Patent GB-373624-A (GB)
Title: Process for the manufacture of therapeutically valuable compounds
IPC: C07D215/20
Filed: 1930-11-20
Abstract: Therapeutic compounds are made (1) by introducing a basic residue into the amino groups of a compound containing two or more residues comprising aromatic, alicyclic or heterocyclic ring systems linked together, one or more of the linkages being of the nature of an ether or thio-ether; (2) a reactive substituent in the nucleus of a compound of the above type is replaced by reaction with a primary or secondary amine containing a basic residue as substituent; (3) an ether or thio-ether linkage is produced between cyclic compounds of which at least one contains in the nucleus a primary or secondary amino group having a basic residue as substituent.  The first process is carried out (a) by condensing the amino group with an ester of an amino or N-substituted amino alcohol or a salt thereof, (b) by condensing the amino group with acyl derivatives or halogen alkyl phthalimides and hydrolysing the intermediate products to the corresponding amino compounds, (c) by introducing the basic residue in several steps by first causing an alkylene dihalide, an alkylene oxide or a halogenated alcohol to act on the amino compound and then converting the hydroxy or halogen alkylamino derivative thus produced, if necessary after esterifying the OH group, e.g. by means of a hydrogen halide acid, into the required product.  The third process is carried out (a) by causing a cyclic compound containing a primary or secondary amino group having a basic residue as substituent and also containing an OH or SH group to react with a cyclic compound containing a reactive substituent, (b) by causing a cyclic compound containing a primary or secondary amino group having a basic residue as substituent and also containing a reactive substituent to react with a cyclic compound containing an OH or SH group, (c) by causing a sulphur chloride to react with a cyclic compound containing a primary or secondary amino group having a basic residue as substituent, (d) by causing a metallic sulphide to react with a cyclic compound in (c) which also contains a reactive substituent.  The basic residue above referred to may be an aminoalkyl or alkylaminoalkyl group or heterocyclic residue and the alkyl chains may be interrupted by N, O or S.  The linkages between the cyclic rings may be a single ether or thioether bond, a double ether or thioether bond (as in diphenylene dioxide), or an ether or thioether bond between two carbon atoms and a direct carbon linkage between the two adjacent carbon atoms (as in diphenylene oxide). Compounds containing a chain of ether linkages between cyclic residues are also referred to.  In examples, (1) 2-, 3- or 4-aminodiphenylether is condensed with diethylaminoethyl chloride in benzene; substitution products of 4-aminodiphenylether may be also used as starting materials (list given in Specification); using 2-2,5 mols. of diethylaminoethyl chloride in nitrobenzene at higher temperatures, the bis-(diethylaminoethylamino) - diphenylethers are obtained, any mono substituted product being removed by reaction with phthalic anhydride which forms the phthalamic acid or the bases may be separated by means of chlorsulphonic acid, (2) 4-aminodiphenylether is melted with a -diethylamino-d -bromopentane hydrobromide to form 4-(a -diethylamino-d -pentylamino)-diphenylether; other aminodiphenylethers and their derivatives are specified as starting materials; 4-(a -diethylamino-d -pentylamino) -4<1>-diethylaminoethoxy-diphenylether is prepared by condensing 4-methoxy - 4<1> - aminodiphenylether hydrobromide with diethylamino-ethylchloride in presence of sodium ethylate and fusing the 4 - amino - 4<1>-diethylamino - ethoxydiphenylether thus obtained with a -diethylamino - d  - bromopentane hydrobromide, (3) 2 : 4 - diamino - 2<1>- or 3<1>-methoxydiphenylether is melted with a -diethylamino-d -bromopentane hydrobromide, (4) 2 : 4-diaminophenylcyclohexylether is reacted as in (3), (5) 5-amino-2-phenoxypyridine is condensed as in (3) or with diethylaminoethyl chloride, (6) 3-amino-6-(2<1>-amino-phenoxy)-pyridine is condensed with diethylaminoethylchloride (both amino groups substituted), (7) 6-phenoxy-8-aminoquinoline and (8) 1 : 2 : 3 : 4 - tetrahydro - 6 - phenoxyquinoline are condensed with diethylaminoethylchloride, (9) 