- N

United States Patent Office Patented May3,732,300 8, 1973 2 amido radical of the formula -CONRRs (where Rs 3,732,300 and R6, which may be the same or different, each represent PHENYLAMNOETHANOL DERVATIVES a hydrogen atom or an arylalkyl radical or a straight or LawrenceEngadassigners H. C. Lunts to and Allen Paul and Toon, Hanbury's Bethnal Limited, Green, 5 branchedbonatoms chain which alkyl may radical be substituticontaining fromby hydroxylor 1 to 6 car NoLondon, ES England application Sept. 20, 1967, Ser. No. aminow groups or where R5 and Rs together with the ad 669,263, now Patent No. 3,644,353. Divided and this jacent nitrogen atom form a heterocyclic ring which may application May 11, 1971, Ser. No. 142,367 contain additional hetero atoms). Claims priority, application Great Britain, Sept. 23, 1966, O As the compounds of general Formula I possess at 42,590/66 least one asymmetric carbon atom, the invention also Int, C. C07c 103/26 includes all the possible optically active forms and racemic U.S. C. 260-559 S 8 Claims mixtures of the compounds. The racemic mixtures may -mm- be resolved by conventional methods, for example, by ABSTRACT OF THE DISCLOSURE 5 salt formation with an optically active acid, followed by Novel 1-phenyl-2-amino ethanol derivatives of the fractional crystallisation. Those compounds in which the formula: side chain substituent is para to the phenolic hydroxyl group or para to substituent X are preferred. X CHCH.NR2R3 The compounds of the invention possess either stimu --- ÖH l, lant or blocking actions on 6-adrenergic receptors. Com Ho-k ? 0 pounds which have a stimulant effect on B-adrenergic receptors are used mainly as broncho-dilators. However, are disclosed. Some have stimulant action and some have known 6-adrenergic stimulants, for example isoprenaline, blocking action on f3-adrenergic receptors. 5-(2-tert which is 3,4-dihydroxy-cv-(isopropylaminomethyl) benzyl butylamino-hydroxyethyl)-salicylamide in particular ex- 25 alcohol erts a marked blocking effect while being remarkably HO non-toxic and free from central nervous depressant ac- CH, tivity. HO- (H-CH-NHCH - This application is a division of copending application Ser. No. 669,263, filed on Sept. 20, 1967, now U.S. Pat. also affect the heart, and are potent cardiac stimulators 3,644,353. at effective bronchodilator doses. The compounds of the This invention relates to novel 1-phenyl-2-amino- invention which possess stimulant activity on 6-adrenergic ethanol derivatives having biological activity, and to receptors have been found to exert a more Selective effect compositions containing the same. 35 on bronchial muscle so that bronchodilation is possible The present invention provides compounds of the gen- without excessive cardiac stimulation. For example, the compound oil-tert-butylaminomethyl - 4 - hydroxy-m- eral formula: xylene-ox,c-diol (AH 3.365) has been tested on asthmatic X H. CH.NR 2R3 40 patients- and it was found that 100 ug., doses of this com HO- IHR pound given by aerosol, are at least equal in speed of onset and intensity of action to isoprenaline at the same dose, and it is longer acting than isoprenaline. It was and physiologically acceptable acid addition salts thereof, also found that AH 3365 did not affect the pulse rate or in which: blood pressure at four times the effective dose whereas R1 represents a hydrogen atom or a straight or branched 45 isoprenaline had a marked effect on both measurements, chain alkyl radical containing from 1 to 6 carbon atoms; as shown in Table I below. In contrast to isoprenaline R2 represents a hydrogen atom, or a benzyl group; which is poorly active when given orally, AH 3365 has R3 represents a hydrogen atom, or a straight or been found to be an effective bronchodilator in human branched chain alkyl radical containing from 1 to 6 car- beings after oral administration again without obvious bon atoms which radical may be substituted by hydroxyl 50 cardiovascular actions. TABLE I. Changes in heart rate and pulse-pressure after administration of AH 3365 and isoprenaline by aerosol. Mean of 6 subjects 5 minutes 10 minutes 15 minutes 20 minutes Pulse rate Pulse pres- Pulse rate Pulse pres- Pulse rate Pulse pres- Pulse rate Pulse pres permin. Sure, mm. Hig per min. Sure, mm. Hg permin. sure, mm. Hg permin. Sure, mm. Hg AH3365, 200 ug------(-1) -0.5 (-2.1) -5(-1) 8(2.9)------6(1) -4-2.2) AEI 3365, 400 ug.----- iSE} 1.5(42.2) -4(1) l(-El.9)------4(1) -1 (1.7) Isoprenaline, 200 pig------Hi9(1-6) --27. 5(3.8) --6(2) --11(2.6) -- (2) 3.5(2.3).------groups, amino groups or heterocyclic rings, containing 60. Amongst the other compounds of the invention which one or more heteroatoms, for example morpholino, or were found to possess p-adrenergic stimulant activity are represents a cycloalkyl, aralkyl or aryloxyalkyl radical those given below: - which radicals T. Eity. substituted E. example 4-hydroxy-al-isopropylaminomethyl-m-xylene-ox,c-diol. y one or more alkoxy or hydroxy groups; an 1- -- a - -ryl rv8 X represents a hydroxyalkyl or hydroxyaralkyl radical 65 O Syclopentylaminomethyl)-4-hydroxy-m-xylene-a,c. having1 to 6 carbona straight atoms, or branched or a carboxyl alkyl chainradical, containing or an alkoxy- from 4-h drs XV-O-(1-iy-ax-(1-isopropylaminopropyl)-m-Xylene-ox,o. lami 1)-m-xylene-clo carbonyl radical of the formula - COOR (where R4 4-hydroxy-a-((2-indol-3-y-1-methylethyl)aminomethyl represents a straight or branched chain alkyl radical con- m-xylene-oza'-diol. taining from 1 to 6 carbon atoms), or represents a radical 70 4-hydroxy-al-I(-methyl-2-phenoxyethyl)aminojmethyl}- of the formula -CONHOH or -CONHNH, or an m-xylene-ox,ox3-diol. 3,782,300 3. . 4. 4-hydroxy-a-(p-methoxy-c-methylphenethyl)aminol The invention therefore includes within its scope phar methyl-m-xylene-a,c-diol. maceutical compositions containing as active ingredients 4-hydroxy-oil-(p-hydroxy-o-methyl phenethyl-amino) 1-phenyl-2-aminoethanol derivatives of the general For methyl-m-xylene-a,c-diol. mula I, or physiologically acceptable acid addition salts 4-hydroxy-al{(1-methyl-2-morpholinoethyl)aminol thereof. Such compounds may be presented for use in a methyl-m-xylene-a,cis-diol. conventional manner with the aid of carriers or excipients These compounds were tested in anaesthetised guinea and formulatory agents as required, and with or without pigs for the ability to relieve bronchospasm induced by Supplementary medicinal agents. the injection of acetylcholine, 5-hydroxy-tryptamine, The compositions may include for instance solid and bradykinin and histamine. O liquid preparations for oral use, suppositories, injections, Other uses for the compounds of the invention which or in a form suitable for administration by inhalation. possess 3-adrenergic stimulant activity may include the Oral administration is most convenient in the form treatment of glaucoma, and also the control of gastric of tablets which may be prepared according to conven acid secretion in the treatment of peptic ulceration. The tional methods, and may be coated if required. Soluble cardiovascular side-effects of known 6-adrenergic stimu 15 tablets suitable for sublingual administration may also be ants limit their usefulness in these cases. used. The compounds of the invention which possess block Injections may be formulated with the aid of physiologi ing activities on 6-adrenergic receptors are of use in the cally acceptable carriers and agents as solutions, suspen treatment or prophylaxis of cardiovascular disorders, for sions or as dry products for reconstitution before use. example, arrhythmias, coronary heart disease, angina 20 For administration by inhalation the compositions ac pectoris and hypertension. Known B-adrenergic blocking cording to the invention are conveniently in the form of agents have undesirable side effects, for example 3,4-di an aerosol spray presentation. chloro-O-(isopropylaminomethyl) benzyl alcohol pos The dosage at which the active ingredients are ad sesses potent sympathomimetic effects, and propranolol, ministered may vary within a wide range and will depend 1-isopropyl-amino-3-(1-naphthyloxy)-propan-2-ol affects on whether their activity is as a 6-adrenergic stimulant or the central nervous system. The compounds of the in as a B-adrenergic blocker. A suitable oral dosage range vention however are virtually devoid of these side effects. for the