Tetrazole intermediates to antihypertensive compounds

Abstract: Tetrazole intermediates useful to prepare antihypertensive compounds described in coassigned application U.S. Ser. No. 884,920, filed July 11, 1986, are described, these tetrazoles have the formula: wherein X¹ and X² are as described in the specification.

Description: This invention relates to substituted tetrazoles useful as intermediates in the preparation of antihypertensive compounds. S. Kozima et al., J. Organometallic Chem. , 33 , 337, (1971) and ibid , 92 , 303 (1975) describes substituted tetrazoles of the formula: wherein R¹ is lower alkyl, benzyl, lower alkenyl or phenyl optionally substituted by nitro, lower alkyl, lower alkoxy or halogen; and R² is SnR₃. R. Lofquist et al., J. Amer. Chem. Soc. , 80 , 3909 (1958) describes substituted tetrazoles of the Formula: wherein R is lower alkyl, benzyl, cycloalkyl of 4 carbon atoms, n -heptyl perfluoro, -SR¹ where R¹ is lower alkyl, benzyl; -(CH₂) n R² where R² is OH, CO₂R¹, OR¹, SO₃Na and n is 1 or 2; or phenyl optionally substituted with amino, lower alkoxy, lower alkyl, nitro or cyano. W. Beck, et al., Chem. Ber. , 116 , 2691 (1983) describes the preparation of 2-trityl-5-phenyl tetrazole. EP-A-0 106 140 discloses tetrazol-substituted biphenyl compounds which are reported to be useful in the reduction or control of blood lipids in animals. According to the present invention, there are provided novel compounds of Formula (I) which are tetrazole intermediates useful for the preparation of antihypertensive compounds. These tetrazoles have the Formula: wherein X¹ is H Sn(R)₃, -C(Phenyl)₃, p -nitrobenzyl, or β-propionitrile; X² is Cl, Br, I, O-tosyl, OH, O-mesyl, or R is alkyl of 1-6 carbon atoms, phenyl or cyclohexyl; R¹ is alkyl of 3-10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, and benzyl substituted with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, nitro and amino; R² is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH₂) m -imidazoyl-1-yl, -(CH₂) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO₂CH₃ and alkyl of 1 to 4 carbon atoms, (CH₂) m -tetrazolyl, -(CH₂) n OR⁴; -(CH₂) n NHSO₂R⁸; -(CH₂) m F; R³ is H, F, Cl, Br, I, NO₂, CF₃, or CN; R⁴ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁵ is H, alkyl or perfluoralkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁶ is H, alkyl of 1-5 carbon atoms, OR⁹ or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R⁸ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH₂) p C₆H₅; R⁹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or phenyl; R¹⁰ and R¹¹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together to form a ring of the Formula Q is NR¹², O, or CH₂; R¹² is H, alkyl of 1 to 4 carbon atoms, or phenyl; m is 1 to 5; n is 1 to 10; s is 0 to 5; p is 0 to 3; t is 0 or 1. with the proviso that when X¹ = H then X² cannot be Preferred compounds are those of Formula (I) where: X¹ is H, Sn(R)₃ or -C(phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl; or X² is Br, Cl, or the substituted imidazole; or R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴; -(CH₂) m NHSO₂R⁸; R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbon atoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹; or N O; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5. Specifically preferred compounds are those of Formula (I) where: (1) X¹ is Sn(CH₃)₃, Sn(Ph)₃, Sn( n -Bu)₃, C(Phenyl)₃, or H; and X² is Br. (2) X¹ is Sn(CH₃)₃ or C(Phenyl)₃: and X² is Synthesis The novel compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazole and other portions of the molecule must be consistent with the chemical transformations proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required, deprotection conditions, and activation of a benzylic position to enable attachment to nitrogen on the imidazole nucleus. Throughout the following section, not all compounds of Formula (I) falling into a given class may necessarily be prepared by all methods described for that class. