by a process as defined in any of claims 41 to 43. 48. Crystalline irbesartan hydrochloride in hydrated form. 49. Crystalline irbesartan hydrochloride sesquihydrate. 50. Crystalline irbesartan hydrochloride sesquihydrate having an IR pattern, or substantially the same IR pattern, as shown in Figure 2. 51. Crystalline irbesartan hydrochloride sesquihydrate having characteristic 1R absorbance at about 3638, 3273, 2451, 1761, 1639, 1514, 1477, 1323 and 1302 cm"1. 52. . Crystalline irbesartan hydrochloride sesquihydrate according to any of claims 49 to 51, further characterised by having a water content from about 5.7% to 7.5%. 53. Crystalline irbesartan hydrochloride sesquihydrate characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 1. 54. Crystalline irbesartan hydrochloride sesquihydrate characterised as having characteristic peaks (20): 7.49, 8.24, 11.01, 14.92, 15.32, 16.28, 17.38, 22.52, 22.98, 23.42, 24.68, 26.57, 27.00 and 28.47°. 55. Crystalline irbesartan hydrochloride hemihydrate. 56. Crystalline irbesartan hydrochloride hemihydrate having an IR pattern, or substantially the same IR pattern, as shown in Figure 4. 57. Crystalline irbesartan hydrochloride hemihydrate having characteristic IR absorbance at about! 772, 1627, 1519, 1476, 1226, 1070, 998, 959, 940, 708 and 645 cm"1. 58. Crystalline irbesartan hydrochloride hemihydrate according to any of claims 55 to 57, further characterised by having a water content from about 1.7% to 2.8%. 59. Crystalline irbesartan hydrochloride hemihydrate according to any of claims 55 to 58, having a melting point of about 186°C. 60. Crystalline irbesartan hydrochloride hemihydrate characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 3. ^61. Crystalline irbesartan hydrochloride hemihydrate characterised as having characteristic peaks (20): 8.2, 10.33, 11.02, 12.42, 12.87, 15.32, 15.76, 16.25, 17.46, 22.42, 22.98, 23.3, 24.81, 25.75, 26.53 and 27.06°. 62. Crystalline anhydrous irbesartan hydrochloride. 63. Crystalline anhydrous irbesartan hydrochloride having an IR pattern, or substantially the same IR pattern, as shown in Figure 6. 64. Crystalline anhydrous irbesartan hydrochloride having characteristic IR absorbance at . about 3400, 2958, 1628, 1515, 1475, and 846 cml. 65. Crystalline anhydrous irbesartan hydrochloride according to any of claims 62 to 64, further characterised by having a water content from about 0.1% to 0.9%. 66. Crystalline anhydrous irbesartan hydrochloride according to any of claims 62 to 65, having a melting point of about 186°C. 67. Crystalline anhydrous irbesartan hydrochloride characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 5. 68. Crystalline anhydrous irbesartan hydrochloride characterised as having characteristic peaks (20): 8.0, 8.35, 8.70, 9.48, 10.05, 11.76, 15.00, 15.48, 16.38, 16.79, 17.47, 20.26. 21.12, 23.54, 25.14, 26.44, 26.78, 28.12, and 32.45°. 69. Amorphous irbesartan hydrochloride. 70. Amorphous irbesartan hydrochloride characterised by an IR pattern, or substantially the same IR pattern, as shown in Figure 8. 71. Amorphous irbesartan hydrochloride having characteristic IR absorbance at about 3402. 1773. 1625. 666 and 624 cm'. 42 72. Amorphous irbesartan hydrochloride characterised as having an X-ray powder diagram, or substantially the same X-ray powder diagram, as shown in Figure 7. 73. Irbesartan hydrochloride sesquihydrate, hemihydrate or anhydrous prepared by a process according to any of claims 1 to 40. 74. Irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, prepared from irbesartan hydrochloride sesquihydrate according to any of claims 49 to 54. 75. Irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, prepared from amorphous irbesartan according to any of claims 69 to 72. 76. A process of preparing irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, which process comprises drying irbesartan hydrochloride sesquihydrate according to any of claims 49 to 54. 77. A process of preparing irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, which process comprises dissolving irbesartan sesquihydrate according to any of claims 49 to 54 in a solvent, concentrating to a residue and subsequently precipitating with a non-solvent. 78. A process according to claim 77. wherein said solvent is methanol. 79. A process according to claim 77, wherein said non-solvent is ethyl acetate. 80. A process of preparing irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, which process comprises dissolving amorphous irbesartan according to any of claims 69 to 72 in a solvent mixture, concentrating to a residue and subsequently precipitating with a non-solvent. 81. A process according to claim 80, wherein said solvent mixture is methanol and water. 82. A process according to claim 80, wherein said non-solvent is ethyl acetate. 83. Irbesartan hydrochloride hemihydrate according to any of claims 55 to 61, prepared from a process according to any of claims 76 to 82. 84. Anhydrous irbesartan hydrochloride according to any of claims 62 to 68, prepared from irbesartan hydrochloride sesquihydrate according to any of claims 49 to 54. 85. A process of preparing anhydrous irbesartan hydrochloride according to any of claims 62 to 68, which process comprises stirring irbesartan hydrochloride sesquihydrate according to any of claims 49 to 54 in a solvent and subsequently precipitating with a non-solvent. 86. A process according to claim 85, wherein said solvent is methanol. 87. A process according to claim 85, wherein said non-solvent is e.thyl acetate. 88. Anhydrous irbesartan hydrochloride according to any of claims 62 to 68, prepared by a process according to any of claims 85 to 87. 89. A pharmaceutical composition comprising a therapeutically effective dose of irbesartan according to any of claims 44 to 75, 82, 84 or 88, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. 90. Irbesartan according to any of claims 44 to 75, 82, 84 or 88, for use in therapy. 91. - Irbesartan according to any of claims 44 to 75, 82, 84 or 88, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II antagonist. Dated this 4th day of May, 2007 44 ABSTRACT "PROCESS FOR THE PREPARATION OF IRBESARTAN HYDROCHLORIDE" The present invention is concerned with a process for the preparation of 2n-butyl-4-spirocyclopentane-l-[(2'-(te, a-zol-5-yl)biphenyl-4-yl) methyl]-2-imidazolin-5-one hydrochloride, irbesartan hydrochloride, novel hydrated and anhydrous crystalline forms thereof, amorphous irbesartan hydrochloride, formulations containing the same, therapeutic uses thereof and methods of treatment employing the same. The process of the present invention is a one-pot process which comprise reacting intermediate compounds 2n-butyl-l, 3-diazaspiro [4,4] non-l-en-4-one and 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole.

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