PROCESS FOR PREPARING A SUBSTITUTED OR AN UNSUBSTITUTED 4(5)-( omega -AMINOALKYL)IMIDAZOLE

Abstract: A process for preparing a substituted or unsubstituted 4(5)-( omega -aminoalkyl)imidazole of formula (5), wherein n is 1 to 6, R1 is hydrogen or a linear, branched or cyclic, saturated or unsaturated alkyl group having 1-6 C-atoms or a phenyl ring being unsubstituted, or mono- or di-substituted with groups such as lower alkyl, halogen, alkoxy, methylendioxy or a combination thereof, and R2 is hydrogen or methyl, by brominating an omega -phthalimidoalkan-2-one with bromine in anhydrous methanol to a 1- or 3-bromo- omega -phthalimido-alkan-2-one, subjecting said derivative to ring closure with an amidine in N.N-dimethylformamide with potassium carbonate under mild conditions followed by hydrolytic separation of the phthalic residue.

Description: Pr.ocess for preparing a substituted or an unsubstituted 4(5)- (ω-aminoalkyl) imidazole . The invention relates to a process for preparing a substituted or an unsubstituted 4 (5) - (ω-aminoalky1) - imidazole, by brominating an ω-phthalimidoalkan-2-one to a 1- or 3-bro_no-ω-phthalimido-alkan-2-one , subjecting said derivative to ring closure with an amidine, followed by hydrolytic separation of the phthalic residue. Such a process is already known from S.Elz and W.Schunack, Z.Naturforsch. , 42b, 238-242 (1987) . Histamine H -receptor agonists, like Impromidine ( 1 ) described in Proc. Vlllth Internat. Symp.Med. Chem. , Uppsala, pages 202-203 (1985) , editors R. Dahlblom and J.L.G. Nilson, SK&E 91486 (2) described by M.E. Parsons et al., Agents and Actions. 5, 464 (1975) and N- (ω- substituted alky1) - '-{ (imidazole-4-yl) -alkyl) } guanidines, described in Dutch patent application 86 01585 and indic¬ ated therein with formula 1, all contain under physiologic¬ al conditions a protonated "substituted" N-{ω- (imidazole- 4-yl) alkyl}guanidine fragment which is essential for the biological activity of this type of compounds. For the preparation of these and other H. and H_- receptor active compσu-nds the 4 (5)- (2-aminoethyl) imidazole or histamine (3) and 4 (5) - (3-aminopropyl) imidazole (4) , in general the substituted 4 (5) - (ω-aminoalkyl) imidazoles 5 (5) are: of crucial importance as starting materials for the preparation of the above mentioned H and H„-receptor_ active coBrpruinds» so that in the field of pharmaceutical industry tire - eere highly interested in the preparation of this kixπi of! compounds, in view of pharmaceutical 10 composition for th.e treatment of heart failures and allergic co~rditions. Tedious syntheses of 4 (5) - (3-aminopropyl) imidazole (4) starting from one of the two difficult obtainable compounds 4 (5) - (2-bromoethyl) imidazolium bromide and 15 4 (5) - (2-choloethyl) imidazolium chloride as described by W.Bloemhσff and K.E.T. Kerling, Rec .Tra . Chim. , 89, 1181-1184 C1970) , followed by chain extension with sodium cyanide 'or potassium cyanide and by reduction of the obtained nitrile with hydrogen and Raney Nickel catalyst 20 as described in German Off nlegungsschrift 2 053 175, results in almost unacceptable low overall yields of the desired 4 (5)- (3-aminopropyl) imidazole (4) . In the process described by S. Elz and W. Schunack Z.Naturforsch., 42b, 238-242 (1987) in the preamble, 25 the bromination of 5-phthalimidopentane-2-one to 1-bromo- 5-phthalimidopentane-2-one (6) is carried out in a b-butanol/methanol mixture with an equivalent bro o/ dioxane complex which results in a yield of only 22%. The following ring closure in liquid NH, under elevated 30 pressure, followed by isolation of the desired imidazole via the dipicrate is impracticable in large scale syntheses . • Preparation of the corresponding halogen compounds from the corresponding diazoketones as described by J. Michalsky, J. Borkovec and J.Hadacek, Chem.Listy Vedu Prum.49, 1979 (1955) , cf. Chem.Abstr .50 , 5681d (1956) does not lend itself for large scale syntheses, and the bromination as described by E. . Garbisch Jr., J.Org.Chem. 30, 2109 (1965) for the 3-phthalimidopropan-2-one , according to M.Gall and B.V. Kamdar, J .Org. Chem.46 , 1575-1585 (1981) does not lend itself for scale enlargement. - Alternatively the ring closure of -a 1-bromo-ω- phthalimidoalkan-2-one with an amidine as mentioned for the preparation of 2-methylhistamine under the reaction con¬ ditions reported by Durant et al. , J.Med. Chem. , 19(7) , 923-928 (1976) is not very advantageous due to low yields obtained in this procedure. It was now found that with the process as described in the preamble a much higher yield can be reached than disclosed in the state of the art, when certain reaction conditions are taken into account towards bromination and the ring closure. In this