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods must then be used. Compounds of the Formula (I), where X¹ is Sn(R)₃ and R is alkyl of 1 to 6 carbon atoms or phenyl and X² is imidazoyl where R¹ is n -butyl, R³ is Cl, and R² is hydroxymethyl may be prepared by the 1,3-dipolar cycloaddition of trialkyltin or triphenyltin azides to the appropriately substituted nitrile (II) (Scheme I). An example of this technique is described by S. Kozima, et al., J. Organometallic Chemistry , 33 , 337 (1971). Other required nitriles and trialkyl or triaryl tin azides are either available commercially, or may be prepared using techniques and methods reported in the chemical literature, J. Luijten et al., Rec. Trav. Chem. , 81 , 202 (1962). Compounds of the Formula (I), where X¹ and X² are H, which compounds as such are, however, not according to the invention, may be prepared by removal of a suitable protecting group on the tetrazole nucleus. Suitable protecting groups for the tetrazole moiety include p -nitrobenzyl, β-propionitrile, triphenylmethyl, and trialkyltin which are prepared via the following methods. The nitrobenzyl protecting group is attached as shown in Scheme II. The acid (IV) is converted to the intermediate acid chloride with oxalyl chloride under standard conditions. The acid chloride is converted to the amide (V) by condensation with 4-nitrobenzylamine hydrochloride in pyridine in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP). The amide (V) is converted to the intermediate iminoylchloride via reaction with phosphorus pentachloride in carbon tetrachloride. One example of this method is described by H. Ulrich, The Chemistry of Imidoyl Halides , Plenum Press, N.Y., N.Y. (1968). The intermediate iminoyl chloride is converted to the tetrazole (VI) with lithium azide in dimethylformamide (DMF). An example of this method is described by Elderfield, Heterocyclic Compounds , John Wiley and Sons, (1967). The protected tetrazole (VI) is then hydrogenated at 344.7 kPa (50 psi) in the presence of a catalytic amount of W6 Raney nickel in ethanol to yield (I). The required acid (IV) is available commercially or may be prepared using techniques and methods reported in the chemical literature. The triphenylmethyl group is attached as shown in Scheme III. The tetrazole (I) reacts with triphenylmethylchloride in methylene chloride containing triethylamine as the base under standard conditions to yield the protected tetrazole (VII). The propionitrile protecting group is attached as shown on Scheme IV. The biphenylcarboxylic acid (IV) may be converted to the acid chloride by a variety of reagents familiar to one skilled in the art. The intermediate acid chloride reacts with β-aminopropionitrile in the presence of an acid scavenger such as aqueous sodium hydroxide to yield amide (VIII). Amide (VIII) reacts with phosphorus pentachloride or phosgene to form the intermediate iminoyl chloride (IX) which when reacted with hydrazine yields amidrazone (X). The amidrazone (X) reacts readily with dinitrogen tetroxide (N₂O₄), which can be conveniently handled as a solution in carbon tetrachloride, to yield tetrazole (XI). Hydrazines and hydrazides have been shown to undergo facile conversion to their corresponding azides with N₂O₄ as described by Y.H. Kim, et. al., Tetrahedron