United States Patent Office Patented Nov
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3,215,732 United States Patent Office Patented Nov. 2, 1965 1. 2 example isopropanol. The reduction product may be 3,215,732 reacted with the said amine in the presence of a diluent NAPHTHALENE DERVATIVES or solvent for example ethanol and the process may be John S. Stephenson, Taplow, England, assignor to Im accelerated or completed by the application of heat. perial Chemical industries Limited, London, England, It is to be understood that the said reduction product a corporation of Great Britain No Drawing. Fied Apr. 26, 1961, Ser. No. 105,571. is believed to be one or other of the two naphthalene Claims priority, application Great Britain, May 4, 1960, derivatives of the formula: 15,716/60; Oct. 7, 1960, 34,438/60 CHOICH2X 9 Caims. (C. 260-501) 10 This invention relates to organic compounds and more Y particularly it relates to new naphthalene derivatives which possess valuable therapeutic properties. According to the invention I provide naphthalene and 15 derivatives of the formula: O CHOECEINR 1Ri of SCH, Y Y 20 NX, Z. wherein R stands for hydrogen or for a metay1 lauva. wherein R1 stands for hydrogen or for a methyl radical, R2 stands for a branched chain alkyl radical of not a mixture thereof, and either of these compounds or a more than 4 carbon atoms and Y and Z stand for hy mixture thereof can be used as starting material for the drogen, halogen, lower alkyl and lower alkoxy, and the 25 manufacture of the compounds of the present invention. non-toxic, pharmaceutically-acceptable salts thereof. Thus according to a further feature of the invention As suitable substituents in the naphthalene nucleus I provide a process for the manufacture of the naph there may be mentioned for example chlorine or bromine thalene derivatives which comprises interaction of a atoms and methyl, ethyl, methoxy and ethoxy radicals. naphthalene derivative of the formula: The substituent R may be for example an isopropyl, 30 isobutyl, sec.-butyl or tert.-butyl radical. Particularly useful compounds are 2-hydroxy-2-(2'- naphthyl)-ethyl-isopropylamine, -tert-butylamine, Sec.- Y butylamine and isobutylamine and, of these, a particu larly valuable compound is 2-hydroxy-2-(2-naphthyl)- 35 2. ethyl)-isopropylamine and the salts thereof. The salts of the invention may be for example salts wherein Y and Z have the meanings stated above, and derived from inorganic acids for example hydrochlorides, R stands for the group hydrobromides, phosphates or Sulphates or salts derived O from organic acids for example oxalates, lactates, tar 40 of Sch, trates, acetates, salicylates and citrates. or for the group CHOHCH2X wherein X has the mean According to a further feature of the invention I ing stated above, and an amine of the formula HNRR provide a process for the manufacture of the said naph wherein R and R2 have the meanings stated above. thalene derivatives which comprises reduction of a naph This process may be carried out in the presence of a thalene derivative of the formula: 45 diluent or solvent for example ethanol and may be ac celerated or completed by the application of heat. CO CH2-X According to yet a further feature of the invention I provide a process for the manufacture of the naph Y thalene derivatives which comprises reduction of a naph 50 thalene derivative of the formula: Z COCHNRR wherein Y and Z have the meanings indicated above, and X stands for a halogen atom, for example a chlorine Y or a bromine atom, followed by reaction of the reduc 55 tion product so obtained with an amine of the formula NHRR2 wherein R1 and R2 have the meaning stated Z. above. wherein Y, Z, R1 and R have the meanings stated above, The said reduction process may be carried out by use or a salt thereof. of sodium borohydride as the reducing agent in the 60 The reduction process may be carried out for example presence of a diluent or solvent for example methanol by use of sodium borohydride as reducing agent in the and at a temperature of about 0-25 C. The reduction presence of a diluent or solvent for example aqueous process may also be carried out by the use of aluminum methanol, or for example by use of a hydrogenation isopropoxide in the presence of a diluent or solvent for catalyst, for example palladium on carbon, and hydrogen 3,215,782 3 4. in the presence of an inert diluent or solvent, for example, Example 1 aqueous methanol. A solution of 10 parts of 2-naphthacyl bromide in 180 According to a further feature of the invention I parts of methanol is stirred and 3 parts of sodium boro provide a process for the manufacture of the naphthalene hydride are added quickly, the