stimulants is generally from 1 to 100 mg. and for For example, the compound 5-(2-tert-butyl-amino-1- the blockers 50 to 1000 mg. The pharmaceutical composi hydroxyethyl)-salicylamide, when tested in conscious tions may with advantage be formulated to provide a dogs, was found to be slightly less active than propranolol 30 dose within this range either as a single unit or a number in reducing the tachycardia produced by the intravenous of units. injection of isoprenaline. At 0.5 mg./kg., for example, In the use of an aerosol for bronchodilatation the dos the compound given orally produced a 50-60% block age unit may be determined by providing a metering valve of the isoprenaline response, whilst propranolol at the in the aerosol pack so that it delivers a metered amount same dose level produced a 70-80% block, the duration 35 on use. Such a metered amount may be of the order of of action of the two compounds being similar. However, 50-1000 ug. in neuropharmacological tests, the compound was found The compounds according to the invention may be pre to be remarkably non-toxic, and free from central nervous pared by a number of processes which at some stage in depressant activity. For example, in mice, it produced only Volve the reduction of the corresponding ketone to the negligible behavioural effects at doses up to 400 mg/kg. 40 alcohol. administered orally, whereas animals treated with pro The invention therefore provides a process for the pranolol showed signs of depression at doses of 100 mg/ preparation of compounds of the general Formula I kg. and at 400 mg./kg. the drug caused very severe and herein which comprises reducing the carbonyl group widespread central depression. Amongst the other compounds of the invention which 45 were found to possess S-adrenergic blocking activity when CO (HNR.R. tested for the ability to inhibit the tachycardia produced by the intravenous injection of isoprenaline in anaesthe Ho-k 2 R1 tised dogs, are to be mentioned the following: of a ketone of the above general formula to an alcoholic 5-(1-hydroxy-2-isopropylaminoethyl)-salicylic acid meth 50 group in which X, R1,R2 and Rs have the meanings given ylester. herein or are groups convertible thereto, if desired with 5-(2-amino-1-hydroxyethyl)-salicylic acid methyl ester. protection of the phenolic hydroxy group, the product 5-(1-hydroxy-2-isopropylaminoethyl)-salicylamide. if desired being isolated in the form of a physiologically 5-(1-hydroxy-2-(1-methyl-2-phenoxyethyl)amino ethyl) acceptable acid addition salt. salicylamide. 55 5-(1-hydroxy-2-isopropylaminoethyl) -N-methyl-salicyl In one method of preparation compounds of the gen amide. eral Formula I are prepared by a process which comprises. a-(benzyl-tert-butylaminomethyl) -4-hydroxy-m-xylene converting the methoxycarbonyl group of the ketone of alo-diol. the general Formula II (X=COMe) 60 Ra NE--(1-hydroxy-2-isopropylaminoethyl)-salicyC X / COCEI.N. 5-Il-hydroxy-2-(p-methoxy-o-methylphenethyl)amino N ethyl)-salicylic acid methyl ester. O R CEPh 5-(1-hydroxy-2-(isopropylamino)-butyl salicylamide. (II) 41-hydroxy-2-(isopropylamino)ethylsalicyclic acid 65 methyl ester. in which R1 and Rs have the meaning given above, by conventional methods to any of the other radicals rep Specific preferred compounds according to the invention resented by Xin Formula I, either directly, or after reduc are those specifically referred to above. tion of the carbonyl group to the alcohol with suitable The compounds according to the invention may be 70 hydrides for example sodium borohydride, or lithium formulated for use in human or veterinary medicine for aluminium hydride. If desired the N-benzyl group may therapeutic and prophylactic purposes. They will in gen then be removed by catalytic hydrogenolysis. Alternative eral be used in the form of their physiologically acceptable ly reduction of the carbonyl group and removal of the salts. Preferred salts include the hydrochloride, Sulphate, N-benzyl group can be effected in one stage by hydrogen maleate, tartrate, citrate, etc. 75 and a noble metal catalyst. In some reactions, it may 3,732,300 5 6 be advantageous to protect the phenol group e.g. as a reacting the ketone II (X=COR4) or the alcohol derived benzyl ether or an acetate. The protecting group may be from it by reduction with an amine of the general for removed by hydrogenolysis or hydrolysis to give the re mula R5RsNH, where R4, R5 and Rs have the meanings quired product. Compounds in which R2 and R3 both given above, followed by catalytic hydrogenolysis. represent hydrogen atoms may be prepared from the di Compounds of the general Formula I in which X is a benzyl amino compound by catalytic hydrogenation. -CONHOH or CONHNH2 radical may be prepared Another subsequent conversion envisaged by the in from the ketone of Formula II (X-COR4) by reducing vention is the reaction of the group COOMe to a tertiary it to the alcohol of general Formula I (X=CO2R) in alcohol by reaction with a Grignard reagent. which R4 has the meaning given above, and reacting this The 1-phenyl-2-aminoethanol derivatives of the gen O compound with hydroxylamine, NHOH or hydrazine eral Formula I in which X is an alkoxycarbonyl radical NH2NH2 and removing the N-benzyl group to give the: of the general Formula -COOR, where Ra has the mean required product. ing given above may be prepared by reacting the ketone In an alternative process for the preparation of the of Formula II (X=CO2H) with an alcohol of the gen 1-phenyl-2-aminoethanol derivatives of the invention, the eral formula ROH, in the presence of an acid catalyst, secondary amine of the general Formula VI (X=COMe) followed by catalytic hydrogenolysis, to give the 1-phen may be used in place of the ketone II, or alcohol I yl-2-aminoethanol derivative. (X=COMe), for the reactions given above in which The compounds of the invention in which X is a hy the methoxycarbonyl group is converted to any of the droxymethyl group may be prepared by reduction of the other radicals represented by X in the general Formula I ester group -COMe, for example with lithium alu 20 minium hydride, followed by catalytic hydrogenolysis, to the alcohol of general Formula I. It has been found that HO co,R HNHR, the addition of a volatile base to the reaction mixture minimises the hydrogenolysis of the -CH2OH group WI during the catalytic reduction. 25. The ketone of general Formula II may be prepared Compounds of the general Formula I in which X is by the condensation of an amine RNH.CH2Ph with a a hydroxymethyl radical may also be prepared by other halogen derivative of general Formula VII processes. In the first of these processes a compound of the gen 30 HO Ri eral Formula III, or a salt thereof Kx.Ž og H. Hal W R3 CEOE / The 1-phenyl-2-aminoethanol derivative of the general COC-N (in which R1 and N R3 are as above Formula I may also be prepared by the condensation of O- R CHPh defined and Ph is a an amine of the general formula R2RNH with a halo phenyl radical). 35 hydrin of the general Formula VIII is subjected to catalytic hydrogenation, preferably using X a palladium oxide on charcoal catalyst to yield a com EO CHOH. RH.Hal pound of the general Formula IV. -{ VIII 40 R3 In a further process the compounds of Formula I may CEOH also be prepared by the reaction of an amine of the Choh H-NC general formula R2R3NH with an epoxide of general no- X R1 (IV) ' Formula IX Alternatively, the ketone of Formula III may be re 45 duced with sodium borohydride to give the alcohol of general Formula V and this latter may also be obtained ce bit by reduction of a compound of Formula II (where no-K ). So IX X=alkoxycarbonyl) by the use of lithium aluminium hy In all of the above processes the phenolic group may dride. 50 be protected, e.g. as the benzyl ether. CEO In these formulae, R1, R2, R3 and X have the meanings R3 given above. Compounds of the general Formula I in which X is (V) 55 a secondary or tertiary alcoholic group may be prepared If desired this compound is then subjected to catalytic via conversion of a compound of the Formula I in which hydrogenation to remove the N-benzyl group, to produce in the X substituent position there is a halogen atom to a compound of Formula IV. -- an organometallic compound and reaction thereof with Use of the alcohol (V) in the hydrogenation instead an aldehyde or ketone. of the ketone III minimises the side reaction in which 60 The following examples illustrate the invention. the -CH2OH group is reduced to a -CH group. The EXAMPLE 1. ketone of the general Formula III can be prepared from Preparation of 5-(1-hydroxy-2-isopropylaminoethyl)- the compound (VII, X=-CH2OH) below in which the hydroxy groups can be protected by acetylation, by con salicylamide hydrochloride densation with an amine of the general formula R2R3NH 65 (a) 5-(N-benzyl - N - isopropylglycyl)-salicylic acid (where R and Rs have the meanings given above) and methylester hydrochloride.