Letters , 27 , 4749(1986). The protected tetrazole (XI) is deprotected with aqueous base such as 1N NaOH with or without an additional organic solvent such as tetrahydrofuran to yield tetrazole (I). The amidrazone (X) may also be converted to the tetrazole (XI) using nitrous acid or its equivalents as described by D. G. Neilson, et. al., Chem. Rev. , 70 , 151(1970). Preferred protecting groups are those where X¹ is Sn(R)₃ and C(Phenyl)₃ and R is as described previously (Scheme V). The above groups may be optionally removed via acidic or basic hydrolysis, catalytic hydrogenation, and irradiation described by Greene, Protective Groups in Organic Synthesis , Wiley-Interscience, (1980). Compounds of the Formula (I) where X¹ is C(phenyl)₃ and X² is Br may be prepared via radical bromination of (VII) with N-bromosuccinimide (NBS) and dibenzoylperoxide (Bz₂O₂) to yield (XII) as shown in Scheme VI. An example of this conversion is described by L. Horner et al., Angew. Chem. , 71 , 349 (1959). Compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is I may be prepared via displacement of the bromine moiety in (XII) with sodium iodide in acetone under standard conditions yielding (XIII). Displacement of the above bromide (XII) with hydroxide ion affords the substituted benzyl alcohol (XIV). The benzyl alcohol (XIV) may be converted to the chloride (XV) via reaction with carbon tetrachloride and triphenylphosphine. The benzyl alcohol (XIV) can be converted to the tosylate or mesylate (XVI) via reaction with p-toluenesulfonyl chloride or methanesulfonyl chloride, respectively, in pyridine under standard conditions (Scheme VII). Compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is imidazoyl where R¹ is n -butyl, R³ is Cl, and R² is hydroxymethyl may be prepared via alkylation of imidazole (XVII) with the appropriately substituted benzyl halide using sodium ethoxide as a base followed by reduction of the formaldehyde moiety on imidazole (XVII) to hydroxymethyl with sodium borohydride affording (XVIII). The preparation of imidazole (XVII) in Scheme VIII is described by Furukawa, et.al. in U.S. 4,355,040. The compounds of this invention and their preparation can be understood further by the following examples. In these examples,unless otherwise indicated, all temperatures are in degrees centigrade and parts and percentages are by weight. Example 1 - Method A Part A: N-trimethylstannyl-5-[2-(4′-methylbiphen-2-yl)]tetrazole To a solution of 2-cyano-4′-methylbiphenyl (19.30 g, 0.100 mole) in toluene (110.0 ml) was added trimethyltin azide (24.60 g, 0.120 mole) at room temperature. The reaction was refluxed for 24 hours, cooled to room temperature and the product isolated by filtration affording N-trimethylstannyl-5-[2-(4′-methylbiphenylyl)]tetrazole (32.60 g, 82%) as an off white solid, m.p. 265° (dec.); ¹H NMR (DMSO-d₆) δ: 7.50 (s,4H); 7.00 (s,4H); 2.25 (s,3H); 0.35 (s,3H). Part B: 5-[2-(4′-methylbiphenylyl)]tetrazole (Compound not according to the invention) To a solution of N-trimethylstannyl-5-[2-(4′-methylbiphenylyl)]tetrazole (32.0 g, 0.080 mole) in toluene (230 ml) and tetrahydrofuran (15.0 ml) was bubbled in enough anhydrous hydrogen chloride to give a clear solution at room temperature. From this solution, 5-[2-(4′-methylbiphenylyl)]tetrazole (19.1 g) crystallized. Recrystallization from toluene afforded 18.1 g (95%) of product, m.p. 149-152°. ¹H NMR (CDCl₃/DMSO-d₆) δ: 7.50 (m,4H); 7.07 (m,4H); 2.35 (s,3H). Example 1 - Method B Part A: 4′-Methyl-biphenyl-2-carbonyl chloride A solution of 4′-methyl-biphenyl-2-carboxylic acid (31.84g, 0.15 mole) in chloroform (200 ml) was added dropwise