United States Patent (19) (11) Patent Number: 4,874,867 Aldrich et al. 45) Date of Patent: Oct. 17, 1989 54 TETRAZOLE INTERMEDIATESTO FOREIGN PATENT DOCUMENTS ANTHYPERTENSIVE COMPOUNDS 2026286 2/1987 Japan ................................... 548/101 75 Inventors: Paul E. Aldrich, Wilmington; John Jonas V. Duncia, Newark; Michael E. Primary Examiner-David B. Springer Pierce, Wilmington, all of Del. Attorney, Agent, or Firm-Black & Sutherland (73) Assignee: E. I. Du Pont De Nemours and 57 ABSTRACT Company, Wilmington, Del. Tetrazole intermediates useful to prepare antihyperten 21 Appl. No.: 275,583 sive compounds described in coassigned application 22 Filed: Nov. 23, 1988 U.S. Ser. No. 884,920, filed July 11, 1986, are described, these tetrazoles have the formula: Related U.S. Application Data CH2X2 62) Division of Ser. No. 53,198, May 22, 1987, Pat. No. 4,820,843. 51 Int. Cl. .... OO CO7D 257/04; C07F 7/22 (52) U.S. C. ...................................... 548/101; 54.6/11; GO) N 544/64; 544/225 (58) Field of Search .................... 544/64, 225; 54.6/11; O-x 548/101 56) References Cited U.S. PATENT DOCUMENTS wherein X1 and X2 are as described in the specification. 4,454,135 6/1984 Lepone ... - O do a 0 m 544/64 4,486,424 12/1984 Wehner .................... ... 548/101 10 Claims, No Drawings 4,874,867 1. TETRAZOLE INTERMEDIATESTO ANTHYPERTENSIVE COMPOUNDS This is a division of application Serial No. 5 07/053,198, filed May 22, 1987, now U.S. Pat. 4,820,843. BACKGROUND OF THE INVENTION 1. Field of the Invention R is alkyl of 1-6 carbon atoms, phenyl or cyclohexyl; This invention relates to substituted tetrazoles useful" R1 is alkyl of 3-10 carbon atoms, alkenyl of 3 to 10 as intermediates in the preparation of antihypertensive carbon atoms, alkynyl of 3 to 10 carbon atoms, and compounds described in copending U.S. patent applin., benzyl substituted with up to two groups selected Ser. No. 884,920 Filed July 11, 1986. from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of S. Kozima et al., J. Organometallic Chem, 33, 337, 15 1 to 4 carbon atoms, nitro and amino; (1971) and ibid, 92, 303 (1975) describes substituted R2 is phenylalkenyl wherein the aliphatic portion is 2 to tetrazoles of the formula: 4 carbon atoms, -(CH2)n-imidazoyl-1-yl, -(CH2)- 1,2,3-triazolyl optionally substituted with one or two R1 groups selected from CO2CH3 and alkyl of 1 to 4 carbon atoms, )= N 20 N V 2 nN.1 N-R wherein R1 is lower alkyl, benzyl, lower alkenyl or 25 phenyl optionally substituted by nitro, lower alkyl, lower alkoxy or halogen; and R2 is SnR3. R. Lofguist et al., J. Amer. Chem. Soc., 80, 3909 (1958) describes substituted tetrazoles of the Formula: 30 )- N. nN.1 NH 35 R3 is H, F, Cl, Br, I, NO2, CF3, or CN: R is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to wherein R is lower alkyl, benzyl, cycloalkyl of 4 carbon 6 carbon atoms, phenyl or benzyl; atoms, n-heptyi perfluoro, -SR1 where R is lower R5 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, alkyl, benzyl; -(CH2)R2 where R2 is OH, CO2R1, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; OR, SO3Na and n is 1 or 2; or phenyl optionally substi R6 is H, alkyl of 1-5 carbon atoms, OR9 or NR10R11; tuted with amino, lower alkoxy, lower alkyl, nitro or R7 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to cyano. 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon W. Beck, et al., Chem. Ber, 116, 2691 (1983) describes atoms, phenacyl; the preparation of 2-trityl-5-phenyl tetrazole. 45 R8 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-napthyl, 1-(1-nap SUMMARY OF THE INVENTION thyl)ethyl, or (CH2)C6H5; According to the present inventon, there are pro R9 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to vided novel compounds of Formula (I) which are tet 6 carbon atoms, or phenyl; razole intermediates useful for the preparation of anti- 50 R10 and R11 independently are H, alkyl of 1 to 4 carbon hypertensive compounds. These tetrazoles have the atoms, phenyl, benzyl or taken together to form a Formula: ring of the Formula CH2X2. 