process the bromination proceeds with great selectively, which enhances the yield highly, in addition the process is suitable for large scale application. The process is practical for a large number of compounds, among which histamine and its analogues, some of which even being novel. The invention has the characterizing features that in a process as described in the preamble a substitut¬ ed or unsubstituted 4 (5)- (ω-aminoalkyl) imidazole of the formula 5 is prepared, wherein n is 1 to 6, R. is hydrogen or a linear, branched or cyclic, saturated or unsaturated alkyl group having 1-6 C-atbms or a phenyl ring being unsubstituted, mono- or di substituted with groups such as lower alkyl, nitro and/or amino, if any halogen, alkoxy, methylenedioxy or a combination thereof, and R„ is hydrogen or methyl and the bromination with bromine is carried out in anhydrous methanol and the ring closure is carried in N.N-dimethylformamide with potassium carbonate under mil ' d conditions . The invention also relates to a pharmaceutical composition that contains a compound obtained according to the just described process. The invention also relates to the use of said compound 5 or pharmaceutical composition as obtained by the earlier mentioned method for the treatment of heart and vasculer diseases or allergic affections. The present synthetic proceeds according to the annexed reaction scheme. 10 As starting materials serve in the above mentioned reaction scheme ω-phthalimido-2-alkanones (7) which can be prepared according to known literature methods. The bromination of these ketones is performed according to the method for the selective bromination 15 of 2-alkanones as mentioned by M. Gaudry and A.Marquet, Tetrahedron, 26, 5611-5615 (1970) which method gives significantly higher yields of the desired primary bromo compounds (10) in comparison with the method described by S. Elz and W. Schunack, Z .Natur . forsch.42b , 238-242 20 (1987) . Deperx ng on the natTfe of the starting materials the intermediate bromo dimethyl acetals (8) and (9) are isolated and purified before hudrolysis, or the total reaction mixture is hydrolysed and the bromo ketones (10) 25 and (11) are separated by fractional crystallization. Although the secundary bromo ketones (11) are prod¬ uced with low yields, they have been isolated from the reaction mixture to serve as starting material for the ring closure to 4- (ω-phthalimidoalkyl) -5-methylimida- 30 zoles (13) and alternatively they can be obtained in much higher yields by bromination in solvents like acetic acid. The ring closure of the bromo ketones (10) and (11) together with lower alkane amidines or substituted benzamidines leading to the formation of 4( 5) -( '-phthal- imidoalkyl ) imidazoles (12) and corresponding methyl derivatives (13) is performed in N .N-dimethyl ormamide with potassium carbonate as proton acceptor under mild conditions. Hydrolysis of the compounds (12) and (13) with diluted hydrochloric acid as described in U.S. patent specification 3 736 331, or hydrazinolysis with hydrazine hydrate as described by ' M.Gail and B.V.Kamdar, J.Org. Chem. 46, 1575-1585 (1981) provides 4( 5)-( .. 1 -aminoalkyl ) imidazoles ( 5) . The invention is illustrated by the following examples. All chemicals and solvents are commercially avail¬ able unless otherwise stated. Melting points were determined with a Mettler FP 52 melting point apparatus. H-NMR-spectra were measured with a Bruker WH-90 spectrophotometer and chemical shifts S (in ppm) are given relative to tetramethylsilane . Mass spectra are recorded on a Varian Mat CH_ spectrometer . Example I a. 4-Phthalimidobutan-2-one (7a) The 4-phthalimidobutan-2-one is prepared according to a modified procedure as mentioned by H.Irai et al . , Kogyo Kagaku Zasshi. , 62, 82-85 (1959) ; cf. Chem.Abstr. , 58, 5659b (1963). To a well stirred suspension of 147 g (1 mole) of phthalimide and 70 g (1 mole) of methyl vinyl ketone in 1000 ml ethyl acetate is added under nitrogen a freshly prepared solution of 2.7 g (0.05 mole) of sodium 5 methoxide in 250 ml anhydrous methanol. After stirring for two hours at room temperature the mixture is heated until reflux remperature and refluxed untii an almost clear solution is obtained and refluxing is continued for an additional two hours. 