to a stirred mixture of chloroform (25ml) oxalyl chloride (25ml), and dimethylformamide (1.0ml) at room temperature. After the mixture had stirred for 24 hours at room temperature, the solution was evaporated in vacuo affording 36.4 grams of the crude acid chloride. IR: 1784.0 cm ⁻¹(COCl). Part B: N-(4-Nitrobenzyl)-4′-methyl-biphenyl-2-carboxamide A solution of the material from Part A (36.4 g) in dry acetonitrile was added dropwise to a cooled (ice-bath), stirred mixture of 4-nitrobenzylamine hydrochloride (23.45 g, 0.12 mole), 4-dimethylamino pyridine (0.5g, 0.0041 mole), and dry pyridine (150.0 ml). After 30 minutes, the reaction was allowed to reach room temperature and stirred for 16 hours at room temperature. The mixture was poured into a stirred mixture of 3N HCl (800.0 ml), ice (400.0 g), and dichloromethane (400 ml). The organic layer was washed with 2N NaOH (2 x 200 ml), brine (100 ml), dried (MgSO₄), and evaporated in vacuo to yield crude product (61.9g). Recrystallization from ethyl acetate gave 31.3 (73%) of product, m.p. 153-154°. ¹H NMR (CDCl₃) δ: 8.03 (d, 2H, aromatic); 7.65-7.69 (m, 1H, aromatic); 7.12-7.48 (m, 7H, aromatic); 7.04 (d, 2H, aromatic); 5.77-5.79 (m, 1H, NH); 4.41 (d, 2H, J = 6.0 Hz, CH₂); 2.39 (s, 3H, CH₃). Mass spec m/z = 347 (M + 1). Part C: N-(4-Nitrobenzyl)-4′-methyl-biphen-2-yl-carboiminoyl chloride In three portions, a total of 20.78g (0.060 mole) of the product of Part B was added to a cooled (ice-bath), stirred solution of phosphorus pentachloride (12.49 g, 0.066 mole) in carbon tetrachloride (200 ml). The mixture was stirred for 30 minutes at 0°, allowed to warm to room temperature, and stirred for 16 hours. The mixture was evaporated in vacuo yielding the crude product (21.3g). IR: 1691 cm⁻¹ (C=N). ¹H NMR (CDCl₃) δ: 4.79 (s, 2H, CH₂). Part D: 1-(4-Nitrobenzyl)-5-(4′-methyl-biphen-2-yl) tetrazole Lithium azide (3.67g, 0.75 mole) was added portionwise to a cooled solution (ice-bath) of the product of Part C (21.3g) in dimethylformamide (200.0 ml). The mixture was allowed to reach room temperature over 16 hrs. The reaction mixture was evaporated in vacuo . The residue was partitioned between water and ethyl acetate (100 ml). The organic layer was washed with water (100 ml), dried (MgSO₄) and evaporated in vacuo to yield 19.5 g of a dark residue. Chromatography on silica (CHCl₃) followed by recrystallization (methanol) afforded 5.37 g, (24.1%), m.p. 95.0-96.0°. ¹H NMR (CDCl₃) δ: 7.98-8.02 (m, 2H, aromatic); 7.55-7.70 (m, 2H, aromatic); 7.37-7.49 (m, 2H, aromatic); 6.99-7.10 (m, 2H, aromatic); 4.87 (d, J=8.7 Hz, aromatic); 4.88 (s, 2H, CH₂); 2.33 (s, 3H, CH₃). Mass spec m/z = 372 (M + 1). Part E: 5-[2-(4′-methylbiphen-2-yl)]tetrazole (Compound not according to the invention) A mixture of the product of Part D (1.00 g, 2.80 mmole), ethanol (150.0 ml), and W6 Raney nickel (5.0 g) was hydrogenated in a Parr® Shaker at 50 psi for 2 hrs. at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo . The residue was partitioned between water and diethyl ether (100 ml) and the organic layer was washed with 1N HCl (50 ml), brine (50 ml), dried (MgSO₄), and evaporated in vacuo to yield a solid residue which was recrystallized from toluene to yield the product (0.19 g, 28.7%), m.p. 154-155°. ¹H NMR (CDCl₃) δ; 11.5 (br s, 1H, NH); 8.02 (d, 1H, aromatic); 7.38-7.61 (m, 3H, aromatic), 7.16 (d, 2H, J=8.0 Hz, aromatic); 7.04 (d, 2H, J=8.0 Hz); 2.35 (s, 3H, CH₃). Mass spec m/z=237 (M + 1). Example 1 - Method C Part A: 2-(β-cyanoethylaminocarbonyl)-4′-methylbiphenyl 4′-methylbiphenyl-2-carboxylic acid (50.00 g, 0.236 mol,), thionyl chloride (87.5 ml, 1.20 mol) and chloroform (500 