-7.3 g. of N-benzylisopropyl removal of protecting groups where these are present. amine were added to a stirred solution of 7.5 g. of 5 The compounds of Formula I in which X is a carboxyl bromoacetyl salicylic acid methyl ester in 100 ml. of group may be prepared by hydrolysis of the ester group methyl ethyl ketone. A colourless crystalline precipitate of the ketone II (X=COMe), for example with an acid 70 was observed at once but stirring and refluxing was con catalyst, followed by catalytic hydrogenolysis to the 1 tinued for 2.5 hrs. After being allowed to stand at room phenyl-2-aminoethanol derivative. temperature for 2 days the solvent was evaporated under Compounds of Formula I in which X is an amide reduced pressure and dry ether was added to the residual group of the general formula -CONR5Rs, where R5 and oil. The ethereal solution obtained was treated with dry Rs have the meanings given above, may be prepared by 75 hydrogen chloride gas to give 6 g. of the hydrochloride 3,782,300 7 8 as an oily solid. Recrystallisation from methanol/ethyl The hydrochloride was prepared by treating 1.8 g. of acetate gave 3.55 g. of the hydrochloride as a colourless the above base in ethyl acetate with a solution of hy. powder, M.P. 168-170° C. drogen chloride in ether and recrystallising the product (b) 5-(N-benzyl-N-isopropylglycyl)-salicylamide hy from methanol/ethyl acetate (9:1). 1.1 g of the N drochloride-A solution of 15 g. of 5-(N-benzyl-N-iso hexyl-5-(1-hydroxyethyl-, 2-isopropylamino) salicylamide propyl glycyl)-salicylic acid methyl ester hydrochloride hydrochloride separated as colourless plates, M.P. 199. in 125 ml. of methanol and 125 ml, of 0.880 ammonia EXAMPLE 4 solution was allowed to stan din a stoppered flask. After six days, the solution was evaporated to dryness and the Preparation of 5-(2-tert-butylamino-1-hydroxy residue was extracted three times, each time with 150 O ethyl) salicylamide hydrochloride ml. of ether. The free base began to precipitate from 1.0 g. of 5-(N-benzyl-N-tert-butylglycyl) salicylamide the ethereal solution. Treatment of the mixture with hy hydrochloride, 0.2 g of 10% palladium oxide on char drogen chloride gas give a white oily material, which on coal catalyst, 20 ml. of ethanol and 15 ml. of water boiling with ethyl acetate gave 12.5 g. of a white solid. were shaken at room temperature in an atmosphere of Recrystallisation from methanol gave 11.0 g. of the hydrogen until uptake of hydrogen ceased. The catalyst amide hydrochloride as colorless crystals, M.P. 217 was filtered off and the solvent was removed by distilla 220, after drying at 70 in vacuo to constant weight. tion. The residue was crystallised from methanol/iso (c) 5-(1-hydroxy-2-isopropylaminoethyl)-salicylamide propyl acetate to give 0.56 g. of a pale pink solid, M.P. hydrochloride- 4.15 g..of 5-(N-benzyl-N-isopropyl gly 203-4. cyl) salicylamide hydrochloride in 250 ml. of methanol EXAMPLE 5 were hydrogenated at room temperature and pressure 20 in the presence of 1.g. of a 10% palladium oxide on Preparation of N-benzyl-5-(1-hydroxy-2-isopropyl charcoal catalyst. Uptake of hydrogen ceased after 40 aminoethyl)-salicylamide, hydrochloride minutes. The solution was filtered and evaporated to dry 8.0 g. of 5-(1-hydroxy-2-isopropylaminoethyl)-salicyl ness. The residue was recrystallised from methanol/ethyl ic acid, methyl ester were dissolved in 40 ml. of eth acetate to give 2.3 g. of the product, M.P. 207-8 C. anol containing 40 ml. of benzylamine. The solution was allowed to stand at room temperature for 4 days EXAMPLE 2 before evaporation to a small volume under reduced Preparation of 5-2-(N-benzyl-N-isopropylamino)- pressure. The gummy residue was treated with 50 ml. 1-hydroxyethylsalicylamide of dilute hydrochloric acid and the white solid was filtered off and recrystallised from methanol/ethyl acetate 1.3 g of 5-(N-benzyl-N-isopropyl glycyl) salicylamide to afford 5.05 g. of N-benzyl-5-(1-hydroxy-2-isopropyl were dissolved in 50 ml. of tetrahydrofuran, then added aminoethyl)-salicylamide, hydrochloride, M.P. 208 to a stirred solution of 1.0 g. of lithium aluminum hy 209. dride in 250 ml. of tetrahydrofuran and heated under re EXAMPLE 6 flux for 3 hours. After cooling, water was added to de compose the excess hydride and the mixture was acidified Preparation of 5-(1-hydroxyethyl-2-isopropylamino with dilute hydrochloric acid. The solution was evapo N-methyl)-salicylamide hydrochloride rated almost to dryness and the pH was adjusted to (a) 5 - (N-benzyl-N-isopropyl-glycyl)-N-methyl-salicyl 8-9. Extraction with ether and ethyl acetate afforded amide, hydrochloride.-2.5 g. of 5-(N-benzyl-N-isopro 0.9 g, of a pale yellow gum. ply-glycyl)-salicylic acid methyl ester, hydrochloride Chromatography on silica gel and elution with cyclo were dissolved in 50 ml. of a 30% solution of methyl hexane ethyl acetate (1:1) gave 0.31 g. of a crystalline amine in ethanol. The solution was left overnight and solid, M.P. 142.5-144.5. Recrystallisation from ether/ 45 was then evaporated to dryness under reduced pressure. petrol provided pure 5-(2-N-benzyl-N-isopropylamino-1- The residue was dissolved in dilute hydrochloric acid hydroxyethyl) salicylamide, M.P. 140-142. and washed with ethyl acetate, and the aqueous layer made alkaline with sodium carbonate solution to pH 8 EXAMPLE 3 and again extracted with ethyl acetate. The latter organic 50 extracts were dried over sodium sulphate, concentrated Preparation of N-hexyl-5-1-hydroxy-2-isopropyl and treated with an ethereal solution of hydrogen chlo aminoethyl salicylamide hydrochloride ride to afford 1.6 g. of 5-(N-benzyl-N-isopropyl-glycyl)- (a) 5-(1-hydroxy-2 - isopropylaminoethyl)-salicylic N-methyl-salicylamide, hydrochloride, M.P. 200-205. acid methylester hydrochloride.-3.0 g. of 5-(N-benzyl Recrystallisation from ethyl acetate/ethanol gave rosettes, N-isopropylglycyl)-salicylic acid methylester hydrochlo 55 M.P. 205-209. - ride in 50 ml. of ethanol were hydrogenated with 0.52 (b) 5 - (1 - hydroxyethyl-2-isopropylamino)-N-methyl g. of 10% palladium oxide catalyst. Hydrogen uptake salicylamide hydrochloride.-4.2g. of 5-(N-benzyl-N-iso was complete after 95 minutes. The solution, after re propylglycyl-N-methyl salicylamide, hydrochloride were moval of the catalyst was evaporated to dryness under dissolved in 35 ml. of 90% aqueous methanol and this reduced pressure to give 2.3 g. of a pale pink solid. Cry 60 solution was added to a pre-reduced suspension of 1 g. stallisation from methanol/ethyl acetate gave 2.03 g. of of 10% palladium on carbon catalyst in 15 ml. of meth colorless needles, M.P. 153-155' C. anol. - - (b) N-hexyl-5-(1-hydroxy-2 - isopropylaminoethyl)- The hydrogenation was stopped when 550 ml. of hy salicylamide hydrochloride.-2.0 g. of the methyl ester drogen had been absorbed. The catalyst was filtered off of 5-(1-hydroxyethyl-2-isopropylamino) salicylic acid 65 and the solution was concentrated to ca. 10 m. and al were dissolved in 10 ml. of ethanol containing 10 ml. of lowed to crystallise, affording 2.3 g. of 5-(1-hydroxy-2- n-hexylamine and the solution was allowed to stand at isoproylaminoethyl-N-methyl salicylamide hydrochloride. room temperature. After 4 days all the ester had reacted Recrystallisation from ethanol gave fine colourless nee and the solution was evaporated to dryness. Trituration dies, M.P. 208-209 C. with ethyl acetate containing a drop of menthanol af 70 EXAMPLE 7 forded 3.0 g., of crystalline solid, M.P. 134-144. Re crystallisation from ethyl acetate/ether containing one Preparation of 4-1-hydroxy-2-(isopropylamino)ethyl] drop of ethanol gave N-hexyl-5-(1-hydroxy-2-isopropyl salicylamide . . aminoethyl) salicylamide as a white powder, M.P. 134 (a) 4 - 2 - benzylisopropylamino - 1 - hydroxyethyl 135°. 