10 The solution is allowed to cool down and concentrat¬ ed in vacuum and the residue is recrystallized from hot 96% ethanol. ' Yield 90%. Melting point 108.5-110.0°C (Lit: H.Irai et al. , 15 111-113-C). H-NMR (CDC1 3 ): 2.22 ppm., singlet, 3 H; 2.96 ppm.,triplet (J = 7 Hz), H; 3.96 ppm., triplet (J = 7 Hz) , 2H; 7.62-7.96 ppm. , multiplet, 4 H. b . l-Bromo-4-phthalimidobutan-2-one lOa) 20 To a suspension of 130 g (0.6 mole) of 4-phthalimi- do butan—2-one (7a) in 1000 ml of absolute methanol is added 96 g (0.6 mole) of bromine and the reaction mixt¬ ure is stirred for 24 hours at room temperature. The precipitate, N-(4-bromo-3.3-dimethoxybutyl ) 25 phthalimide (8a) is filtered off, suspended in methanol and 30 ml of 10 N sulfuric acid is added, after which the reaction mixture is heated until a clear solution is obtained. After cooling down the precipitate is collected and 30 rrecrystallized from hot methanol. Yield 60%. SUBSTITUTESHEET Melting point: 120-122°C (lit: R.G.Jones et al . , J.Am. Chem.Soc , 72, 4526-4529 (1950) , 119-120-C). 1 H-NMR (CDC1 ) : 3.13 ppm. , triplet , 2 H (J = 7.2Ηz) ; 3.92 ppm. , singlet, 2 H; 4.04 ppm. , triplet (J = 7.2 Hz) , 2 H; 7.60-7.96 ppm. , multiplet, 4 H. c. 4( 5)-(2-phthalimidoethyl ) imidazole (12a) A mixture of 29.6 g (0.1 mole) of l-bromo-4- phthalimido- butar.-2-one (10a) , 10.4 g (0.1 mole) formamidine acetate, 27.6 g (0.2 mole) of carefully 10 grounded anhydrous potassium carbonate and 150 ml of anhydrous N. N-dimethylformamide is slowly heated in a shaking autoclave for about 24 hours to 80°C. After cooling down the solid inorganic materials are filtered off and the filtrate is concentrated in 15 vacuum. To the residue 50 ml of xylene is added and again concentrated in vacuum to remove traces of N . - dimethylformamide , after which the residue is taken up in 200 ml of ethyl acetate and extracted three times with 50 ml of demineralized water. 20 The organic layer is dried on anhydrous sodium sul- fate, filtered and concentrated in vacuum. The residue is taken up in aceton and a saturated solution of oxalic acid in aceton is added until no more precipitation occurs. 25 The precipitate is filtered off, washed with three portions of warm aceton and dried in vacuum. Yield 60%. Melting point: the o-xalate decomposes on heating. 1 *l H-NMR ' (CDCl_/d.-DMS0) : 2.91 ppm., triplet ( J = 7.2 Hz), b 30 2 H; 3.96 ppm., triplet (J = 7.2 Hz) , 2 H + 6.84 ppm. , singlet, _L H; 7.63 ppm., singlelt, 1 H; 7.74 ppm. broad singletr, 4 H *: 8-12 ppm., broad singlet, 1 H free base SUBSTITUTE SHEET d. 4(5)—(2-Aminoethyl) imidazoledihydrochloride (histarninedihydrochloride) (5a) The 4(5)-(2-aminoethyl ) imidazole dihydrochloride is prepared by hydrolysis of 4( 5)-(2-phthalimidoethyl ) 5: imidazole (12a) according to.U.S. patent specification 3r 736-- 331. A solution of 16.55 g (0.05 mole) of 4(5)-(2- phthalimidoethyl) imidazole (12a) oxalate is dissolved in 200 ml of distilled water and brought on pH = 12 with 10 a diluted sodium hydroxide solution. The base is extract¬ ed with ethyl acetate, and the organic layer is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is hydrolysed by refluxing with 5 N 15 hydrochloric acid and after cooling down the volume is reduced in vacuum, the phthalic acid is filtered off and the filtrate is concentrated to dryness, after which the residue is recrystallized from hot ethanol. Yield 85%. 20 Melting point 249-252°C. H-NMR (D O): 3.38-3.80 ppm. ,multiplet, 4 H; 7.72 ppm., doublet (J =0.6 Hz), 1 H; 8.98 ppm., doublet (J = l Hz), 1 H. Example II -"" a • 5-Phthalimido pentan-2-one (7bj 5-Phthalimidopentan-2-one is prepared according to a modified procedure as mentioned by M.Sletzinger et al. , Chem. & Ind. (London) , 1957, 1215. A mixture of 294 g (2 moles) of phthalimide, 30 241 g (2 moles) of 5-chloropentan-2-one and 198 g (2 moles) of carefully grounded anhydrous potassium carbonate in SUB TT 1000 ml of anhydrous .N-dimethylformamide was heated while stirring for a period of 12 hours at 110°C. After cooling down the inorganic solids were filtered off and the filtrate was concentrated in vacuum. 5 The residue was dissolved in 500 ml ethyl acetate and after- standing overnight at 0°C the unreacted phthal¬ imide was filtered off, the filtrate was concentrated in vacuum and the residue was recrystallize from hot methan¬ ol. 10 Yield 53%. Melting point: 72-74 °C (Lit: M. Sletzinger et al . , 75-77°C; S. Elz and W.Schunack, Z .Natur .Forsch . , 42b, 238-242 (1987) , 71-72°C) . " "Ή-NMR (CDClg): 1.89-2.12 ppm. , multiplet, 2 H; 2.15 ppm. , 15 singlet, 3 H; 2.51 ppm., triplet (J = 7.2 Hz) , 2 H; 3.72 ppm., triplet ( J = 6.6 Hz) , 2 H; 7.67-7.92 ppm. , multiplet, 4 H. b . l-Bromo-5-phtalimidopentan-2-one ( lObj To a solution of 231 g (1 mole) of 5-phtalimido- 20 pentan-2-one (7b) in 1350 ml of anhydrous methanol was added at 0°C in one portion 160 g (1 mole) of bromine. While stirring, the mixture was allowed to warm up to ambient temperature and stirring was continued for an additional 24 hours. 25 To the clear solution 200 ml of 10 N sulfuric acid was added and the reaction mixture was left over¬ night. The precipitate was collected, suspended in 500 ml of methanol and refluxed for 15 minutes and the B STITUTESHEET crystalline material was filtered off while hot, washed with two portions of 100 ml of hot methanol and ' dried in vacuum. Yield 52%. 