Patent GB-360027-A (GB)
Title: Process for the manufacture of heterocyclic compounds
IPC: C07D471/04
Filed: 1930-07-31
Abstract: Heterocyclic compounds are obtained by condensing according to the customary methods a cyclic compound containing a partially or completely hydrogenated carbon ring carrying two reactive substituents in o-position with a heterocyclic compound containing nitrogen in the ring and carrying a hydrogen atom in o-position to an amino group, the condensation being such as to form a five atom ring containing nitrogen uniting the components. The products may be further hydrogenated by the customary methods, e.g. with sodium and alcohol, with stannous chloride, or catalytically.  The following examples are specified.  (1) 2-Aminopyridine is heated with sodamide in toluene until evolution of ammonia ceases, 2-chlorocyclohexanone is added, most of the toluene is distilled off, the mixture is made weakly acid and extracted with ether, the ether is removed, the remaining solution is made strongly alkaline with potassium carbonate and the crystalline intermediate product 2-(a -pyridylamino) cyclohexanone-1 is extracted with ether containing a little alcohol; this product is boiled for 4 hours with acetic anhydride, the mixture is poured into water and made alkaline with potassium carbonate whereupon the condensation product of the formula <FORM:0360027/IV/1> separates and is recrystallized from ethers; it forms crystalline double salts with bichromates in acetic acid solution; (2) 2-aminopyridine in absolute alcohol is boiled for 10 hours under reflux with 2-chloro-cyclohexanone, the alcohol is distilled off, the residue is acidified with acetic acid and extracted with ether, sodium bichromate is added to the acid solution, and the precipitated chromate is separated; this is decomposed with caustic soda and the resulting oil is purified by extraction with ether containing alcohol, fractionation and crystallization; the product is identical with that of (1).  (3) 2-Aminopicoline in alcohol is boiled for 10 hours under reflux with 2-chlorocyclohexanone and the product is separated as in (2).  (4) 2-Aminopyridine is heated for 10 hours at 100 DEG  C. with 4-methyl-2-chlorocyclohexanone and the product is separated as in (2).  (5) 2-Aminopyridine in alcohol is boiled for 10 hours under reflux with 4-benzyl-2-chlorocyclohexanone, the alcohol is distilled off, the residue is dissolved in water with addition of acetic acid and extracted with ether, the aqueous solution is made alkaline with potassium carbonate and extracted with ether containing alcohol, and the solvent is distilled off.  (6) 2-Aminopyridine in alcohol is boiled for 10 hours under reflux with 3-methyl-5-isopropyl-2-chlorocyclohexanone and the product is extracted as in (5).  (7) 2-Aminopyridine in alcohol is boiled for 10 hours under reflux with o-dibromocyclohexane or with 2-methoxycyclohexanol and the product is extracted as in (5).  (8) N-methyl-2-aminopyridine is melted with 2-chlorocyclohexanol for 20 hours at 150 DEG  C., and the product is dissolved in water and extracted as in (5).  (9) The product of examples (1) or (2) is reduced by sodium in absolute alcohol and the product is extracted with ether.  (10) 2-Aminopyridine in alcohol is boiled for 10 hours under reflux with 2-chloro-6-methoxycyclohexanone and the product is extracted as in (5).  (11) 2-Amino-5-nitropyridine is melted with 2-chlorocyclohexanone for 10 hours at 120 DEG  C., the mixture is dissolved in dilute hydrochloric acid, the solution is decolorized with animal charcoal and the product is precipitated with sodium acetate, filtered, and crystallized from acetone. (12) 2-Amino-5-iodopyridine in alcohol is boiled for 10 hours under reflux with 2-chlorocyclohexanone and the product is extracted as in (5). (13) 4-Aminopyridine is heated to 170 DEG  C. and 2-chlorocyclohexanone is dropped in, the cooled reaction mixture is dissolved in dilute hydrochloric acid and extracted with ether, the aqueous solution is made alkaline with potassium carbonate and extracted with ether containing alcohol, the ether is removed and the residue is dissolved in water and precipitated with acetone.  (14) 2-Aminopyridine in alcohol is boiled for 10 hours with 2-bromocyclopentanone and the product is extracted as in (5).  (15) 2-Aminopyridine in alcohol is boiled for 10 hours with 1-oxo-2-bromo-1 : 2 : 3 : 4-tetrahydronaphthalene and the product is extracted as in (5); the acid solution of the base yields a nearly insoluble yellow chromate on addition of a bichromate.  (16) 2-Amino-6-methoxyquinoline in alcohol is boiled for 12 hours with 2-chlorocyclohexanone, the alcohol is distilled off and the residue is treated with dilute hydrochloric acid and the hydrochloride of the required base which separates is recrystallized from water; the base which separates on addition of potassium carbonate solution to the hot aqueous solution of the hydrochloride is filtered off, dissolved in alcohol and precipitated with ether.  (17) 1-Aminoisoquinoline in alcohol is boiled for 7 hours with 2-chlorocyclohexanone and the product is extracted as in (5).  (18) 2-Amino-5 : 6-dimethylpyrimidine in alcohol is boiled for 12 hours with 2-chlorocyclohexanone and the product is extracted as in (5).  (19) 2-Amino-4-methyltriazole in alcohol is boiled for 12 hours with 2-chlorocyclohexanone and the product is extracted as in (5). 4-Methyl-2-chlorocyclohexanone is obtained by chlorination of 4-methylcyclohexanol.  4-Benzyl-2-chlorocyclohexanone is obtained by catalytic hydrogenation of 4-benzylphenol and chlorination of the 4-benzylcyclohexanol so produced. 3-Methyl-5-isopropyl-2-chlorocyclohexanone is obtained by chlorination of 3-methyl-5-isopropylcyclohexanol. 2-Chloro-6-methoxycyclohexanone is obtained by chlorination of 6-methoxycyclohexanol.  2-Bromocyclopentanone is obtained by bromination of cyclopentanone in glacial acetic acid. 1-Aminoisoquinoline is obtained by heating isoquinoline with sodamide.