Patent GB-1341375-A (GB)
Title: Aminoalkylimidazoles and process for their production
IPC: C07D233/54
Filed: 1969-11-19
Abstract: 1341375 Aminoalkylimidazoles SMITH KLINE & FRENCH LABORATORIES Ltd 19 April 1971 [19 Nov 1969] 56512/69 Heading C2C  Aminoalkylimidazoles of the Formula I wherein A is a saturated C 1-6  alkyl group, optionally substituted by one or more alkyl or aralkyl groups; R is a substituted or unsubstituted alkyl, aryl or aralkyl group; R 1  is hydrogen, alkyl, phenyl, phenylalkyl or imidazolylalkyl group; R 20  is hydrogen, alkyl optionally substituted by halogen, hydroxy, cyano, carboxy, amino or amidino, or -COY, wherein Y is R 11 O or R 11 NH and R 11  is substituted or unsnbstituted alkyl, aryl or aralkyl or amidine; and X is 0 to 3 provided that when X is 0 and R 20  is hydrogen or a C 1-3  alkyl, R 1  may not be hydrogen, benzyl or C 1-3  alkyl and that when R 1  and R 20  are both hydrogen, A is (CH 2 ) 2  optionally substituted by methyl and X is 1, R may not be methyl or except when substituted in the 4(5) position of the ring, phenyl or benzyl may be prepared by (1) reacting a compound III with R 3 X followed by hydrolysis to produce a compound V wherein R 2  and R 3  are H or substituted or unsubstituted alkyl, aryl or aralkyl; R 4  to R 7  are H, alkyl or aralkyl, R 9  is alkyl, amino alkyl or carboxyalkyl or substituted or unsubstituted aryl or aralkyl and R 8  is R 9  or which produces R 9  on hydrolysis, provided that when R 1  to R 3  are all H and one of R 4 -R 7  is H or methyl when the others of R 4 -R 7  are hydrogen, R 9  may not be methyl, phenyl or benzyl; (ii) reacting a compound IV wherein R 1  to R 8  are as above and additionally R 8  may be hydrogen and Z- is a suitable anion with a nucleophilic reagent, YH, wherein Y is R 11 NH or R 11 O, where R 11  is substituted or unsubstituted alkyl, aryl or aralkyl or an amidine group to produce a compound VII (iii) converting a compound V wherein R 9  and R 1  are hydrogen to the phthalimido compound by treatment with N-carbethoxyphthalimide, which is reacted with R 10 X, where X is halogen and R 10  is optionally substituted aralkyl provided that when R 2  and R 3  are both H and one of R 4 -R 7  is H or methyl when the others of R 4 -R 7  are hydrogen, R 10  may not be benzyl and phthalimido group is removed by hydrolysis to produce V wherein R 1  is H and R 9  is R 10 ; (iv) reacting a compound III in which R 1  is H with a base and then with R 8 X followed by hydrolysis to produce V in which R 9  is H and R 1  is R 9 ; (v) reducing a compound III in which R 1  is R 8  to a compound XV wherein R 12  is R 8  or a reduction product thereof; (v) acylation of a compound XI followed by reduction of the amide to R 13 CH 2  NH- attached to A in XI in place of NH 2 , wherein R 13  is hydrogen, alkyl, phenyl, phenylalkyl or imidazolylalkyl provided that, when R 2  and R 3  are both hydrogen, R 13  may not be H, methyl, ethyl or phenyl; (vi) treating XI, wherein R 2  and R 3  are as defined above provided that when R 3  is H, R 2  may not be H or methyl and when A is a chain of 2 carbon atoms R 2  may not be hydrogen, with formic acid and formaldehyde to give (CH 3 ) 2 N- attached to A in place of NH 2 ; (vii) reacting XI with a carbonyl compound R 19 .CO.R 21  and reducing the Schiff's base so formed to give -NHCH R 19 R 21  attached to A in XI in place of NH 2 , wherein R 19  and R 21  are H, alkyl, phenyl, phenylalkyl or imidazolylalkyl, provided that R 19  and R 21  may not both be phenyl, phenylalkyl or imidazolylalkyl and that, when R 2  and R 3  are both H, CHR 19 R 21  may not be benzyl or a C 1-3  alkyl and when R 19  and R 21  are both H or alkyl, A is a saturated straight chain of 2 carbon atoms optionally substituted by methyl and one of R 2  and R 3  is H, R 2  may not be methyl, phenyl or benzyl; (viii) reacting