5 Melting point: 131-133.4°C (Lit: S.Elz and W.Schunack, Z.Natur.forsch. 42b, 238-242 (1987), 122-125°C, J. Micnalksk-y e-t al. r Chem.Listy, 49, 1379-1384 (1955), cf. Chem.Abstr.. 50, 5681 d (1956), 139-C. L H-NMR (CDClg): 1.82-2.24 ppm., multiplet, 2 H; 2.74 ppm., 1 0 triplet (J= 7.2 Hz), 2 H; 3.74 ppm.,triplet (J -= 7.2 Hz), 2H; 3.94 ppm., singlet, 2 H; 7.64-7.88 ppm., multiplet, 4 H. c. 4(5)-(3-Phthalimidopropyl) imidazole (12b) A mixture of 114.0 g (0.37 mole) of l-bromo-5- 15 phthalimidopentan-2-one (10b), 38.3 g (0.37 mole) of formamidine acetate, 101.5 g (0.74 mole) of carefully grounded anhydrous potassium carbonate and 500 ml of anhydrous N.N-dimethylformamide is slowly heated in a shaking autoclave for 24 hours at 80°C. After cooling 20 down the solid inorganic materials are filtered off and the filtrate is concentrated in vacuum. To the residue 200 ml of xylene is added and it is again concentrated in vacuum to remove traces of N.N-dimethylformamide ,after which the residue is taken up in 750 ml of ethyl acetate 25 and is extracted three times with 100 ml of demineralized water. The organic layer, is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is taken up in aceton and a saturated 30 solution of oxalic acid in aceton is added until no more precipitation occurs. The precipitate is filtered off, washed with warm aceton and dried in vacuum. Yield 55%. Melting point: the oxalate decomposes on heating. " " " H-NMR* (CDC1 3 ): 1.80-2.12 ppm., quintet ' (J = 7.2 Hz) , 2 H÷ 2.60 ppm., triplet (J = 7.2 Hz), 2 H; 3.68 ppm., triplet (J = 7.2 Hz), 2 H; 6.81 ppm., singlet, 1 H; 7.54 ppm. , singlet, 1 H; 7.54-7.85 ppm., multiplet, 4 H. Position of NH-proton strongly depends on concentration. free base. -• ^ . ^^ -^J^S-^A ^nopropy^^^m^dazole_ dihydrochloride H-.l 4( 5)-(3-aminopropyl ) imidazole (5b) dihydrochlori.de is prepared by hydrolysis of 4( 5)-3-phthalimidopropyl )- imidazole (12b) according to U.S. atent specification 3 736 331. l A solution of 17.25 g (0.05 mole) of 4(5)-(3- phthalimidopropyl ) imidazole (12b) oxalate is prepared in 200 ml of distillated water and brought on pH = 12 with a diluted sodium Hydroxide solution. The base is extract¬ ed with ethyl acetate and the organic layer is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is hydrolysed by refluxing with 5 N hydrochloric acidj/and after cooling down the volume is reduced in vacuum, the phthalic acid is filtered off and the filtrate is concentrated to dryness, after which the residue is recrystallized from ethanol/ether. Yield 92%. Melting point: 154-155°C (Lit: J.W. Black et al , U.S. patent speci ication 3 736 331, 156°-158°C). 1 H-NMR (d e -DMS0): 1.80-2.13- ppm. ,multiplet, 2 H: 2.80 pprn. , broad triplet ( = 7.2 Hz), 4 H; 2.8 H; 7.52 ppm., doublet (J = 0.6 Hz), 1 H; 8.30 ppm., broad singlet, 2.6 H, 9.14 ppm., doublet ( - 1 Hz), 1 H. Example IIX 3-Bromσ—4—phthalimidobutan-2-one (lib ) The filtrate obtained after the removal of 10 N-(4-bromo-3.3-dimethoxybutyl)phthalimide (8a) in example lb is treated with diluted sulfuric acid and worked up as mentioned for the preparation of l-bromo-4-phthalimido- butan-2-one (10a) in the same example. Yield 30%. 15 Melting point: 104°-105°C. "" H-NMR (CDC1 ): 2.46 ppm.; singlet, 3 H; 4.16-4.28 ppm., double doublet, 2 H; 4.76-4.92 ppm., broad triplet, 1 H; 7.71-7.95 ppm., multiplet, 4 H. Example IV a • 3-Bromo-5-phthaIimidopentan-2-one ( lib) The mother liquor obtained after the filtration of the l-bromo-5-phthalimidopentan-2-one (10b) in example lib was concentrated to approximately half of its original volume and the precipitate was filtered off and 25 recrystallized from hot methanol. Yield 35%. Melting point 99.0°-100.7°C. 1 H-NMR (CDClg): 2.22-2.70 ppm., multiplet, 2 H; 2.42 ppm. I J- singlet, 3 H; 3.80 ppm. , triplet (J = 6.6 Hz) , 2 H; 4.34 ppm., triplet ( J = 7.2 Hz) , 1 H 7.66-7.90 ppm. , multiplet, 4 H. Mass spectrum M/Z (% rel . , fragm.): 267(20) 230(99) , 5 188(47) , 174(52) , 161(94) , 160(100) , 148(23) , 133(20) , 104(43) . M +" =--M/Z 309-0006 calculated c 13 H 12 BrN0 3 309.0001 b . 4-methyl-5 (2-phthalimidoethyl) imidazol A mixture of 31.0 g (0.1 mole) of 3-bromo-5- 10 phthalimidopentan-2-one (lib), 10.4 g (0.1 mole) of formamidine acetate, 27.6 g (0.2 mole) of carefully grounded anhydrous potassium carbonate and 150 ml of anhydrous N.N-dimethylformamide is heated in a shaking autoclave at 80°C for 24 hours. 