ml) were mixed and refluxed for 4 hours. The thionyl chloride and solvent were removed in vacuo , and the residue suspended in toluene (300 ml). The mixture was evaporated in vacuo and the residue suspended once more in toluene and evaporated to insure removal of traces of thionyl chloride. The resultant acid chloride was dissolved in tetrahydrofuran (100 ml) and slowly added in five equal portions alternatingly with five equal portions of 1,0N NaOH (236.0 ml, 0.236 mol) to a solution of β-aminopropionitrile fumarate (30.3 g, 0.236 mol) in 1,0 N NaOH (236.0 ml, 0.236 mol) at 0° with stirring. The reaction was allowed to warm slowly to room temperature. After 24 hrs, water (500 ml) was added and the aqueous mixture extracted with ethyl acetate (3 x 500 ml). The organic layers were combined and dried (MgSO₄), and the solvent removed in vacuo to yield a crude solid which, after recrystallization from methylcyclohexane/butyl chloride, yielded 53.5 g of a white solid. M.P. = 102.0-103.5°. NMR (200MH₂, CDCl₃) δ:7.68 (d, 1H, J=7H z ); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H); 2.39 (t, 2H, J=7H z ). Anal. calcd. for C₁₇H₁₆N₂O; C, 77.25; H, 61.0; N, 10.60. Found; C, 77.42; H, 6.40; N, 10.68. Part B: N³-(β-cyanoethyl)-4′-methylbiphenyl-2-yl-amidrazone. 2-(β-cyanoethylaminocarbonyl)-4′-methylbiphenyl (33.48g, 0.127 mol) and phosphorous pentachloride (28.01g, 0.139 mol) were combined in a round bottom flask which was then connected to aspirator vacuum via a trap filled with calcium chloride. The flask was gently heated with a heat gun until the solids melted. The flask was intermittantly heated for 15-20 minutes. The crude iminoyl chloride was taken up in dry dioxane (100 mL) and added dropwise to a stirred mixture of hydrazine (20.1 mL, 0.634 mol) in dry dioxane (200 mL). After 24 hours, the excess hydrazine and solvent were removed in vacuo . Water (300 mL) was added, and the aqueous mixture extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, dried (MgSO₄) and the solvent removed in vacuo to yield an oil. The oil was treated with a 1:1 hexane/ethyl acetate solution (30-50 mL), and solids precipated. These were collected and dried to yield 16.14g of light pink solids. M.P. = 146.5-147.5°. Chemical ionization mass spectrum detected (M+H)⁺ = 279 for C₁₇H₁₉N₄. Anal. calcl. for C₁₇H₁₈N₄·(N₂H₄) 0.1 : C, 72.52; H, 6.44; N, 20.89. Found: C, 72.50; H, 6.54; N,21.13. NMR indicated a mixture of tautomeric forms. Part C: 2-[1-(β-cyanoethyl)-1-H-tetrazol-5-yl]-4′-methylbiphenyl. A solution of N₂O₄(g) in carbon tetrachloride (0.73M, 19.6 mL, 14.3mmol) was added to a stirred slurry of N 3 (β-cyanoethyl)-4′-methylbiphenyl-2-ylamidrazone (2.00g, 7.2mmol) in anhydrous acetonitrile (40 mL) at 0°. The reaction was warmed to room temperature and stirred overnight. The solvent was removed in vacuo to yield a crude solid. This solid was taken up in butyl chloride and the insoluble matter filtered. The filtrate was evaporated, and the residue flash chromatographed on silica in 1:1 hexane/ethylacetate to yield 1.10g of a pale yellow oil, which slowly crystallized. Recrystallization from hexane/butyl chloride yielded 910 mg of pale yellow crystals. M.P. = 90.0-92.0°. NMR(200 MH z , CDCl₃) δ: 7.76-7.50 (m,4H); 7,17(d, 2H, J=10H z ); 7.04(d,2H, J=10H z ); 3.80 (t,2H, J=7H z ); 2.37 (s,3H); 2.24(bt, 2H, J=7H z ). Anal. calcd. for C₁₇H₁₅N₅: C, 70.57; H,5.23; N,24.20. Found: C, 70.49; H, 5.45; N, 24.44. Part D: 5-(4′-methylbiphenyl-2-yl)tetrazole (Compound not according to the invention) 2-[1-(β-cyanoethyl)-1-H-tetrazol-5-yl]-4′-methylbiphenyl (689mg, 2.38 mmol), 1,0N NaOH (2.62 mL), 2.62 mmol) and THF (15 mL) were mixed