75 salicylamide-A solution of 3.55g of 4-(2-benzylisopro 3,782,300 O pylamino-1-hydroxyethyl salicylic acid, methyl ester, hy EXAMPLE 10 drochloride in hot water was basified with sodium bicar Preparation of 5-1-hydroxy-2-(isopropylamino)ethyl bonate solution and the resulting suspension was extracted N-(2-hydroxyethyl) salicylamide, hydrate with ethyl acetate. The ethyl acetate solution was dried and evaporated, and the gummy residue dissolved in 50 (a) 5 - (N - benzyl, N-isopropyl)glycyl)-2-benzyloxy ml. of ethanol. To this solution was added 30 ml. of 0.880 benzoic acid, methyl ester, hydrochloride.-A solution of ammonia solution, and the resulting mixture was allowed 2.33 g. of 2-benzyloxy-5-bromoacetylbenzoic ester, meth to stand at room temperature for one week. The Solution yl ester and 1.935 g. of N-benzylisopropylamine in 40 ml. was then evaporated to dryness and the residue extracted of methyl ethyl ketone was stirred under reflux for 5 with ether. The ether solution was evaporated to dryness, O hours, and then allowed to stand at room temperature giving a whitish solid residue which was crystallised from overnight. Benzylisopropylamine hydrobromide crystal benzene to give 1.53 g. of the product, M.P. 155-6 C. lised out and was filtered off. The filtrate was evaporated (b) 4 - hydroxy-2-(isopropylamino)ethyl salicylam to dryness, dissolved in either and washed with water. The ide-A solution of 0.456 g. of 4 - 2 - benzylisopropyl ether layer was then shaken with dilute HCl to produce amino-1-hydroxyethyl salicylamide in methanol was hy 5 a gum, which was extracted from the aqueous layer with drogenated over 0.1 g. of pre-reduced 10% palladium on chloroform. The chloroform solution was washed with carbon catalyst. Uptake of hydrogen was complete in 19 brine, dried and evaporated, giving a gummy residue. mins. After filtering off the catalyst, the methanol solu When this was triturated with boiling acetone/ether 2.0 tion was evaporated to dryness, leaving a glassy residue g. of a white solid was obtained, M.P. 160-162. which was allowed to crystallise from a mixture of ether 20 (b) 5-2-(N-benzyl, N-isopropyl)amino]-1-hydroxy and ethyl acetate. This gave 0.236 g. of white prisms. ethyl-2-benzyloxybenzoic acid, methyl ester, hydrochlo M.P. 114-6. From the analysis, infra-red spectrum, and ride, hemihydrate-4 g. of 5-(N-benzyl, N-isopropyl) equivalent weight the compound was found to contain glycyl)-2-benzyloxybenzoic acid, methyl ester hydrochlo 0.5 mole of ethyl acetate of crystallisation. ride was dissolved in 90 ml. of ethanol and to the stirred The benzoate derivative (prepared from a solution of 25 solution was added 0.9 g, of sodium borohydride in small the base in tetrahydrofuran and benzoic acid in ether) portions over 30 minutes, with stirring. The resulting crystallised from isopropanol in small white prisms. M.P. suspension was stirred at room temperature for a further 146-152. hour, and was then evaporated to dyness and the residue EXAMPLE 8 shaken with ether and filtered. The filtrate when treated with ethereal hydrochloric acid, gave 4.2 g of a white Preparation of 5-1-hydroxy-2-(isopropylamino)-butyll 30 solid, M.P. 120-30. Crystallisation from ethyl acetate salicylamide, hydrochloride raised the M.P. to 134-36. (c) 5-1-hydroxy - 2 - (isopropylamino)ethyl N-2-hy (a) 5 - (or - isopropylamino) - butyryl-salicylamide, droxyethyl salicylamide, hydrate.-10 g. of 5-(2-benzyl hydrochloride-A solution of 3.0 g. of 5-(o-isopropyl isopropylamino - 1 -hydroxyethyl] - 2 - benzyloxybenzoic amino)-butyryl-salicylic acid methyl ester hydrochloride 35 acid, methyl ester, hydrochloride, hemihydrate was basi in 50 ml. of ethanol and 0.880 ammonia was allowed to fied to give 9.05 g. of white crystals. This was dissolved stand for 7 days at room temperature in a stoppered flask. in a mixture of 100 ml. of ethanol and 40 m. of ethanol The solution was evaporated to small bulk and the yel amine and left to stand at room temperature for 2 weeks. lowish solid was filtered off. This was very insoluble in 40 The solution was then hydrogenated over 1.0 g of 10% ether. The hydrochloride was prepared by dissolving the pre-reduced palladium on carbon catalyst. Uptake of amide in ethanol and acidifying with dry hydrogen chlo hydrogen was complete in 2.5 hours. The catalyst was ride gas to pH 4-6. The solvent was evaporated off and filtered off and the solvents were evaporated, leaving a the off-white solid, residue was crystallised from ethanol white solid. This was crystallised from ethyl acetate/ to yield 2 g. of a white solid, M.P. 300. 45 methanol, to give 5.2 g of white micro-crysals, M.P. (b) 5 - 1 - hydroxy-2-(isopropylamino)-butylsalicyl 52-3. amide, hydrochloride-1.5 g. of 5 - (o-ispropylamino) The hydrochloride of this product, M.P. 195, was butyryl-salicylamide hydrochloride in 175 ml. of meth crystallised from isopropanol. anol were hydrogenated at room temperature and pres sure in the presence of 10% palladium oxide on carbon EXAMPLE 11 catalyst for 10 hours. The solution was filtered and evap 50 Preparation of 5-1-hydroxy-2-(isopropylamino)ethyl orated to dryness. The white solid residue recrystallised salicylhydroxamic acid from methanol/ethyl acetate as pale pink prisms con taining 0.5 mole of ethyl acetate of crystallisation. The (a) oz (benzylisopropylamino)methyl]-6-benzyloxy material was further crystallised from methanol/ether to ox-hydroxy-m-toluhydroxamic acid.-4.0 g. of 5-2-[ben 55 Zylisopropylamino - 1 - hydroxyethyl - 2 - benzyloxy give 1.0 g. of pale pink micro-crystals containing no sol benzoic acid, methyl ester, hydrochloride, hemihydrate, vent of crystallisation, M.P. 220-221. in 30 ml. of methanol was added to hydroxylamine solu EXAMPLE 9 tion prepared by mixing a solution of 16.3 g. of hydroxyl amine hydrochloride in 110 ml. of methanol with a solu Preparation of 5-(2-tert-butylamino - 1 - hydroxy-ethyl)- 60 tion of 5.5 g. of sodium in 50 ml. of methanol, and N-2-(dimethylamino) ethyl salicylamide, dihydrogen filtering the precipitated NaCl. maleate After 1 month standing in a stoppered vessel at room 5.0 g. of 5-(2-tert-butylamino-1-hydroxyethyl) salicylic temperature, the solution was evaporated, and the oily acid methyl ester were dissolved in 25 ml. of dimethyl residue was extracted with ether (3 x 150 ml.). Evapo aminoethylamine and allowed to stand at room tempera 65 ration of the ether gape an oil which was dissolved in ture. After 24 hours, the solution was evaporated to dry a large volume (ca. 500 ml.) of cyclohexane. On cool ness and the residue crystallised from ethyl acetate to af ing, an oil precipitated and solidified within two days ford 5.0 g. of a cream solid, M.P. 146-51. This base to give 2.2 g of a white solid. was not purified further but a portion of 2 g. was dis Recrystallisation from cyclohexane gave white crystals solved in 50 ml. of tetrahydrofuran and treated with a 70 of the hydroxamic acid, M.P. 138-140°. solution of 1.5 g. of maleic acid in 10 ml. of tetrahydro (b) 5-1-hydroxy - 2 - (isopropylamino)ethyl salicyl furan. A white solid separated out which on recrystallisa hydroxamic acid-1.45 g. of O-I (benzylisopropylamino) tion from 95% ethanol gave 2.63 g. of 5-(2-tert-butyl methyl-6-benzyloxy-a-hydroxy-m-toluhydroxamic acid amino - 1 - hydroxy-ethyl)-N-(2-(dimethylamino) ethyl in 32 ml. of methanol was hydrogenated in the presence salicylamide, dihydrogen maleate, M.P. 199-200. 75 of 0.4 g. of pre-reduced 10% palladium oxide on carbon 3,732,300 11 12 catalyst suspended in 8 ml. of water. Hydrogenation was EXAMPLE 1.5 completed after 15 minutes. The solution was filtered Preparation of 41-hydroxy-2-(isopropylamino)ethyl) and evaporated to yield a white solid. Further material was obtained by extracting the catalyst residues with 75 salicylic acid, methyl ester, hydrochloride rated with tetrahydrofuran, followed by ethanol, to yield (a) 4-2-benzylisopropylamino - 1 - hydroxyethylsali ml. of hot water. The solids were combined and tritu 5 cylic acid, methyl ester, hydrochloride.