15 After cooling down the solid inorganic materials are filtered off and the filtrate is concentrated in vacuum. To the residue 50 ml of xylene is added and it is again concentrated in vacuum to remove traces of N.N- dimethylformamide , after which the residue is taken up in ' 20 200 ml of ethyl acetate and extracted three times with 50 ml of demineralized water. The organic layer is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is taken up in aceton and the mixture 25 is allowed to crystallize. The precipitate is filtered off, washed with 3 portions of warm aceton and dried in vacuum. Yield 70%. Melting point: 197.0°-198.5°C . 30 H-NMR (CDC1 /dg-DMSO) : 2.10 ppm., singlet, 3 H; 2.90 prp -. , triplet (J s 7.2 Hz) , 2 H; 3.90 ppm. , triplet (J = 7.2 Hz) , 2 H; 7.40 ppm, singlet ' , 1 H; 7.43 ppm., singlet, 0.7 H; 7.64-7.85 ppm., multiplet, 4 H. Mass spectrum M/Z (% rel., fragm.) : 255(37) , 230(5) , 174(52) , 160(33) , 108(100) , 95(92) . M + = M/Z 255.1021 calculated C 14 H 13 N 3 0 2 255.1008. c. 4-(2-Aminoethyl)_-5-methylimidazole_dihydro- chloride (5c) 4-2-AminoethyL) -5-methylimidazole dihydrochloride is prepared " by- hydrolysis of 4-methyl-5 (2-phthalimido- 10 ethyl) imidazole (13a) according to U.S. patent specificat¬ ion 3 736 331. A solution of 15.3 g (0.06 mole) 4- (2-phthalimido- ethyl) -5-methylimidazole (13a) in 150 ml 5N hydrochloric acid is heated under reflux for 5 hours and after cool- 15 ing down the volume is reduced in vacuum, the phthalic acid is filtered off and the filtrate is concentrated to dryness, after which the residue is recrystallized from ethanol/ether. Yield 86%. 20 Melting point: hydrochloride decomposes on heating. H-NMR (D 0/DMSO) : 2.15 ppm., singlet, 3 H; 3.25-3.70 ppm., broad singlet, 4 H; 7,40 ppm., singlet, 1 H. Example V 25 a. 2.5-dimethyl 4- (2-phthalimidoethyl) _imidazole ill≥l A mixture of 31.0 g (0.1 mole) of 3-bromo-5- phthalimidopentan-2-one (lib), 11.8 g (0.1 mole) of acetamidine acetate, 27.6 g (0.2 mole) of carefully 30 grounded anhydrous potassium carbonate and 150 ml of an¬ hydrous N.N-dimethylformamide is heated in a shaking autoclave at 80°C for 24 hours. After cooling down the solid organic materials are filtered off and the filtrate is concentrated in vacuum. To the residue 50 ml of xylene is added and it is again concentrated in vacuum to remove traces of N.N-di- methylformamide , after which the residue is taken up in 200 ml of ethyl acetate and extracted three times with 50 ml of demineralized water. The organic layer is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is taken up in aceton and a saturated solution of oxalic acid in aceton is added until no more precipitation occurs. The precipitate is filtered off, washed with three portions of warm aceton and dried in vacuum. Yield 40%. Melting point: the oxalate decomposes on heating. 1 H-NMR* (CDCl 3 /dg-DMS0) : 2.10 ppm. , singlet, 3 H; 2.25 ppm. , singlet, 3 H; 2.90 ppm. , triplet (J = 7.2 Hz) , 2 H; 3.90 ppm. , triplet ( J = 7.2 Hz) , 2 H; 7.43 ppm. , singlet, 0.7 H; 7.64-7.85 ppm. , multiplet, 4 H. * " free base ~* - -__i -_--_--?.iΞ-?^ £l_L££i__. __ -_-l• 4-(2-Aminoethyl )-5-methylimidazole dihydrochloride (5d) is prepared by hydrolysis of 2.5-dimethyl 4- (2-phthalimid< ethyl) -imidazole (13b) according to U.S.patent specif¬ ication 3 736 331. A solution of 9.4 g (0.035 mole) 2.5-dimethyl 4(2- phthalimidoethyl) -imidazole (13b) oxalate in 200 ml distill- ed water is- brought on pH = 12 with diluted sodium hydrox¬ ide solution. The base is extracted with ethyl acetate and the organic layer is dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is hydrolysed by refluxing with 5 N hydrochloric acid and after cooling down the volume 5 is reduced in vacuum, the phtalic acid is filtered off and the filtrate is concentrated to dryness, after which the residue is recrystallized from ethanol/ether . Yield 91%. Melting point: the hydrochloride decomposes on 10 heating. 1 H-NMR (D 2 0/DMS0): 2.10 ppm., singlet, 3 H; 2.38 ppm, singlet, 3 H; 3.23-3.65 ppm., broad singlet, 4 H. Example VI a. 2-Phenyl-4(5)-( 2-phthalimidoethyl) imidazole- •**-•• hydrochloride (13c) A mixture of 12.0 g (0.1 mole) benzamidine, 29.6 (o.l) mole l-bromo-4-phthalimidobutan-2-one (10a), 27.6 g (0.2 mole) of carefully grounded anhydrous potassium car¬ bonate and 125 ml of anhydrous .N-dimethylformamide is 20 "heated under stirring at 35°C for 24 hours, after which it is subsequently heated at 50°C for 2 hours. After cooling down the reaction mixture is con¬ centrated in vacuum, after which to the residue deminer¬ alized water is added. Subsequently it is extracted 3 25 times with 50 ml ethyl acetate, the combined organic phases are collected, dried on anhydrous sodium sulfate, filtered and concentrated . in vacuum. To the residue a circa 3% -hydrochloric acid- solution is added and under stirring carefully heated to 30 40°C. After cooling down the precipitate is filtered off and dried in vacuum, after which it is crystallized from methanol . Yield 40%. Melting point: 222.0-225.0°C (dec ) 1 H-NMR ( d -DMSO) : 3.23 ppm. , triplet ( J = .5 Hz) , 2 H, o 4.13 ppm. , triplet (J = 7.5 Hz) , 2 H; 7.60-7.87 ppm. , multiplet, 4 H; 8.00 ppm. , singlet, 4 H; 8.20-8.40 ppm. , multiplet, 2 H; 15.17 ppm. , broad singlet, 1.4 H. b. 4 (5) - (2-aminoethyl) 2-phenyl-imidozole-dihydro £___i££__.