temperature being kept derivatives in which R1 stands for hydrogen and R has 5 below 25 C. The mixture is stirred at 20 C. for a the meaning stated above which comprises reaction of further 30 minutes and is then poured on to ice and ex a naphthalene derivative of the formula: tracted with ether. The ethereal extract is washed with A-CBNE water, dried over sodium sulphate and evaporated to dry / ness thus providing a crude reduction product. This Y 10 product is dissolved in 90 parts of anhydrous ethanol and is heated under reflux with 20 parts of isopropylamine for 16 hours. The solution is then evaporated to dryness 2. under reduced pressure and the solid residue is suspended wherein Y and Z have the meanings stated above and in 50 parts of water, acidified with hydrobromic acid and A stands for the group CO or CHOH, with a carbonyl 5 allowed to crystallise. The product is crystallised from compound of the formula: aqueous acetone and there is thus obtained 2-hydroxy-2- (2'-naphthyl)-ethyllisopropylamine hydrobromide, M.P. 177-179 C., otherwise known as 2-hydroxy-2-(2-naph wherein R3 stands for hydrogen or for an alkyl radical thyl)-N-isopropyl-ethylamine. and R4 stands for an alkyl radical, provided that R. 20 and R together contain not more than 3 carbon atoms, Example 2 under reducing conditions. As suitable values of R3 and R4 there may be men A solution of 5 parts of the crude reduction product, tioned the methyl, ethyl or propyl radical. Suitable obtained from 2-naphthacyl bromide by use of the process reducing conditions are those provided by the presence 25 as described in Example 1, in 50 parts of absolute ethanol of a hydrogenation catalyst, for example platinum oxide, is heated under reflux with 10 parts of tert-butylamine hydrogen and an excess of the carbonyl compound, for for 16 hours. The solution is then evaporated to dryness example, acetone. under reduced pressure, the residue is basified with aque According to a further feature of the invention I ous sodium hydroxide solution and the resulting mixture provide a process for the manufacture of the naphthalene 30 is then extracted with ether. The ethereal extract is derivatives wherein R stands for hydrogen and R has dried and evaporated to dryness. The residue is crystal the meaning stated above which comprises hydrolysis lised from ether and there is thus obtained 2-hydroxy-2- of an acyl derivative of a naphthalene derivative of the (2-naphthyl)-ethyl)-tert-butylamine, M.P. 124° C. The formula: oxalate, prepared by treatment of an ethereal solution of 35 the base with ethereal oxalic acid, has M.P. 249 C. with CHOH-CHNIR2 decomposition. Example 3 Y A solution of 7 parts of the crude reduction product, obtained from 2-naphthacyl bromide by use of the proc Z. 40 ess as described in Example 1, in 100 parts of absolute wherein Y, Z and R2 have the meanings. ethanol is heated under reflux with 20 parts of sec.-butyl It is to be understood that the acyl derivative is such amine for 16 hours. The solution is then evaporated to that the acyl radical may replace the hydrogen atom of dryness under reduced pressure, the residue is basified the -OH group or the hydrogen atom of the -NH with aqueous sodium hydroxide and the resulting mix group. It is also to be understood that the acyl radical ture is extracted with benzene. The benzene extract is may be mono- or di-functional and in the latter case 45 dried and is then treated with ethereal hydrogen chloride. the acyl radical forms part of a heterocyclic ring. Thus There is thus obtained 2-hydroxy-2-(2'naphthyl)-ethyl suitable starting materials are 2-acetoxy-2(2-naphthyl)- Sec.-butylamine hydrochloride which after crystallisation ethylisopropylamine and 3-isopropyl-5-(2-naphthyl)-2- from acetone has M.P. 142-144° C. oxazolidone. Hydrolysis may be carried out in an aqueous medium in the presence of acid or alkali. Example 4 The compounds with which this invention is concerned A solution of 7 parts of the crude reduction product, possess valuable therapeutic properties for example they obtained from 2-naphthacyl bromide by use of the process antagonise certain effects of adrenaline on heart muscle as described in Example 1, in 100 parts of absolute and are therefore of value in the treatment or prophylaxis ethanol is heated under reflux with 20 parts of isobutyl of coronary artery disease. amine for 16 hours. The solution is then evaporated to Thus according to yet a further feature of the invention dryness, the residue is basified with aqueous sodium hy I provide pharmaceutical compositions containing as droxide and the resulting mixture is extracted with ben active ingredient one or more naphthalene derivatives of Zene.