- 2.7 g. of 4 rated with tetrahydrofuran, followed by ethanol, to yield (bromoacetyl)salicylic acid, methyl ester were dissolved 0.46 g. of the product as a white solid, M.P. (186-188. in 7.5 ml. of dry tetrahydrofuran and added at room tem perature to a solution of 2.94 g. of N-benzylisopropyl EXAMPLE 12 amine in 7.5 ml. of dry tetrahydrofuran. The resulting O mixture was left to stand for 4 hours. After this time the Preparation of 5-(2-tert-butylamino-1-hydroxyethyl) crystals of N-benzylisopropylamine hydrobromide were salicylic acid hydrazide filtered off and the filtrate was treated with a solution of 5.0 g of 5-(1-tert-butylamino-1-hydroxyethyl)salicylic 0.6 g. of sodium borohydride in 15 ml. of 90% ethanol. acid, methyl ester was dissolved in a solution of 30 ml. 5 The resulting mixture was allowed to stand at room tem of hydrazine hydrate in 20 ml. of ethanol and allowed perature for 3 days. The mixture was then evaporated to to stand overnight at room temperature. The solution dryness, the residue was partitioned between ether and was evaporated to dryness and the brown residue tritu water, and the ether solution was dried and evaporated. rated with ethanol/tetrahydrofuran to give 4 g. of a cream The liquid residue was dissolved in 60 ml. of dry ether/ solid which did not melt but gradually decomposed with 20 ethyl acetate (1:1). This gave, on scratching with a glass charring above 300. rod, 2.4 g of a white solid, M.P. 150-160. Crystallisa tion from ethyl acetate/methanol gave 1.615 g. of the EXAMPLE 13 product, M.P. 174-175.5°. (b) 4.1-hydroxy - 2 - (isopropylamino)ethylsalicylic Preparation of 5-(2-benzylisopropylamino-1-hydroxy acid, methyl ester, hydrochloride-A solution of 1.0 g. ethyl)-salicylic acid methyl ester hydrochloride 25 of 4-2-(N-benzyl,N-isopropyl)amino - 1 - hydroxyethyl - 12.0 g. of 5-(N-benzyl-N-isopropyl glycyl)-salicylic salicylic acid, methyl ester, hydrochloride in 50 ml. of acid methyl ester hydrochloride in 230 ml. of ethanol ethanol was hydrogenated over 0.2g. of pre-reduced 10% were treated with 2.404 g. of sodium borohydride, added palladium oxide on charcoal catalyst. The volume of hy portionwise over 30 mins. at room temperature. The 30 drogen absorbed in 10 minutes was 60 ml. The catalyst mixture was allowed to stand overnight. Reduction was was then filtered off and the filtrate evaporated to dryness. shown to be complete by the disappearance of the band. Trituration of the residue with ethyl acetate/ether gave at 278 mu, in the U.V. spectrum. The mixture was then 0.68 g. of a white solid, M.P. 166-8. Crystallisation from evaporated to dryness under reduced pressure at 40, and ethyl methyl ketone gave 0.31 g. of the product as large the residue was extracted with ether (3 x 100 ml.). The 35 white crystals, M.P. 171.5-173° C. ether extracts were dried over MgSO4, and treated with hydrogen chloride gas. The precipitated white oily mate EXAMPLE 16 rial gave 6.8 g. of a white solid on boiling with ethyl Preparation of oil-tert-butylaminomethyl-4-hydroxy acetate. Recrystallisation from acetone/ether gave 5.5 g. m-xylene-o,ox3-diol of the ester hydrochloride as colorless microcrystals. 40 (a) oz-Benzyl-tert-butylaminomethyl - 4 - hydroxy-m- xylene-a,c-diol-3.0 g of 5-(N-benzyl - N - tert-butyl EXAMPLE 14 glycyl)-salicylic acid methyl ester hydrochloride in 40 ml. Preparation of 4-hydroxy-al-isopropylaminomethyl of water was basified with sodium bicarbonate solution m-xylene-a,c-3 diol and extracted into ether. The ethereal solution was dried 45 over MgSO4 and evaporated and the basic residue in 20 (a) al-Benzylisopropylaminomethyl - 4 - hydroxy-m- ml. of dry tetrahydrofuran was added with stirring to xylene-ox, a diol.-22.0 g. of 5-(N-benzyl-N-isopropyl 1.0 g. of lithium aluminium hydride in 100 ml. of dry glycyl)salicylic acid methyl ester hydrochloride was basi tetrahydrofuran, over a period of 5 minutes. The light fied with aqueous sodium bicarbonate solution and ex gelatinous precipitate that formed was stirred and refluxed tracted into ether. After drying over sodium sulphate, the 50 for 8 hours after which time 7 ml. of water was carefully solution was evaporated to dryness and the residue was added and the solvents were removed under reduced dissolved in 150 ml. of tetrahydrofuran. This solution pressure. was added dropwise to 4 g. of lithium aluminum hydride The residue was acidified with dilute hydrochloric acid in 300 ml. of tetrahydrofuran. An insoluble complex and brought to pH 8 with sodium hydroxide and sodium formed. The mixture was refluxed for 7 hours under 55 bicarbonate. The mixture was filtered and the filtrate and nitrogen, cooled, treated with 10 ml. of water and filtered. orange solid were separately extracted with chloroform. The solid together with the residue from evaporation of The combined, dried, chloroform solutions were evapo the filtrate was dissolved in dilute hydrochloric acid, and rated to give 2.2 g of the crude basic triol as an orange. this solution was basified with aqueous sodium bicar solid, when triturated with ether. A portion of the ma bonate solution, and continuously extracted with ether to 60 terial was recrystallised from ether/light petroleum (B.P. give the free base as a gum. Crystallisation from ether/ 40-60) to give a white solid, M.P. 109-111 C. petrol gave oil-benzylisopropyl-amino-methyl-4-hydroxy In an alternative process, sodium borohydride was used m-xylene-o,as diol as white crystals, M.P. 115-6. as the reducing agent, as follows: (a) 4-hydroxy-o-isopropylaminomethyl - m - xylene 36 g. of 2 - (benzyltert-butylamino)-4-hydroxy-3'-hy al,a diol.-4.5 g. of al-benzylisopropylaminomethyl-4- 65 droxymethyl acetophenone, hydrochloride was shaken hydroxy-m-xylene-ox, a diol in 100 ml. of ethanol and 10 with 100 ml. of 10% sodium carbonate solution and 100 ml. of water were hydrogenated at room temperature and ml. of ethyl acetate. The ethyl acetate layer was sepa pressure in the presence of 1.2 g. of a 10% palladium rated, washed with water, dried over anhydrous sodium oxide on charcoal catalyst, until the uptake of hydrogen sulphate and evaporated in vacuo. slowed markedly. The solution was filtered and evaporated O The residual gum was dissolved in 360 ml of ethanol to dryness. The oily residue solidified on being allowed and cooled to 15 in an ice/water bath. 8 g. of sodium to stand in 25 ml. of ethyl acetate to give 3.5 g. of the borohydride was then added in portions over 30 min. crystalline hydroxy diol, M.P. 139-140 C. Purification whilst maintaining the temperature at 15-20. After a by precipitation from a solution of tetrahydrofuran with further 30 mins. at 20 the solution was stirred at room ether raised the melting point to 143-45 C. 75 temperature for 2 hours. The solution was again cooled 3,732,300 13 14 in ice and 250 ml. of 2 N sulphuric acid were slowly leaving to stand overnight, the excess lithium aluminium added, then the solution was evaporated in vacuo until the hydride was decomposed with the minimum of water ethanol had been removed. The clear aqueous Solution and the resulting mixture was evaporated to dryness. The was then treated with 250 ml. of 10% sodium carbonate residue was shaken with dilute HCl and filtered, the filtrate solution and the oil which precipitated was extracted into 5 was extracted with ether, then the aqueous layer was ethyl acetate. The ethyl acetate layer was Washed with basified to pH 8 with sodium bicarbonate solution and sodium carbonate solution, then with water, and was dried extracted with ethyl acetate. The ethyl acetate solution over anhydrous sodium sulphate and evaporated in vacuo, was dried and evaporated to dryness. The residue was to a small volume. Petroleum ether (B.P. 40-60) was allowed to crystallise from ether, giving 0.99g. of yel added, and after standing overnight a white solid was ob 10 lowish crystals, M.P. 103-8. tained. This was filtered off to give 23 g. of the product, (b) 3 - hydroxy-ox-(isopropylamino) methyl-p-xylene M.P. 110-114. ox,c-diol.-0.6 g. of ox-benzylisopropylaminol methyl-3- (b) oil-tert-butylaminomethyl-4-hydroxy - m - Xylene hydroxy-p-xylene-ox,o'-diol was dissolved in 30 ml. of ol,or 3-diol.