55 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; wherein 6S p is 0 to 3; X1 is H, Sn(R)3, -COPhenyl)3, p-nitrobenzyl, or 6-pro t is 0 or . pionitrile; with the proviso that when X = H then X2 cannot be X2 is H, Cl, I, O-tosyl, OH, O-mesyi, or 4,874,867 4. able attachment to nitrogen on the imidazole nucleus. Throughout the followiong section, not all compounds of Formula (I) falling into a given class may necessarily be prepared by all emthods described for that class. Substituents on the starting materials may be incompati ble with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction Preferred compounds are those of Formula (I) where: conditions will be readily apparent to one skilled in the X1 is H, Sn(R)3 or -COphenyl)3 where R is alkyl of 1 to 10 art and alternative methods must then be used. 6 carbon atoms or phenyl; or Compounds of the Formula (I), where X is Sn(R)3 X2 is H, Br, Cl, or the substituted imidazole; or and R is alkyl of 1 to 6 carbon atoms or phenyl and X? R1 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; is H or imidazoyl where R1 is n-butyl, R3 is Cl, and R2 R2 is -(CH2)OR; 15 is hydroxymethyl may be prepared by the 1,3-dipolar cycloaddition of trialkyltin or triphenyltin azides to the O R5 appropriately substituted nitrile (II) (Scheme I). An I example of this technique is described by S. Kozima, et -(CH2)OCR5, -CH=CH-CHOR7 al., J. Organometallic Chemistry, 33, 337 (1971). The O O 20 nitrile (II) is described in the coassigned application I U.S. Ser. No. 884,920, filed July 11, 1986. Other re -(CH2)C-R6, -CH2NHCOR; -(CH2)NHSO2R; quired nitriles and trialkyl or triaryl tin azides are either N-N W O available commercially, or may be prepared using tech W niques and methods reported in the chemical literature, -CH-4 N; or -CR5, 25 J. Luijten et al., Rec. Tray, Chem, 81, 202 (1962). N H Scheme R3 is H, Cl, Br, or I; CH3 CH3 R is H, or alkyl of 1 to 4 carbon atoms; 3O R5 is H, or alkyl of 1 to 4 carbon atoms; Sn(R)3N3St Ge. R6 is H, alkyl of 1 to 5 carbon atoms; OR9; or NO; N-N R7 is H, alkyl of 1 to 4 carbon atoms, or acyl, of 1 to 4 O -A-Sn(R)3 carbon atoms; CN N R8 is CF3, alkyl of 1 to 6 carbon atoms or phenyl; 35 m is 1 to 5. Specifically preferred compounds are those of For O O N1 mula (I) where: (1) (II) (III) X1 is Sn(CH3)3, Sn(Ph)3, Sn(n-Bu)2, C(Phenyl)3, or 9 Compounds of the Formula (I), where X and X2 are H; and H may be prepared by removal of a suitable protecting X2 is H or Br. group on the tetrazzole nucleus. Suitable protecting (2) groups for the tetrazole moiety include p-nitrobenzyl, X is Sn(CH3)3 or C(Phenyl)3; and g-propionitrile, triphenylmethyl, and trialkyltin which X2 is 45 are prepared via the following methods. The nitroben zyl protecting group is attached as shown in Scheme II. (CH2)3CH3 The acid (IV) is converted to the intermediate acid e chloride with oxalyl chloride under standard condi N N- 50 tions. The acid chloride is converted to the amide (V) by condensation with 4-nitrobenzylamine hydrochlo Cl CHOH ride in pyridine in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP). The amide (V) is converted to the intermediate iminoylchloride via reac SYNTHESIS 55 tion with phosphoruspentachloride in carbon tetrachlo The novel compounds of Formula (I) may be pre ride. One example of this method is described by H. pared using the reactions and techniques described in Ulrich, The Chemistry of Imidoyl Halides, Plenum Press, this section. The reactions are performed in a solvent N.Y., N.Y. (1968). The intermediate iminoyl chloride is appropriate to the reagents and materials employed and 60 converted to the tetrazole (VI) with lithium azide in suitable for the transformation being effected. It is un dimethylformamide (DMF). An example of this method derstood by those skilled in the art of organic synthesis is described by Elderfield, Heterocyclic Compounds, that the functionality present on the imidazole and other John Wiley and Sons, (1967). The protected tetrazole portions of the molecule must be consistent with the (VI) is then hydrogenated at 50 psi in the presence of a chemical transformations proposed. This will fre 65 catalytic amount of W6 Raney nickel in ethanol to yield quently necessitate judgment as to the order of syn (I). The required acid (IV) is available commercially or thetic steps, protecting groups required, deprotection may be prepared using techniques and methods re conditions, and activation of a benzylic position to en ported in the chemical literature.