£ ____l -l 10 A .solution of 12.4 g (0.035 mole) 2-phenyl-4( 5 ) - ( 2-phthalimidoethyl ) imidoethyl ) imidazole hydrochloride (13c) and 8.8 g (0.175 mole) hydrazine hydrate in 150 ml absolute ethanol is heated under reflux for 5 hours. After cooling down and after standing overnight 15 the crystalline material is filtered off, after which the filtrate is concentrated in vacuum. The residue was taken up in 50 ml of absolute ethanol and by means of a concentrated hydrochloric acid solution acidified to acid reaction, after which the 20 precipitate is filtered off. Subsequently " the precipitate is recrystallized from ethanol/water. Yield 85%. Melting point: 268.9-271.0°C (dec) 25 1 H-NMR( d -DMS0) : 3.00-3.50 ppm. , multiplet, 4 H; 7.50-7.75 o ppm. , multiplet, 4 H; 8.00-8.55 ppm. , multiplet, 5 H; 15.16 ppm. , broad singlet, 2 H. Example VII 30 imidazole hydrochloride (13d) A mixture of 15.4 g (0.1 mole) of 4-chlorobenz- amidine, 29.6 g (0.1 mole) of l-bromo-4-phthalimidobutan- 2 -one (10a), 27.6 g (0.2 mole) of carefully grounded anhydrous potassium carbonate and 125 ml anhydrous N.N- 5. dimethyl formamide is heated while stirring at 35°C for 24 hours, after which heating at 50° is continued for A-fTter- cooling down the reaction mixture is concen¬ trated in vacuum, after which demineralized water is added 10." to the residue. Subsequently there is extracted three time ' s with 50 ml of ethyl acetate, the combined organic phases are collected, dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. 15 To the residue a circa 3% -hydrochloric acid- solution is added and while stirring carefully heated to 40°C. After cooling down the precipitate is filtered off and dried in vacuum, after which it is crystallized 20 from an ethanol/ether mixture. Yield 54%. Melting point: 250°C (dec.) 1 H-NMR (db_-DMS0): 3.15 ppm., triplet (J = 7.5 Hz), 2 H; 4.00 ppm., triplet (J = 7.5 Hz), 2 H; 7.70-8.20 ppm., 25 multiplet, 9 H; 14.50 ppm., broad singlet, 2 H. b . 4 5 )-(2-Aminoethyl)-2-(4-chlorophenyl)- imi.da.zole dihydrochloride (5f) A solution of 19.4 g (0.050 mole) of 2-(4-chloro- phenyl)-4(5)-(2-phthalimidoethyl)imidazole hydrochloride 30 (13d) and 12.5 g (0.0250 mole) of hydrazine hydrate in 150 ml of absolute ethanol is heated under reflux for 5 hours . After cooling down and after standing overnight the crystalline material is filtered off, after which the filtrate is concentrated in vacuum. 5 The residue is subsequently taken up in 50 ml- of absolute- e hanol and by means of concentrated hydro¬ chloric: aici L ' s:o.lution acidified to acid reaction, after- wh ch- - r precipitate is filtered off. Thereafter recrystallisation takes place from 10 an ethanol/water mixture. Yield 92% Melting point: 191.3-195.6°C (dec.) 1 H-NMR (d -DMSO) : 2.90-3.60 ppm. , multiplet, 4 H; 7.50 b ppm. , singlet, 1 H; 7.80 ppm. , doublet (J = 9.0 Hz) , 2 H; 15 7.90-8.20 ppm. , broad multiplet, 5 H; 15.10 ppm. , broad singlet, 2 H. Example VIII a . 2-_(4-methoxyoheny1 )_4 { 5 ^-^2~Phtha1^mi^tr^y^^) - ^ i_!li_^__:Ξ£_L£_._i y £ ££_!_L££i-_:£_X__._£l 20 A mixture of 15.0 g (0.1 mole) of 4-methoxybenz- amidine, 29.6_ g (0.1 mole) of l-bromo-4-phthalimidobutan- 2-one (10a) , 27.6 g, (0.2 mole) of carefully grounded anhydrous potassium carbonate and 125 ml of anhydrous N.N-dimethyL formamide is heated while stirring at 35°C 25 for 24 hours-, after which the heating is continued at 50°C for 2 hours. After cooling down the reaction mixture is con¬ centrated in vacuum, after which to the residue deminer¬ alized water is added. 30 " There is extracted three times with 50 ml ethyl acetate, the combined organic phases are collected, dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. To the residue a circa 3% - hydrochloric acid solution is added and carefully heated while stirring to 40 C. After cooling down the precipitate 5- is f.il_.ter:ed. α_ff and dried in vacuum, after which it- is c y-st-BE f.zed from an ethanol/ether mixture. Yield 50% Melting point: 191.3 - 195.6°C (dec.) H-NMR (d 6 -DMSO) : 2.90-3.60 ppm., multiplet, 4 H; 10 " 7.50 ppm., singlet, 1 H** 7.80 ppm., doublet (J = 9.0 Hz) , 2 H; 7.90 - 8.20 ppm., broad multiplet, 5 H; 15.10 ppm., broad singlet, 2 H. Example_VIII 4 (5) -2-Aminoethyl)_-2-^4-methoxyphenyl) i?i^-.52i___^i__∑5E2EΪ-:° r -:-!:_i_-2l A solution of 17.3 g (0.0045 mole) of 4 ( 5) - 2 - (4-methoxypheny1) - ( 2-phthaiimi oethyl) imidazole hydrochloride (13e) and 11.3 g (0.225 mole) of hydrazine hydrate in 150 ml of absolute ethanol is heated under reflux fior 5 hours . After cooling down and after standing overnight the crystalline material is filtered off, after which the filtrate is concentrated in vacuum. The residue is taken up in 50 ml of absolute ethanol and acidified by means of a concentrated hydrochloric acid solution to acid reaction, after which the precipitate is filtered off. Thereafter there is crystallized from an ethanol/water mixture. Yield 80%. Melting point: 219.0 - 221.5 C 1 H-NMR (d -DMSO) : -3.