-0.8 g. of cal-benzyl-tert-butylaminomethyl-4- ethanol and to this solution was added 0.15 g. of triethyl hydroxy-m-xylene-a,a-diol in 20 ml. of ethanol and 2 ml. 5 amine. This solution was hydrogenated over 0.15 g. of of water was shaken with hydrogen in presence of 0.5 g. pre-reduced 10% palladium on carbon catalyst. A total of pre-reduced 10% palladium on charcoal catalyst. When of 46.5 ml. of hydrogen was absorbed in 10 minutes. uptake of hydrogen was complete, the solution was filtered After filtering and evaporating to dryness, the residue and evaporated under reduced pressure to give 0.4 g. of was crystallised from ethyl acetate/ether, then from tetra the base as a colourless oil which yielded a white solid 20 hydrofuran/petrol (B.P. 40-60) and was then dried in M.P. 144-145 when triturated with ether/cyclohexane. vacuo at 50 for 3 hours to give 0.3 g. of a white crystal Recrystallisation from ethyl acetate-cyclohexane gave a line solid, M.P. 103-5° C. white Solid M.P. 147-149. EXAMPLE 1.9 Preparation of 4-hydroxy-ox-(1-isopropylaminopropyl)- EXAMPLE 17 25 m-xylene-a,c-diol Preparation of 4-hydroxy-cyl-[(methylamino)methyll (a) 5 - (2 - bromo-butyryl)-salicylic acid, methyl m-xylene-ox,a-diol ester.-A solution of 104 g. of bromine in 1000 ml. of (a) c.1-(Benzylmethylamino) methyl - 4 - hydroxy chloroform was added dropwise to a stirred solution of m-xylene-ol,or 3-diol.-21.3 g of 5 - (N-benzyl-N-methyl 30 144 g. of 5-butyryl-salicylic acid, methyl ester in 300 ml. glycyl)-salicylic acid ethyl ester was dissolved in 140 of chloroform at room temperature. The reaction was at m. of tetrahydrofuran. This solution was added dropwise first extremely slow, and only after about 1 hr. was hy to a stirred suspension of 5.6 g. of lithium aluminium hy drogen bromide gas evolved at an appreciable rate. dride in 175 ml. of dry tetrahydrofuran in an atmosphere The bulk of the bromine solution was then run in over of nitrogen. After the addition was completed, the mix a further hour. The solution was stirred for an additional ture was stirred at room temperature for one hour, then 15 mins. cooled and washed three times with cold water. 45 ml. of water was added dropwise. The tetrahydrofuran The solvent was distilled off under reduced pressure leav was removed by distilling in vacuo and dilute hydro ing a pure white solid residue which was recrystallised chloric acid was added. The acid solution was basified 40 once from ethanol, to give 200 g. of the product, M.P. with sodium bicarbonate solution and extracted with 83. ether (5X 50 ml.). The ethereal solution was washed (b) 5 - (2 - isopropylamino-butyryl)-salicyclic acid, three times with saline and after drying over anhydrous methyl ester hydrochloride-A solution of 45 g. of 5-(2- NaSO4 it was evaporated in vacuo to give 8.7 g. of the bromo-butyryl)-salicyclic acid methyl ester and 30 g. of product as a white solid, M.P. 132-134 C. isopropylamine in 30 ml. of methanol was boiled under (b) 4 - hydroxy-a-(methylamino) methyl-m-Xylene 45 reflux for 5 hrs. The mixture was evaporated under re cx,c,3-diol-2.0 g. of al-(benzylmethylamino)methyl)- duced pressure, the oily residue treated with dry ether, 4-hydroxy-m-xylene a,c-diol were reduced in 30 ml. of and the insoluble hydrobromide filtered off. The ethereal ethanol containing 1 ml. of triethylamine and 1 ml. of solution was boiled with charcoal and filtered. Dry hy water, using 0.5 g. of 10% palladium oxide on charcoal drogen chloride gas was then bubbled into the solution 50 and the hydrochloride precipitated as a white crystalline as catalyst. Hydrogen uptake was complete after 15 Solid which was crystallised twice from methanol/ether, minutes. The catalyst was removed by filtration and the to give 20 g. of the product, M.P. 250° C. solution was evaporated to dryness in vacuo to give 1.55 (c) 4-hydroxy-o'-(1-isopropylaminopropyl)-m-xylene g. of a friable solid. This base in methanol was added to o,c-diol-An aqueous suspension of 10 g. of 5-(2-iso a solution of 0.9 g, of maleic acid in methanol. The solu 55 propylaminobutyryl)-salicylic acid, methyl ester hydro tion was warmed and ethyl acetate was added to effect chloride was basified with 10% sodium bicarbonate solu crystallisation. 1.15 g. of the maleate were obtained as tion and extracted into ether. The ethereal solution was colourless needles, M.P. 109-111. dried over MgSO4, the solvent evaporated and the gummy EXAMPLE 8 residue, in 60 ml. of Sodium-dried tetrahydrofuran, was 60 added cautiously with stirring to 3.0 g. of lithium alumin Preparation of 3-hydroxy-ol-(isopropylamino) methyl ium hydride in 300 ml. of dry tetrahydrofuran. The p-Xylene-cy,c-diol mixture was heated under reflux with stirring for 30 mins. and was then cooled. 21 ml. of water was added drop (a) al-Benzylisopropylaminomethyl - 3 - hydroxy Wise with vigorous stirring and the mixture was allowed p-Xylene-clo'-diol.-A solution of 1.58 g. of N-benzyl 65 to stand overnight before the solvents were evaporated isopropylamine in 4 ml. of dry tetrahydrofuran was added off. The Solid residue was acidified with dilute hydro all at once at approx. 10 to a solution of 1.45 g. of chloric acid to pH 6 and this solution was basified with 4-bromoacetylsalicylic acid, methyl ester in 4 ml. of dry dilute sodium hydroxide and sodium bicarbonate to pH tetrahydrofuran and the flask was stoppered and left to 8. The gelatinous insoluble hydroxides were then centri stand for 3 hours. The crystalline benzylisopropylamine 70 fuged and the filtrate was continuously extracted with hydrobromide which formed was filtered off and the fil chloroform. The solvent was evaporated off and the oily trate was slowly added to a slurry of 1.7 g. of lithium basic residue taken up in ether. Dry hydrogen chloride aluminium hydride in 100 ml. of dry tetrahydrofuran, gas was passed into the solution and the white crystalline with stirring. The resulting mixture was heated to boiling precipitate thus obtained was filtered off and crystallised and stirred under reflux for 15 minutes. After cooling and 75 from ethanol, to give 5 g. of the product, M.P. 199. 3,732,300 15 16 EXAMPLE 20 ethanol/ether gave the product as colorless needles M.P. 169-171 C. Preparation of 5-(2-amino-1-hydroxyethyl)-salicylic acid (b) 5-1-hydroxy-2(methylamino)ethyl)-salicyclic acid methylester hydrochloride ethyl/ester hydrochloride.-3.0 g. of 5 - (N-benzyl-N- (a) 5-(N,N-dibenzylaminoglycyl)-o-anisic acid methyl methylglycyl) salicylic acid ethyl/ester hydrochloride in ester, hydrochloride.-6.0 g. of 5-bromoacetyl-o-anisic 30 ml. of ethanol was hydrogenated with 1. g. of 10% pal acid methyl ester (see Example 34(a)) and 7.8 g. of di ladium oxide on charcoal as catalyst. Hydrogen uptake benzylamine in 200 ml. of ethyl methyl ketone were re was complete after 2.75 hours. The solution, after re fluxed for 2 hours with stirring. Solid appeared within 2 moval of the catalyst by filtration, was evaporated to dry mins. After removal of the dibenzylamine hydrobromide O ness under reduced pressure, and the residue was crystal by filtration, the solution was evaporated to dryness and lised from ethanol/ethyl acetate to give 1.6 g. of the prod treated with ether. Some insoluble brown material was uct as colourless microneedles, M.P. 129-130 C. removed and hydrogen chloride was passed through the EXAMPLE 23 ethereal solution. The dark gummy solid which precipi tated was recrystallised from methanol/ethyl acetate to 5 Preparation of 5- 1-hydroxy-2- (p-methoxy-o-methylphen give 2.0 g. of the hydrochloride as a white solid, M.P. ethyl)amino ethyl salicyclic acid, methyl ester, hydro 163-165. chloride After two recrystallisations from methanol/ethyl ace 1.08 g. of 5(1-hydroxy-2-amino)ethyl salicylic acid tate, colourless needles were obtained, M.P. 166-8. methyl ester hydrochloride in 100 ml. of methanol, basi (b) 5-(N,N-dibenzylglycyl)-salicylic acid hydrobro 20 fied by the addition of 25 ml. of methanolic sodium meth mide.-2.0 g. of 5-(N,N-dibenzylglycyl)-o-anisic acid, oxide containing 0.10 g. of sodium and 0.72 g. of p-me methyl/ester hydrochloride and 40 ml. of 48% aqueous thoxyphenyl-2-propanone, were hydrogenated in the hydrobromic acid were refluxed for 2 hours. The initially presence of 1.0 g. of prereduced 10% palladium oxide on clear solution gradually deposited a white solid. After charcoal catalyst, suspended in 25 ml. of methanol. Up being cooled the mixture was filtered to give 2.0 g. of 25 take of hydrogen ceased within twenty hours. The solution the acid hydrobromide as a white solid, M.P. 165-166. was filtered and evaporated, and the resulting oil was dis (c) 5-(N,N-dibenzylglycyl)-salicylic acid methyl ester solved in ether. After filtering to remove sodium chloride, hydrochloride.