and stirred at room temperature. After 15 minutes, water (100 mL) was added and the pH adjusted to 3.0 with conc. HCl. The aqueous mixture was extracted with ethyl acetate (3 x 100 mL) and the organic layers were combined, dried (MgSO₄) and evaporated in vacuo to yield 550 mg of a white powder. M.P. = 148.5-150.0°. The spectral data matched those of a sample prepared via Method A. Example 5 N-triphenylmethyl-5-[2-(4′-methylbiphenylyl)]tetrazole (Compound not according to the invention) To a solution of 5-[2-(4′-methylbiphenyl)] tetrazole (17.0 g, 0.072 mole) in methylene chloride (260 ml) was added triphenylmethyl chloride (21.20 g, 0.076 mole) at room temperature. Triethylamine (12.0 ml, 0.086 mole) was added at room temperature, and the solution was refluxed for 2.5 hrs. The solution was cooled to room temperature, washed with water (2 x 50 ml), dried (MgSO₄), and evaporated in vacuo . The residue was crystallized from toluene (80 ml), yielding, N-triphenylmethyl-5-[2-(4′-methylbiphenylyl)]tetrazole (31.2 g, 90%), m.p. 163-166°; ¹H NMR (CDCl₃) δ: 8.10-6.80 (complex, 23H); 2.28 (s, 3H). Example 6 N-triphenylmethyl-5-[2-(4′-bromomethyl-biphenylyl)] tetrazole To a solution of N-triphenylmethyl-5-[2-(4′-methylbiphenylyl)]tetrazole (31.0 g, 0.065 mole) in carbon tetrachloride (390.0 ml) was added N-bromosuccinimide (11.50 g, 0.065 mole) and dibenzoylperoxide (1.10 g, 0.0045 mole) at room temperature. The reaction mixture was refluxed for 3 hrs., cooled to 40° and filtered. Evaporation of the filtrate in vacuo followed by trituration of the residue with isopropyl ether (100.0 ml) yielded N-triphenylmethyl-5-[2-(4′-bromomethyl-biphenylyl)]tetrazole (33.10 g, 92%), m.p. 135-138°. ¹H NMR (CDCl₃) δ: 8.20-6.70 (complex, 23H); 4.33 (s, 2H). Example 7 1-{[2′-(N-triphenylmethyl-tetrazol-5-yl)-biphenyl-4-yl] methyl}-2-butyl-4-chloro-5-hydroxymethyl imidazole To a solution of 2-butyl-4-chloro-5-formyl-imidazole (1.24 g, 0.007 mole) dissolved in dimethylformamide (10.0 ml) was added sodium ethoxide (0.45 g, 0.0066 mole) and the reaction mixture was cooled to 5°. N-triphenylmethyl-5-[2-(4′-bromomethylbiphenylyl]tetrazole (3.70 g, 0.0066 mole) was added and the reaction mixture was allowed to warm to room temperature. After 72 hrs. the reaction was diluted with water (25.0 ml) and extracted with ethyl acetate (3 x 25 ml). The organic phase was washed with water (2 x 25 ml) and brine (3 x 25 ml), dried (MgSO₄), and evaporated in vacuo to an oil. The crude oil was dissolved in methanol (20.0 ml), and sodium borohydride (0.24 g, 0.0063 mole) was added at room temperature. The reaction was stirred for 1.5 hrs., diluted with water (40.0 ml), and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with water (1 x 25 ml), dried (MgSO₄), and evaporated in vacuo . The residue was recrystallized once from toluene/heptane, once from toluene, and finally from methanol to give 1-{[2′-(N-triphenylmethyl-tetrazol-5-y)}-biphenyl-4-yl] methyl}-2-butyl-4-chloro-5-hydroxymethyl imidazole (0.98 g, 21%), m.p. 95-98°; ¹H NMR (CDCl₃) δ: 8.20- 6.60 (complex, 23H); 5.16 (s, 3H); 4.40 (s, 3H); 2.85 (brs, 1H); 2.54 (t, 3H); 1.9-1.1 (m, 4H); 0.88 (t, 3H). Example 8 1-{[2′-(N-trimethylstannyl-tetrazol-5-yl)-biphenyl-4-yl] methyl}-2-butyl-4-chloro-5-hydroxymethyl imidazole To a solution of 1-[(2′-cyano-biphenyl-4-yl) methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole (4.40 g, 0.011 mole) in xylenes (40.0 ml) was added trimethyltin azide (2.80 g, 0.014 mole), and the reaction was heated at 115-120° for 40 hrs. The mixture was cooled to 50° and filtered to yield 1-{[2′-(N-trimethylstannyl-tetrazol-5-yl)-biphenyl-4-yl] methyl}-2-butyl-4-chloro-5-hydroxymethyl imidazole (6.55 g, 99%), m.p. 154-160°; ¹H NMR (CDCl₃/DMSO-d₆) δ: 7.80-7.30 (m, 4H), 7.03 (q, 4H), 5.23 (s, 3H), 4.43 (s, 3H), 2.54 (t, 3H); 2.00 (s, 1H), 1.80-1.10 (m, 4H); 0.85 (t, 3H); 0.40 (s, 9H). The compounds of Examples 1,5,6,7, and 8 above as well as other compounds which were prepared or could be prepared using the procedures of the aforementioned examples are shown in Table I.