2-aminodiphenylene oxide is refluxed with diethylaminoethylchloride in benzene and the product heated with diethylaminoethylchloride to give the 2-bis-(diethylaminoethyl) derivative; diethylaminoethoxyethylchloride, diethylaminoethylthioethylchloride, and 2 : 7-diaminodiphenyloxide may be used as starting materials and the N-piperidylethyl and the g -N-piperidyl-b -hydroxypropyl residues may also be introduced, (10) bromo-2-aminodiphenyleneoxide is heated in nitrobenzene with diethylaminoethylchloride, (11) 1 : 3-diamino-diphenylene-dioxide is heated in benzene with diethylaminoethylchloride (both amino groups substituted), (12) 2-aminodiphenylsulphide is melted with a -diethylamino-d -bromopentane hydrobromide; other aminodiphenylsulphides and other alkylating agents may also be used (see list in Specification); 4- diethylaminoethylamino - 4<1> - methyldiphenyl sulphide is made by adding diazotized 4-diethylaminoethylaminoaniline to a solution of thiocresol in caustic soda, (13) (5-aminopyridyl-2)-phenylsulphide, and (14) (5-aminopyridyl-2)-quinolyl-2<1>-sulphide are condensed with diethylaminoethylchloride; in the latter case in addition to the monoalkylated compound quaternary salts are obtained, (15) 2-chlorodicyclohexylether is condensed with bis-diethylaminoethylamine NH [CH2CH2NEt2]2, (16) 2-aminohydroquinone - 1 : 4 - diphenylether, and (17) 2-amino - methyldiphenylene disulphide are condensed with diethylaminoethylchloride, (18) p-hydroxy - N - methyl - N - diethylaminoethylaniline (c.f. Specification 274,058, [Class 2 (iii), Dyes &c.], is condensed with p-nitrochlorobenzene in presence of caustic soda to form 4 - (diethylaminoethyl - methylamino) - 4<1>-nitrodiphenyl ether, (19) diethylaminoethylaminobenzene is heated with sulphur dichloride in carbon tetrachloride to form 4 : 4<1>-bis(diethylaminoethylamino)-diphenylsulphide, which is also obtained from 4 : 4<1>-diaminodiphenyl sulphide and diethylaminoethylchloride.  Specifications 267,169, 274,058, 282,453, 286,087 302,984 and 303,093, [all in Class 2 (iii), Dyes &c.], are referred to.  a  - Diethylamino - d  - bromopentane hydrobromide is made from a -diethylamino-d -pentanol (see Specification 267,169) and hydrobromic acid.  2 : 4 - Diamino - 2<1> - methoxydiphenylether is made from guaiacol (sodium salt) and 2 : 4 dinitrochlorobenzene and reducing.  2 : 4 - Diaminophenyl - cyclohexylether is similarly obtained from cyclohexanol.  5-Amino-2-phenoxypyridine is made from sodium phenate and 2-chloro-5-nitropyridine and reducing.  3 - Amino - 6 - (2<1>-aminophenoxy) - pyridine is obtained by refluxing sodium o-nitrophenate, 2-chloro-5-nitropyridine and alcohol and reducing the dinitro compound obtained.  6-Phenoxy-8-aminoquinoline is made by condensing p-phenoxy-o-nitraniline, arsenic acid, glycerol and sulphuric acid and reducing the nitro product. p-Phenoxy-o-nitraniline is obtainable by nitration of p-phenoxyacetanilide and deacetylation.  1 : 2 : 3 : 4 - Tetrahydro - 6 - phenoxyquinoline is made by heating p-aminodiphenylether, p-nitrodiphenylether, arsenic acid, glycerol and sulphuric acid and the 6-phenoxyquinoline thus obtained is reduced with sodium and alcohol.  Bromo - 2 - aminodiphenyleneoxide is made by saponifying bromo-2-acetylaminodiphenyleneoxide obtained by brominating 2-acetylaminodiphenyleneoxide.  Aminodiphenylsulphides referred to in example (12) as starting materials are made from the corresponding thiophenolates and o- or p-halogennitrobenzenes and reducing the nitro products obtained.  (5 - Aminopyridyl - 2) - phenylsulphide is obtained from sodium thiophenate and 2-chloro-5-nitropyridine by boiling in alcohol in presence of copper bronze and reducing the nitro product.  (5-Aminopyridyl-2) - quinolyl - 2<1> - sulphide is made from 2-mercaptoquinoline (sodium salt) and 2-chloro-5-nitropyridine and reducing.  2-Chlorodicyclohexylether is made by condensation of cyclohexanol with 2-chlorocyclohexanone, reduction of the 2-keto-dicyclohexylether and chlorination of the hydroxydicyclohexylether formed in presence of dimethylaniline by means of thionylchloride.  Bis-diethylaminoethylamine is made from the p-nitroso derivative of N-bis-diethylaminoethylaniline (c.f. Specification 274,058).  2 - Aminohydroquinone - 1 : 4 - diphenylether is made by condensing phenol, sodium phenate and 4-amino-3-nitrodiphenylether and reducing.