-8.78 g. of the acid hydrobromide were ethereal hydrogen chloride was added to the ether solu obtained in (b) were refluxed with a mixture of 22% tion to precipitate an oil which gradually solidified within methanolic hydrogen chloride (20 ml.) and methanol 30 15 minutes. The solid crystallised from acetone-ether to (50 ml.) for 16 hrs. The solution was evaporated to dry give 0.6 g. of the product as white crystals M.P. 155 ness and an ethereal solution of the residue was shaken 161. with sodium bicarbonate solution. The ethereal solution EXAMPLE 24 was dried over MgSO and treated with methanolic hy drogen chloride to give 7.0 g. of a white solid, M.P. 167 35 Preparation of 4 - hydroxy-ox1-(2-indol-3-yl-1-methyl 169. ethyl) amino) methyl-m-xylene-ox,a-diol hydrogen (d) 5-(2-amino-1-hydroxyethyl)salicylic acid methyl tartrate ester hydrochloride.-6.4 g. of 5-(N,N-dibenzylamino glycyl)-salicylic acid methyl ester hydrochloride in 150 (a) 5-1-hydroxy-(2-indol-3-yl-1-methylethyl)aminol ml. of methanol were hydrogenated in the presence of 40 ethyl)-salicyclic acid methyl ester-A solution of 0.71 g. 1.0 g. of a 10% palladium oxide on charcoal catalyst. Up of sodium hydroxide in ethanol was added to a solution take of hydrogen ceased after 9 hrs. The catalyst was of 4.4 g. of 5-(2-amino-1-hydroxyethyl)-salicyclic acid removed by filtration, and the filtrate was concentrated methyl ester hydrochloride in ethanol. The total volume and treated with ether to precipitate 2.75 g. of the prod of the solution was 250 ml. Sodium chloride was then re uct as a white solid, M.P. 168-170, which was recrystal moved and the solution was hydrogenated in presence lised from methanol/ethyl acetate to give colourless 45 of 1.0 g. of 10% palladium on charcoal catalyst and 3.8 plates, M.P. 187-188. g. of indol-3-yl-2-propanone. Uptake of hydrogen ceased after 25 hours. The catalyst and solvent were removed to EXAMPLE 21 leave a straw coloured oil. This was separated from so dium chloride by solution in ether, followed by filtration Preparation of al-aminomethyl-4-hydroxy-m-xylene 50 and evaporated to give 7.1 g. of the crude ester as an oil. al.,as-diol (b) 4-hydroxy-ox-((2-indol - 3 - y1 - 1 - methylethyl) A solution of 1.9 g, of al-dibenzylaminomethyl-4-hy aminol methyl-m-xylene-a,c-diol, hydrogen tartrate droxy-m-xylene-cy,o.3-diol in 50 ml. of ethanol and 5 ml. 6.5 g. of 5-(1-hydroxy-2(2-indol-3-yl-1-methylethyl) of water was shaken in an atmosphere of hydrogen in aminoethyl) salicylic acid methyl ester in 100 ml. of tet presence of 0.5 g. of pre-reduced 10% palladium on char 55 rahydrofuran were added to a stirred suspension of 1.4 coal catalyst. Uptake of hydrogen was complete in 6 g. of lithium aluminium hydride in 50 ml. of tetrahydro hours. The catalyst was removed and the solution was furan, in an atmosphere of nitrogen, at a rate sufficient evaporated to dryness under reduced pressure to leave to maintain refluxing of the solvent. After 1 hour, 10 ml. 0.9 g of the product as a cream solid, M.P. 151-152. of water was cautiously added and the mixture was con 60 centrated under reduced pressure. The residue was treated EXAMPLE 22 with dilute hydrochloric acid and non-basic indole deriva Preparation of 5-(1-hydroxy-2(methylamino)ethyl) tives were removed by extraction with ethyl acetate. salicylic acid ethyl ester, hydrochloride The acid solution was neutralised with sodium bicar bonate and extracted four times with ethyl acetate. After (a) 5-(N-benzyl-N-methylglycyl)-salicylic acid ethyl 65 being dried over MgSO4 and evaporated, the latter yielded ester hydrochloride-20 g. of 5-bromoacetylsalicylic acid 2.0 g. of a buff friable solid. This base was dissolved in ethyl ester, 15.2 g. of N-benzylmethylamine and 250 ml. 30 ml. of ethyl acetate and added to a solution of 0.8 g. of ethyl/methyl ketone were stirred and refluxed for 1.5 of racemic tartaric acid in 30 ml. of methanol, to precipi hours. The solid that precipitated was filtered and the 70 tate a pale brown gum. When triturated with ethyl ace filtrate was evaporated in vacuo leaving a yellow oil. tate this slowly yielded 1.6 g. of a friable tan solid M.P. Dry ether was added to the residue and the ethereal ca. 93-100'. Recrystallisation from methanol/dry ether solution was filtered. The clear filtrate was treated with afforded a brown gum which when triturated with dry dry HCl gas and 13.4g. of the white precipitate M.P. 158 ether gave 0.8 g. of the product as a buff solid M.P. ca. 160 was removed by filtration. Recrystallisation from 75 112, frothing from ca. 70.

3,732,300 17 18 EXAMPLE 25 (b) 4 - hydroxy-ol-(o-methylphenethylamino) meth yl)-m-Xylene-a,c-diol.-1.3 g. of 5 - 1-hydroxy-2-(o- Preparation of 5-1-hydroxy-2-(1-methyl-2-piperidino methylphenylamino)ethyl-salicylic acid methyl ester in ethyl)aminoethylsalicylic acid methyl ester 20 ml. of dry tetrahydrofuran were added to a stirred 3.65 g. of 5-(2-amino-1-hydroxy)ethylsalicylic acid suspension of 1.5 g. of lithium aluminium hydride in 50 methyl ester hydrochloride in 75 ml. of methanol were 5 ml. of dry tetrahydrofuran at a rate to maintain refluxing basified by the addition of 25 ml. of methanolic sodium of the solvent. methoxide containing 0.34 g. of sodium, and then added After 1 hour at the reflux the mixture was codled and to 2.10 g. of 1-piperidino-2-propanone. The mixture was decomposed by dropwise addition of 5 ml. of water, with hydrogenated in the presence of 1 g of 10% palladium O stirring. The mixture was evaporated nearly to dryness oxide on charcoal catalyst suspended in 25 ml. of meth under reduced pressure and the residue was treated with anol. Uptake of hydrogen was completed within 25 hours. excess dilute hydrochloric acid, followed by sodium bi The solution was filtered and evaporated and the re carbonate solution. sulting oil was separated from sodium chloride by ex The resulting basic mixture was extracted four times traction with ethyl acetate. The ethyl acetate was evap 5 with ethyl acetate which was dried and evaporated to orated and the resulting oil taken up in acetone/ether. yield a yellow oil. When triturated with ether this gave The solution deposited an oil which after two days formed 0.3 g. of the product as a white solid. Recrystallisation a solid. This was recrystallised from cyclohexane/light from ethyl acetate gave colourless crystals, M.P. 113 petroleum (B.P. 70-80), to yield white crystals of the 115. product, M.P. 112.5-113.5. 20 The p-hydroxy-o-methyl compound has been prepared by processes analogous to those described above for the EXAMPLE 26 unsubstituted o-methyl compound. The structure of p Preparation of 4-hydroxy-o'-(1-methyl-2-phenoxyethyl) hydroxy-o-methyl compound, that is, 4-hydroxy-ox-(p- aminomethyl-m-xylene-a,c-diol hydroxy- or - methylphenethylamino)methyl-m-xylene-ox, (a) 5-1-hydroxy - 2 - I (1 - methyl-2-phenoxyethyl) 25 a3-diol was confirmed by nuclear magnetic resonance and amino)ethyl}-salicylic acid methyl ester.-5.0 g. of 5-(N, ultraviolet and infrared spectra. N-dibenzylglycyl)-salicylic acid methyl ester hydrochlo EXAMPLE 28 ride in ethanol was reduced with hydrogen in presence of 1.0 g. pre-reduced 10% palladium on charcoal catalyst. Preparation of 4-hydroxy-cyl-I(3,4,5-trimethoxy-a-meth After 17 hours uptake of hydrogen ceased. 30 ylphenethyl)amino methyl)-m-xylene-a,c-diol A solution of 0.45 g. of sodium hydroxide in 20 ml. of 4 - hydroxy - or- (3,4,5-trimethoxy-o-methylphenethyl) ethanol and 1.9 g. of 1-phenoxy-2-propanone was added aminol methyl-m-xylene-a,c-diol.