-06 -- 3.57 ppm., broad triplet, 4 H ; 4.00 ppm., singlet, 3 H; 7.32 ppm., doublet (J = 9.0 Hz) 2 H; 7.67 ppm. , singlet, 1 H; 8.19 - 8.63 ppm. , broad singlet, 3 H ; 8.35 ppm. , doublet (J = 9.0 Hz) , 2 H ; 15.06 ppm., broad doublet, 2 H. Exampl e IX a.2-(3.4-nrethylene-dioxyphenyl) 4(5)- . (2-phthal- i idoethyl) -imidazole hydrochloride (13f) A mixture of 16.4 g (0.1 mole) of 3.4-methylene- 5 dioxybenzamidine, 29.6 g (0.1 mole) of l-bromo-4-phthal— imidobutan-2-one (10a), 27.6 g(0.2 mole) of carefully gr-ounded anhydrous potassium carbonate and 125 ml of anhydrous N.N-dimethyl formamide is heated while stirr¬ ing at 35°C for 24 hours, after which the heating is 10 continued at 50°C for 2 hours. After cooling down the reaction mixture is con¬ centrated in vacuum, after which to the residue deminer¬ alized water is added. The residue is extracted three times with 50 ml of ethyl acetate, the combined organic 15 phases are collected, dried on anhydrous sodium sulfate, filtered and concentrated in vacuum. To the residue a circa 3% - hydrochloric acid solution is added, while stirring it is carefully heated to 40 o C. 20 After cooling down the precipitate is filtered off and dried in vacuum, after which it is crystallized from an ethanol/ether mixture. Yield 55%. Melting point 241.8-245.9 & C (dec) . 255 ^ " H-WMR (d -DMS0) : 3.12 ppm. , triplet (J = 7.5 Hz) , 2 H; b 4-',.0 ~ 5T ppm. , triplet (J = 7.5 Hz) , 2 H; 6.27 ppm. , singlet, 2 H; 7.28 ppm. , doublet (J = 9.0 Hz)., 1 H; 7.60 ppm., singlet, 1 H; 7.66 ppm. , multiplet , 3 H; 7.93 ppm., singlet, 4 H; 14.85 ppm. , broad singlet, 2 H. SUBSTITUTE SHEET b . 4j_5 )_-^2-Aminoeth l)_-2-(3 i 4-methylenedioxy- phenyl)_imidazole_dihydrochloride (5h)_ A solution of 19.9 g (0.050 mole) or 2-(3.4- methylene dioxyphenyl) 4(5)- (2-phthalimidoethyl) imidazole hydrochloride (13f) and 12.5 g (0.025 mole) of hydrazinehydrate in 150 ml of absolute ethanol is heated under reflux for 5 hours. After cooling down and after standing overnight the crystalline material is filtered off, after which the filtrate is concentrated in vacuum. The residue is taken up in 50 ml of absolute ethanol and acidified with the aid of a concentrated hydrochloric acid solution to acid reaction, after which the precipitate is filtered off. Then the residue is recrystallized from an ethanol/water mixture. Yield 90% Melting point: 250.0 - 255.0°C (dec.) H-NMR (d 6 -DMS0) : 2.86 - 3.60 ppm., multiplet, 4 H ; 6.16 ppm., singlet, 2 H; 7.16 ppm. , doublet (J = 9.0 Hz) , 1 H; 7.50 ppm., singlet, 1 H; 7.88 ppm. , doublet (J = 9.0 Hz) , 1 H; 8.00 ppm., singlet, 1 H ,- 8.40 ppm. , broad singlet, 3 H; 15.27 ppm ' ., broad singlet, 1 H. Example X a. 2-_(3 i 4-dimethoxy-phenyl imidazole 4(5)- _(2-phthalimidoethyl) hydrochloride (13g) A mixture of 18.0 g (0.1 mole) of 3.4-dimethoxy- benzamidine, 29.6 g (0.1 mole) of 1-bromo-4-phthal- imidobutan-2-one (10a) , 27.6 g (0.2 mole) of carefully grounded anhydrous carbonate and 125 ml of of anhydrous . -dimethylformamide is heated while stirring at 35°C for 24 hours, after which the heating is continued at 50°C for 2 hours. After cooling down the reaction mixture is con- 5 centrated in vacuum, after which to the residue demin- erral izred water is added. T_tτ.e residue is extracted three times with 50 ml ethyll acetate, the combined organic phases are collected, dried, on anhydrous sodium sulfate, ^ filtered and con- 10- cent-rated: in vacuum. T " o the residue a circa 3% - hydrochloric acid solution is added and carefully heated while stirring to 40°C. After cooling down the precipitate is. filtered 15 off and dried in vacuum, after which it is crystall¬ ized from an ethanol/ether mixture. Yield 52% Melting point: 208.5-211.9°C (dec.) L H-NMR (d b-DMS0): 3.14 ppm., triplet (J = 7.5 Hz), 2 H; 20 3.50-4.40 ppm. , broad multiplet, 8 H; 7.20-8.20 ppm. , multiplet, 7 H; 15.00 ppm., broad singlet, 2 H. b . 