Process for the preparation of a tetrazole derivative in two crystalline forms and novel the crystalline forms thereof

#The present invention concerns a process for the preparation of the 2-n.butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]- 2-imidazolin-5-one in two different crystalline forms, a novel crystalline form of this product and pharmaceutical compositions containing said novel crystalline form. More particularly, the invention relates to the preparation of the 2-n.butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl] -2-imidazolin-5-one by reaction of the corresponding nitrile with an alkaline azide and triethylamine hydrochloride and to the isolation of said 2-n.butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]met hyl]-2-imidazolin-5-one in two different crystalline forms.

#The 2-n.butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl] -2-imidazolin-5-one, or 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one, is a powerful angiotensin II receptor antagonist prepared by reaction of 2-n.butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazol in-5-one, or 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4.4]non-1-en-4 -one, either with tributyltin azide and triphenylchloromethane in xylene at reflux, by elimination of the triphenylmethyl protecting group and by isolation from a solution in ethyl acetate, duly dried (EP-A-0 454 511), or directly with tributyltin azide, in xylene at reflux and isolation from a solution in dichloromethane, duly dried (C. A. Bernhart et al., J. Med. Chem., 1993, 36, 3371-3380). The compound thus prepared, to which the formula (A) ##STR1## has been attributed, is presented in the form of stable, non-hygroscopic needles which can be stored and formulated without any degradation. However, it has been observed that the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one obtained according to the above described processes, must be formulated with much care because the powder tends to remain attached to the apparatus, for example to the sieves, to the punches or to the mixer walls, due to its high electrostaticity.

#It is known that another non-peptide angiotensin II antagonist, losartan, namely the potassium salt of the 2-n.butyl-4-chloro-5-hydroxymethyl-1-[2'-(tetrazol-5-yl)biphenyl-4-yl]imid azole exists in two polymorphic forms: one (form I) being regularly obtained at the end of the process of preparation and the other one (form II) being obtained by heating form I at 250.degree. C. Form I of losartan is stable at room temperature whereas form II is stable at high temperature. Consequently, form II is gradually converted to form I which is thermodynamically more stable at room temperature (K. Raghavan et al., Pharm. Res., 1993, 10, 900-904; L. S. Wu et al., Pharm. Res., 1993, 10, 1793-1795).

#The difference between the novel crystalline form of the 2-n.butyl-3-[[2'(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]-n on-1-en-4-one according to the present invention (Form B) and the Form A described by the above-cited C. A. Bernhart et al. emerges from the examination of FIGS. 1 and 2, while FIGS. 3 to 5 show the structure of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro-[4.4] non-1-en-4-one in the crystals of Form B. More particularly:

#FIG. 1 gives the X-ray powder diffraction spectrum of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one, Form B, showing the maximal intensity at the interreticular spacing of 11.22.ANG. and high intensities at 5.60 and 4.17.ANG.;

#FIG. 2 gives the X-ray powder diffraction spectrum of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one, Form A, showing the maximal intensity at the interreticular spacing of 18.99.ANG. and relatively high intensities at 7.13 and 4.58.ANG.;

#The following examples illustrate the invention without however implying a limitation. The abbreviation THF designates tetrahydrofurane.

#(a) A mixture of 1 kg of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl]methyl-1,3-diazaspiro[4.4]non-1-en-4-o ne, 713 g of triethylamine hydrochloride, 337 g of sodium azide in 2 I of 1-methylpyrrolidin-2-one is heated 12 hours under stirring at a temperature of 121.degree.-123.degree. C., then it is left to cool at a temperature of 40.degree.-50.degree. C. A 35% aqueous solution of sodium hydroxide and water are added under stirring thereto and stirring is continued for 30 minutes at a temperature of 20.degree.-40.degree. C. Stirring is stopped, the medium is allowed to settle, the aqueous phase is eliminated and the organic phase is treated with a mixture of water/toluene 5/2. The medium is stirred for 30 minutes at 20.degree.-30.degree. C., then stirring is stopped, the medium is left to settle, the organic phase is eliminated and the aqueous phase is washed by adding ethyl acetate thereto under stirring and the aqueous phase containing the sodium salt of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one is recovered.

#(b) To the resulting aqueous solution of pH 9-11, 36% of hydrochloric acid are slowly added until the pH is 4.7-5.3. At the end of the hydrochloric acid addition, the precipitation of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4-one is complete. The resulting suspension is stirred for one hour at 20.degree.-25.degree. C., the product is recovered, wrung at 20.degree.-25.degree. C. and washed with water. A mixture of 500 ml of isopropanol and 4.5 I of water is added to the product thus obtained, the medium is heated one hour at 50.degree.-55.degree. C., then cooled to 20.degree.-25.degree. C. After one hour at this temperature the product is well wrung, the crystals are washed with water and dried at 60.degree. C. In a preparation, 949 g of partially amorphous crude 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]n on-1-en-4one which are pure at 98%, were obtained (yield: 86%).