a compound LVIII wherein X is a halogen with an amine R 14 R 15 NH to produce LVIII in which X is replaced by -NR 14 R 15 , wherein R 14  is alkyl optionally substituted by halogen, hydroxy, cyano, carboxy, amino or amidino; and R 15  is hydrogen, alkyl, phenyl, phenylalkyl, imidazolylalkyl provided that when R 2  and R 3  are both H, R 15  may not be H, C 1-3  alkyl or benzyl and, when R 14  and R 15  are both alkyl, A is a saturated straight chain of 2 carbon atoms optionally substituted by methyl and one of R 2  and R 3  is H, R 2  may not be methyl and R 3  may not be methyl, phenyl or benzyl; (ix) chlorination or bromination of a compound LIX in which R 2 , R 3 , R 15  and A are as defined in process (viii) and X is hydroxy to give a compound LIX in which X is Br or Cl; (x) reacting a compound LX wherein P is phthalimido, with pivaloyloxymethyl halide to introduce the pivaloyloxymethyl radical into the 1-position of the ring followed by reaction with R 16 X, wherein R 16  is optionally substituted alkyl or aralkyl provided that when R 2  and R 3  are both H and A is a saturated straight chain of two carbon atoms optionally substituted by methyl, R 16  may not be methyl, phenyl, or benzyl and removing the protective phthalimido and pivaloyloxymethyl groups to give compound XXVIII (xi) oxidizing R 2 C#C-A-N : P to R 2 CO.CO. A-N : P and cyclizing this product with formaldehyde and ammonium acetate to produce a compound LX in which R 3  is hydrogen followed by hydrolysis to remove the P-group; (xii) reacting a nitrile LIV with a carbonyl R 22 COAr 2  wherein R 22  is H or alkyl and Ar 2  is optionally substituted aryl reducing the C=C in the product followed by reduction of the nitrile to produce LXX in which R 4  is an optionally substituted aryl methyl, provided that R 2  and R 3  may not both be hydrogen; (xiii) reducing the ester group of XXXII to CH 2 OH, followed by halogenation and conversion to the cyanomethyl and reduction thereof to produce LXI (xiv) reacting a compound LXI with N,N<SP>1</SP>- carbonyl di-imidazole to produce a compound VII in which Y is substituted 4-(aminoethyl) imidazole identical to that attached to COY in VII; (xv) ring opening of an imidazole-pyridine by hydrogenation to produce a 4(5)-substituted- 5(4)-aminoethylimidazole; (xvi) addition of acrylonitrile to an N-unsubstituted compound I to produce an N-propionitrile substituted compound I; (xvii) reacting an N-unsubstituted 4(5)-aminoalkylimidazole with a 4(5)-cyanoalkylimidazole to produce a compound I wherein R 1  is imidazolylalkyl. The intermediates III may be formed by reacting a histamine derivative with N,N<SP>1</SP>- carbonyldi-imidazole, and optionally forming the quaternary compound IV by the usual methods. The intermediates XXXII may be produced by cyclizing R 2 COCHXCOOEt, wherein X is halogen or amino and R 2  is alkyl other than methyl, substituted alkyl or substituted or unsubstituted aryl or aralkyl other than phenyl or benzyl with formamide. 2 - Amino - 4 - methyl - 3 - oxo - pentanoate hydrochloride may be prepared by reacting ethyl isobutyryl acetate with nitrous acid to yield ethyl 2 - oximo - 4 - methyl - 3 - oxopentanoate which on hydrogenation yields the required compound. The intermediates R 2 C#C-CH 2 CH 2 N : P may be prepared converting the alcohol R 2 C#CCH 2 CH 2 OH to the tosyl ester and reacting the product with potassium phthalimide. 7-Phenyl hept-3-yn-l-ol may be prepared by reaction of 5-phenyl pent-1-yne with ethylene oxide in the presence of strong base. 2 - Bromo - 4 - phthalimidobutyrophenone may be prepared by reacting 4-chlorobutyrophenone with phthalimide to form 4-phthalimidobutyrophenone which yields the required compound on treatment with bromine. Pharmaceutical compositions of I show antihistamine activity when administered externally or internally with a carrier.