4(5)-(2-Aminoethyl)-2-(3.4-dimethoxyphenyl )- imidazole dihydrochloride (5i) A solution of 20.7 g (0.050 mole) 2- (3.4-dimethoxy- 25 phenyl) 4 (5) - (2-phthalimidoethyl) imidazole hydrochlori¬ de (13 g) and 12.5 g (0.25 mole) hydrazine hydrate in 150 ml of absolute ethanol is heated under reflux for 5 hours. After cooling down and after standing overnight the crystalline material is filtered off, after which 30 the filtrate is concentrated in vacuum. The residue is taken up in 50 ml of absolute ethanol and with a concentrated hydrochloric acid solution acidified to acid reaction, after which the precipitate is filtered off. Then the residue is recrystallized from an ethanol/water mixture. Yield 85%. Melting point: 26 .8°-265.8°C (dec. ) 1 H-NMR (d.-DMSO) : 2.90-3.51 ppm. , broad triplet, 4 H; o 10 3.88 ppm. , singlet, 3 H; 3.92 ppm. , singlet, 3 H; 7.20 ppm. , doublet (J = 9..0 Hz, 1 H; 7.53 ppm. , singlet, 1 H; 7.87 ppm. , doublet (J = 9.0 Hz) , 1 H; 8.05 ppm. , singlet, 1 H; 8.25 ppm. , broad singlet, 3 H; 15.00 ppm, broad doublet, 2 H. • j c Example XI i£i Ξ£i£__!∑d_£££_!_L££Ade_ (_13h_) _ A mixture of 13.4 g (0.1 mole) 4-methyl benzamid- ine , 29.6 g (0.1 mole) l-bromo-4-phthal imi do- utan-2-one 20 (10a) , 27.6 g (0.2 mole) of carefully grounded anhydrous potassium carbonate and 125 ml of anhydrous N . N-dimethy 1- formamide is heated while stirring at 35°C for 24 hours, after which the heating is continued at 50°C for 2 hours. After cooling down the reaction mixture is con- 25 centrated in vacuum, after which demineralized water is added to the residue. The residue is three times extracted with 50 ml ethyl acetate, the combined organic phases are collected, dried on anhydrous sodium sulfate, filtered and con- 30 centrated in vacuum To the residue a circa 3% ' -hydrochloijic acid solution is added and carefully heated under stirring to 40°C. After cooling down the precipitate is filtered off and dried in vacuum, after which it is crystallized from an ethanol/ether mixture. 5 Yield 60%. Melting point: 238°C (dec.) H—NMK- (d -DM.SO) : 2.40 ppm. , singlet, 3 H-; 3.23 ppm., triple*-,. Hz) , 2 H; 4.15 ppm. , triplet (J = 7.5 Hz), 2 H; 7.49 ppm. , doublet (J = 9.0 Hz) , 2 H; 7.71 ppm., 10' doublet (J= 9.0 Hz) , 2 H; 7.80-8.10 ppm: , broad singlet, 5 H; 15.15 ppm., broad singlet, 2 H. b . 4( 5)-(2-Aminoethyl)2-(4-methy1phenyl) imidazole dihydrochloride (5j) A solution of 18.4 g (0.050 mole) 2- (4-methylphenyl) 15 4 (5) - (2-phthalimidoethyl) imidazole hydrochloride (13h) and 12.5 g (0.25 mole) of hydrazine hydrate in 150 ml of absolute ethanol is heated under reflux for 5 hours. After cooling down and after standing overnight 20 the crystalline material is filtered off, after which the filtrate Is concentrated in vacuum. The residue is taken up in 50 ml of absolute ethanol and with a concentrated hydrochloric acid solut¬ ion acidified to acid reaction, after which the 25 precipitate is filtered off. Then the precipitate is recrystallized from an ethanol/water mixture. Yield 80%. Melting point: 232.2-236.5°C (dec.) 30- H-NMR (D O) : 2.42 ppm. , singlet, 3 H; 3.04-3.54 ppm., multiplet, 4 H; 7.38 ppm., singlet, 1 H; 7.47 ppm., doublet (J= 9.0 Hz) , 2 H;7.76 ppm..doublet (J = 9.0 Hz), 2 H.

Claims: CLAIMS 1. A process for preparing a substituted or an unsubstituted 4 (5)- (ω-aminoalky1) imidazole , by brominating an ω-phthal- imidoalkan-2-one to a 1- or 3-bromo-ω-phthalimido-alkan- 2-one, subjecting said derivative to ring closure with an amidine, followed by hydrolytic separation of the phthal¬ ic residue, characterized in that a substituted or unsubstituted 4 (5 )-(ω-aminoalky1) imidazole of the formula 5 is prepared, wherein n is 1 to 6, R is hydrogen or a linear, branched or cyclic, saturated or unsaturated 10 alkyl group having 1-6 C-atoms or a phenyl ring being unsubs i uted, mono- or di-substi u ed with groups such as lower alkyl, halogen, alkoxy, methylenedioxy or a combination thereof, and R„ is hydrogen or methyl and the bromination with bromine is carried out in anhydrous 15 methanol and the ring closure is carried our in N.N- dimethyIformamide with potassium carbonate under mild conditions . 2. New compounds of the formula 5 as defined in claim 1, which may be produced according to the process of claim 1. 20 UBSTITUTESHEET 3_ Pharmaceutical composition, characterized in that it contains a new compound according to claim 2. 4. Pharmaceutical composition, characterized in that it contains a compound as obtained according to the process of claim 1. 5. Use of a compound or pharmaceutical composition according to any of the preceding claims, for the treatment of heart failures or allergic conditions.

Inventors: ERIKS JOHN CHARLES, KOPER JAN GIJSBERT, TIMMERMAN HENDRIK, VAN DER GOOT HENDERIKUS, ERIKS, JOHN, CHARLES, KOPER, JAN, GIJSBERT, TIMMERMAN, HENDRIK, VAN DER GOOT, HENDERIKUS
Applicants: CEDONA PHARM BV, CEDONA PHARMACEUTICALS B.V.
Application year: 1989
Main classification: C07D233
IPC codes: A61K31, A61P9, A61P37, C07D233