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, GR, IT, LI, LU, NL, SE A tetrazole having the formula: wherein X¹ is H, Sn(R)₃, -C(Phenyl)₃, p -nitrobenzyl, or β-propionitrile. X² is Cl, Br, I, O-tosyl, OH, O-mesyl, or R is alkyl of 1-6 carbon atoms, phenyl or cyclohexyl; R¹ is alkyl of 3-10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, and benzyl substituted with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, nitro and amino: R² is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH₂) m -imidazoyl-1-yl, -(CH₂) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO₂CH₃ and alkyl of 1 to 4 carbon atoms, (CH₂) m -tetrazolyl, -(CH₂) n OR⁴; -(CH₂) n NHSO₂R⁸; -(CH₂) m F; R³ is H, F, Cl, Br, I, NO₂, CF₃, or CN; R⁴ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁵ is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁶ is H, alkyl of 1-5 carbon atoms, OR⁹ or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R⁸ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH₂) p C₆H₅; R⁹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or phenyl; R¹⁰ and R¹¹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together to form a ring of the Formula Q is NR¹², O, or CH₂; R¹² is H, alkyl of 1 to 4 carbon atoms, or phenyl; m is 1 to 5; n is 1 to 10; s is 0 to 5; p is 0 to 3; t is 0 or 1. with the proviso that when X¹ = H then X² cannot be The tetrazole of Claim 1 wherein X¹ is H, Sn(R)₃ or -C(Phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl. The tetrazole of Claim 1 wherein X² is Br, Cl or where R¹, R² and R³ are as defined in Claim 1. The tetrazole of Claim 3 wherein R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴; -(CH₂) m NHSO₂R⁸; R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbon atoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹; or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5. The tetrazole of Claim 1 wherein X¹ is H, Sn(R₃) or -C(Phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl, and X² is Br, Cl or where R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴; -(CH₂) m NHSO₂R⁸; R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbon atoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹; or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5. with the proviso that when X¹ = H then X² is not The tetrazole of Claim 5 wherein X² is Br or wherein R¹ is alkyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴ where m is 1 to 5 and R⁴ is H or alkyl of 1 to 4 carbon atoms; and R³ is Cl. The tetrazole of Claim 6 wherein X² is Br. The tetrazole of Claim 6 wherein X² is wherein R¹, R² and R³ are as defined in Claim 6. The tetrazole of Claim 8 wherein R¹ is n -butyl, R² is -CH₂OH and R³ is Cl. Claims for the following Contracting State : ES Process for the production of a tetrazole having the formula : wherein X¹ is H, Sn(R)₃, -C(Phenyl)₃, p -nitrobenzyl, or β-propionitrile. X² is Cl, Br, I, O-tosyl, OH, O-mesyl, or R is alkyl of 1-6 carbon atoms, phenyl or cyclohexyl; R¹ is alkyl of 3-10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, and benzyl substituted with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, nitro and amino; R² is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, -(CH₂) m -imidazoyl-1-yl, -(CH₂) m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO₂CH₃ and alkyl of 1 to 4 carbon atoms, (CH₂) m -tetrazolyl, -(CH₂) n OR⁴; -(CH₂) n NHSO₂R⁸; -(CH₂) m F; R³ is H, F, Cl, Br, I, NO₂, CF₃, or CN; R⁴ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁵ is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁶ is H, alkyl of 1-5 carbon atoms, OR⁹ or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R⁸ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH₂) p C₆H₅; R⁹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or phenyl; R¹⁰ and R¹¹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or taken together to form a ring of the Formula Q is NR¹², O, or CH₂; R¹² is H, alkyl of 1 to 4 carbon atoms, or phenyl; m is 1 to 5; n is 1 to 10; s is 0 to 5: p is 0 to 3; t is 0 or 1 whereby a) compounds of the Formula (I), where X¹ is Sn(R)₃ and R is alkyl of 1 to 6 carbon atoms or phenyl and X² is imidazoyl where R¹ is n -butyl, R³ is Cl, and R² is hydroxymethyl may be prepared by the 1,3-dipolar cycloaddition of trialkyltin or triphenyltin azides to the appropriately substituted nitrile (II) b) compounds of the Formula (I) where X¹ is C(phenyl)₃ and X² is Br may be prepared via radical bromination of (VII) with N-bromosuccinimide (NBS) and dibenzoylperoxide (Bz₂O₂) c)compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is I may be prepared via displacement of the bromine moiety in (XII) with sodium iodide in acetone under standard conditions d) compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is OH may be afforded by a displacement-reaction of the bromide in Formula (XII) with a hydroxide ion; e) compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is the chloride can be afforded by reaction of the alcohol (XIV) with carbontetrachloride and triphenylphosphine; f) compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is tosylate or mesylate can be afforded by reaction of the alcohol (XIV) with p-toluenesulfonyl chloride or methanesulfonyl chloride, respectively in pyridine under standard conditions; The process of Claim 1 wherein X¹ is H, Sn(R)₃ or -C(Phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl. The process of Claim 1 wherein X² is Br, Cl or where R¹, R² and R³ are as defined in Claim 1. The process of Claim 3 wherein R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴; -(CH₂) m NHSO₂R⁸; R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbon atoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹; or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5. The process of Claim 1 wherein X¹ is H, Sn(R₃) or -C(Phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl, and X² is Br, Cl or where R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴; -(CH₂) m NHSO₂R⁸; R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbon atoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹; or NR¹⁰R¹¹; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5. with the proviso that when X¹ = H then X² is not The process of Claim 5 wherein X² is Br or wherein R¹ is alkyl of 3 to 7 carbon atoms; R² is -(CH₂) m OR⁴ where m is 1 to 5 and R⁴ is H or alkyl of 1 to 4 carbon atoms; and R³ is Cl. The process of Claim 6 wherein X² is Br. The process of Claim 6 wherein X² is wherein R¹, R² and R³ are as defined in Claim 6. The process of Claim 8 wherein R¹ is n -butyl, R² is -CH₂OH and R³ is Cl.

Inventors: ALDRICH PAUL EDWARD, DUNCIA JOHN JONAS VYTAUTAS, PIERCE MICHAEL ERNEST, ALDRICH, PAUL EDWARD, DUNCIA, JOHN JONAS VYTAUTAS, PIERCE, MICHAEL ERNEST
Applicants: DU PONT, E.I. DU PONT DE NEMOURS AND COMPANY
Application year: 1988
Main classification: C07D257
IPC codes: C07F7, C07D403, C07D257