Patent GB-481874-A (GB)
Title: Process for the manufacture of n-basically substituted amino compounds of the heterocyclic series
Filed: 1936-08-14
Abstract: Py-Aminoquinoline compounds in which the benzene nucleus is condensed with a benzene or pyridine nucleus and in which the amino group is substituted by a basic radicle are prepared by (1) reacting a py-aminoquinoline compound whose benzene nucleus is condensed with a benzene or pyridine nucleus, with the halide or other reactive ester of a basic alcohol or with the basic alcohol itself in presence of a condensing agent; (2) treating a quinoline compound whose benzene nucleus is condensed with a benzene or pyridine nucleus and whose pyridine nucleus contains a halogen atom or other reactive substituent, with an amine containing a basic substituent; or (3) condensing a pyridine ring according to Skraup's or Conrad-Limpach's method to the benzene ring of a bz-aminoquinoline compound containing a basically substituted amino group in the pyridine nucleus.  The basic radicle comprises an aminoalkyl or alkylaminoalkyl radicle whose carbon chains may be interrupted by oxygen, sulphur or nitrogen; it may contain cyclic constituents or substituents such as alkyl and hydroxyl groups.  The methods of (1) and (2) may be effected in stages, e.g. by causing alkylene dihalides or alkylene oxides to react upon the amino-heterocyclic compounds and treating the products, if desired after replacing the hydroxyl group by halogen, with primary or secondary amines.  A derivative of the basic component, e.g. an acyl or azomethine compound, may be used and the compound formed saponified to the amine.  The products possess therapeutic properties.  According to the examples, (1) 4-chloro-7 : 8-benzoquinoline is heated with 5-diethylamino-2-aminopentane to give 4-(51-diethylaminopentyl-21-amino)-7 : 8-benzoquinoline; similar products are obtained from 4 : 31-dichloro-7 : 8-benzoquinoline (only the 4-chloro atom reacting), 4-chloro-5 - 6-benzoquinoline, 4 : 6-dichloro-7 : 8-benzoquinoline (the 4-chloro atom reacting) and 4 - chloro - 5 - methoxy - 7 : 8 - benzoquinoline; (2) 4 - chloro - 5 : 6 - benzoquinoline is treated with 1-diethylamino-2-aminoethane; (3) 4-(51-diethylaminopentyl - 21 - amino) - 8 - chloro-6 : 7-benzoquinoline is prepared from 4 : 8-dichloro-6 : 7-benzoquinoline and 5-diethylamino-2-aminopentane; (4) 7-methyl-5-chloropara-phenanthrolin is reacted with diethylamino-ethylamine and 5-diethylamino-2-aminopentane; (5) 4-chloro-41-bromo-(benzo-11 : 21 : 5 : 6-quinoline) is heated with 5-diethylamino-2-aminopentane; in the same manner are treated 4-chloro-61-bromo- (benzo-11 : 21 : 7 : 8-quinoline) (only the 4-chloro atom reacting), 4 - chloro - 41 - methoxy - (benzo - 11 : 21 : 7 : 8 - quinoline), 4 - chloro - 61 - methoxy - (benzo-11 : 21 : 7 : 8 - quinoline), 4 - chloro - 51 - methoxy - (benzo - 11 : 21 : 7 : 8 - quinoline), 3-methyl - 4 - chloro - 61 - methoxy - (benzo-11 : 21 : 7 : 8 - quinoline), 3 - ethyl - 4 - chloro-61 - methoxy - (benzo - 11 : 21 : 7 : 8 - quinoline, 3 - ethyl - 4 - chloro - 7 : 8 - benzoquinoline, 3 - ethyl - 4 - chloro - 5 : 6 - benzoquinoline, 4 - chloro - 31 - methoxy - (benzo - 11 : 21 : 5 : 6 - quinoline), 4 - chloro - 51 - methoxy - (benzo-11 : 21 5 : 6 - quinoline) and 3 - methyl - 4-chloro - 51 - methoxy - (benzo - 11 : 21 : 5 : 6 quinoline; (6) 4-diethylaminoethylamino-6-aminoquinaldine is heated with glycerin in the presence of sodium nitrobenzene-sulphonate and sulphuric acid and the product treated with sodium nitrite, whereby 7-methyl-5-diethylaminoethylamino - para - phenanthrolin; the acetyl or benzylidene compounds of the quinaldine, obtained by reaction with acetic anhydride or benzaldehyde, may be used; (7) 3 - methyl - 4 - chloro - (benzo - 11 : 21 : 7 : 8-quinoline) is heated with 1-diethylamino-4-aminopentane; (8) 4-chloro-7 : 8-benzoquinoline is treated first with aminoethanol and then with phosphorus oxychloride to give 4-(b -chloroethylamino)-7 : 8-benzoquinoline, which is then reacted with diethylaminoethanol to form the 4 - (b  - diethylaminoethoxy - ethylamino) compound, or with diethylamine to give the 4-diethylaminoethylamino product, or with piperidine to produce the 4-b -piperidinoethylamino compound, or with b -diethylamino-ethylmercaptan to give 4-(b .b 1-diethylamino-ethylmercapto - ethylamino) - 7 : 8 - benzoquinoline; (9) 2 - methyl - 4 - chloro - 7 : 8 - benzoquinoline is heated with excess sodium sulphite solution and the 4-sulphonic acid compound so obtained reacted with diethylaminoethylamine to give 2 - methyl - 4 - diethylaminoethylamino - 7 : 8-benzoquinoline; the same compound is obtained from 2-methyl - 4 - chloro - 7 : 8-benzoquinoline and diethylaminoethylamine; (10) 3 - diethylaminoethylamino - phenanthrolin is prepared by heating the 3-bromo- or 3-hydroxy compounds with diethylaminoethylamine of the 3-amino compound with diethylaminoethyl chloride.  Specifications 267,169, [Class 2 (iii)], 363,392, and 433,625 are referred to.  The sample furnished under Sect. 2 (5) consists of 4 - (diethylamino - hydroxypropylamino) - 7 : 8 - benzoquinoline prepared by heating 4-chloro-7 : 8-benzoquinoline with 1-diethylamino-2-hydroxy-3-aminopropane.  Benzoquinoline derivatives.-4 - Hydroxybenzoquinoline and its substitution products are prepared by saponification and decarboxylation of the corresponding 2-carbethoxy-4-hydroxy-benzoquinilines, which are obtained from naphthylamines by a variant of Conrad-Limpach's method using, instead of acetoacetic ester, oxaloacetic ester or alkyl-substituted oxaloacetic esters.  By treatment with phosphorus oxychloride, the 4 - hydroxy - benzoquinolines yield the 4-chloro compounds.  Phenanthrolin derivatives.-7 - Methyl - 5-chloro-para-phenanthrolin is obtained from 6-aminoquinoline by condensation with acetoacetic ester according to Conrad-Limpach's method, followed by treatment with phosphorus oxychloride. 3-Bromo-phenanthrolin is prepared from 3 - bromo - 6 - aminoquinoline by Skraup's method; treatment with ammonia under pressure gives the 3-amino compound, from which the 3-hydroxy product is prepared by means of nitrite.  4-Diethylaminoethylamino-6-amino-quinaldine is obtained by condensing p-aminoacetanilide with acetoacetic ester according to Conrad-Limpach's method, chlorinating the hydroxyl group with phosphorus oxychloride, splitting off the acetyl group with hydrochloric acid and treating the resulting 4-chloro-6-aminoquinaldine with 1-diethylamino-2-aminoethane.