-1.7 g. of ox-amino and reduction was continued in presence of a similar quan methyl - 4 - hydroxy-m-xylene-g,a-diol in 12.5 ml. of tity of fresh catalyst. After 52 hours uptake of hydrogen methanol containing 1 g. of triethylamine, and 2.2 g. of ceased. The catalyst and solvent were removed and the 35 (3,4,5-trimethoxyphenyl)-2-propanone were hydrogenated residue was partitioned between water and ether. The in the presence of 0.25 g. of pre-reduced Adams catalyst ether was dried and removed to leave 3.0 g. of the crude suspended in 15 ml. of water. Uptake of hydrogen ester as a pale amber oil. ceased within 16 hours. (b) 4-hydroxy-ol-(1-methyl-2-phenoxyethyl)amino The solution was filtered and evaporated, and the re methyl-m-xylene-a,c,3-diol-2.7 g of 5-1-hydroxy-2-(1- 40 sulting oil extracted with boiling benzene. On cooling methyl-2-phenoxyethyl)amino)ethyl-salicylic acid meth the solution, a white gum was deposited which, on stand yl ester dissolved in 50 ml. of dry tetrahydrofuran, were ing overnight in a small volume of ether followed by added to a warm stirred suspension of 0.6 g. of lithium drying in vacuo at 40 for 24 hours, gave 1.65 g. of the aluminium hydride in 20 ml. of tetrahydrofuran, in an product as white crystals, M.P. 90–98. atmosphere of nitrogen, at a rate to maintain the solvent 45 at the reflux. The resulting white gelatinous precipitate EXAMPLE 29 was stirred and warmed for 1 hour, then cooled and de Preparation of 4-hydroxy-ox-(p-methoxy-o-methylphen composed by dropwise addition of 5 ml. of water. The ethyl)aminol methyl-m-xylene-o',03-diol mixture was concentrated under reduced pressure, more water was added and the pH was adjusted to 8 by addition 50 1.03 g. of oz - aminomethyl-4-hydroxy-m-xylene-ox,a- of hydrochloric acid followed by sodium bicarbonate. diol in 75 ml. of methanol containing 10 ml. of water, The mixture was extracted with ethyl acetate, which 0.5 g. of triethylamine and 0.92 g. of p-methoxyphenyl was dried and evaporated to yield an amber oil. Tritura 2-propanone were hydrogenated in the presence of 0.5 g. tion with ether gave 0.9 g. of the triol as a cream solid. of pre-reduced Adams catalyst suspended in 25 ml. of Recrystallisation from ethyl acetate/cyclohexane afforded 55 methanol. a white solid M.P. 128-130' C. Uptake of hydrogen ceased within fifteen hours. The ... solution was then filtered and evaporated, and the result EXAMPLE 27 ing oil was extracted with boiling benzene. On cooling Preparation of 4-hydroxy-al-I(c-methylphenethylamino) the solution, a white gum was deposited, which, on dry methyl-m-xylene-a,c-diol 60 ing in vacuo over paraffin wax, gave 0.70 g. of the prod uct as white crystals, M.P. 89-93° C. (a) 5 - 1 - hydroxy-2-(o-methylphenethylamino)eth yl)-salicylic acid methyl ester.-3.2 g. of 5-(N,N-diben EXAMPLE 30 zylaminoglycyl)-salicylic acid methyl ester and 1.2 g. of Preparation of 4-hydroxy-o'-(I( 1-methyl-2-morpholino benzyl methyl ketone in 100 ml. of ethanol were shaken 65 ethyl)aminomethyl-m-xylene-ox',08 diol in an atmosphere of hydrogen in presence of 1.0 g. of 10% prehydrogenated palladium on charcoal catalyst. Up 1.63 g. of al-aminomethyl - 4-hydroxy-m-xylene-ox,x3 take of hydrogen ceased after 40 hrs. The catalyst and diol in 110 ml. of methanol, containing 1.0 g of triethyl solvent were removed to give an oil which was extracted amine, and 1.22 g. of 1-morpholino-2-propanone, were into dilute hydrochloric acid and ether. The aqueous Solu 70 hydrogenated in the presence of 0.25 g. of pre-reduced tion was washed with ether and treated with excess so Adams catalyst suspended in 15 ml. of water. Uptake of dium bicarbonate solution. The liberated base was ex hydrogen ceased within 16 hr. tracted by ether which was washed, dried over MgSO4 The solution was filtered and evaporated to give an and evaporated to give 1.3 g of the crude basic ester as a oil which only partially solidified. Crystallisation from colourless oil. 75 ethyl acetate gave an oil, which when triturated, afforded 3,782,300 19 20 the product as a white solid, 0.60 g of the product, M.P. The stirred mixture was refluxed for 6 hours, then cooled 134-145 was obtained. and 5 ml. of water was added dropwise with stirring. The cloudy mixture was evaporated under reduced pressure EXAMPLE 31 and the residue was treated with 100 ml. of 5 N hydro chloric acid. The oily hydrochloride which precipitated Preparation of 4-hydroxy-al-((4-hydroxy-1-methylbutyl) was separated from the acid solution, washed with a amino methyl-m-xylene-a,c-diol little water and treated with sodium bicarbonate solution. 1.5 g. of a 1-amino-4-hydroxy-m-xylene-a,c-diol in 85 The liberated base was extracted into ether which was ml. of methanol containing 15 ml. of water, 0.5 g. of dried and evaporated to yield 6.8 g. of the product as a triethylamine and 0.87 g. of 5-hydroxy-2-pentanone were O white solid, M.P. 105-107. Recrystallisation from ether/ hydrogenated in the presence of 0.16 g. of pre-reduced light petroleum (B.P. 40-60') gave 5.7 g. of colourless Adams catalyst suspended in 25 ml. of methanol. rods, M.P. 110-111. After 60 hours, uptake of hydrogen ceased, but thin (c) ox-(Cyclopentylaminomethyl)-4-hydroxy-m-Xylene layer chromatography showed that some of the unchanged oxa-diol.-3.0 g. of ox-(dibenzylaminomethyl)-4-hy primary amine was still present. Reduction was continued 5 droxy-m-xylene-a,c3-diol dissolved in 100 ml. of ethanol in the presence of a further portion of 0.16 g. of pre and 5 ml. of water were reduced in the presence of 1.0 g. reduced Adams catalyst. Uptake ceased after a further of triethylamine and 1.0 g. of 10% pre-reduced palladium 25 hours when thin layer chromatography showed only on charcoal catalyst. a trace of the primary amine. Hydrogen uptake ceased after 2.5 hours and 0.76 g. of The solution was filtered and evaporated to give an oil 20. cyclopentanone was then added and reduction was con which, on trituration with dry ether and prolonged drying tinued. Owing to slow uptake of hydrogen the catalyst in vacuo, became a white, highly deliquescent, friable was replaced by 0.5 g. of prehydrogenated Adam's plat solid. A preparative thin layer chromatogram (silica/ inum oxide and reduction was completed within 1 hour. methanol) containing 3% 0.880 ammonia solution on After removal of catalyst the solution was evaporated to 280 mg. of this solid gave two fractions at Rf 0.60 and 25 dryness and the resultant oil was triturated with ether to Rf 0.80, visible under U.V. light. The former was ex give 0.9 g. of the cyclopentylamino triol as a white solid, tracted with dry methanol (2X 50 ml.) to give 140 mg. M.P. 121-124, which was crystallised from ethyl acetate of a white, highly deliquescent friable solid. The N.M.R. to give a white solid 129-131. -- spectrum showed the structure of this solid to be con sistent with the required base, although it contained ca. 30 Preparation of 5-(N-benzyl-N-isopropylglycyl)-salicylic of the product of hydrogenolysis of the oxalcohol group. acid hydrobromide monohydrate EXAMPLE 32 (a) 5-bromoacetyl-o-anisic acid methyl ester.-1.4 g. of bromine in 10 ml. of chloroform were added dropwise Preparation of 4-hydroxy-ox{(a-methyl-p-ethoxyphen 35 to a stirred solution of 1.7 g. of 5-acetyl-o-anisic acid oxyethyl annino)methylm-xylene-ox,c-diol methyl ester in 50 ml. of chloroform at 0.10, at a rate which just maintained decolourisation of the bromine. The 1.5 g. of di-amino-4-hydroxy-m-xylene-ox,c-diol in 110 solution was evaporated under reduced pressure to leave ml. of methanol containing 1 g. of triethylamine and 1.93 g. of the crude bromoacetyl ester as a white solid, 1.63 g. of (p-ethoxyphenoxy)-2-propanone were hydro 40 M.P. 143-144. Recrystallisation from methanol gave genated in the presence of 0.20 g. of pre-reduced Adams colourless plates, M.P. 153-154 C. catalyst. Uptake of hydrogen ceased within 17 hr. (b) 5-(N-benzyl-N-isopropylglycyl)-o-anisic acid meth The solution was filtered and evaporated to give an yl ester hydrochloride.-A solution of 10 g. of 5-bromo oil which was extracted with ether (2X 50 ml.). The acetyl-o-anisic acid methyl ester and 11.0 g. of benzyliso ... ether was evaporated to give a gum which was crystallized 45 propylamine in 200 ml. of ethyl methyl ketone was stirred from ethyl acetate/cyclohexane to yield a gum which and refluxed for 6.5 hours. The precipitated benzylisopro solidified after drying in vacuo for 3 days. Recrystallisa pylamine hydrobromide was filtered off and the filtrate tion from ethyl acetate/cyclohexane gave 0.30 g. of the was evaporated to dryness. The residue was triturated with product as white prisms, M.P. 98-107. 250 ml. of ether and separated from a little insoluble ma 50 terial, and the ethereal solution was treated with gaseous EXAMPLE 33 hydrogen chloride. A brown gum was obtained which Preparation of al-(cyclopentylaminomethyl)-4-hydroxy crystallised from a mixture of methanol and ethyl acetate m-xylene-a,c,3-diol - to give 6.14 g. of the product as colourless plates, M.P. 194-195. (a) 5-(N,N-dibenzylglycyl)salicylic acid methyl ester 55 (c) 5-(N-benzyl-N-isopropylglycyl)salicylic acid hydro hydrochloride.-24.1 g of dibenzylamine were added to bromide monohydrate.-3.3 g. of 5-(N-benzyl-N-isopro a solution of 18.5 g. of 5-(bromoacetyl) salicylic acid pylglycyl)-o-anisic acid methyl ester hydrochloride and methyl ester in 500 ml. of ethyl methyl ketone. After 50 ml. of 48% hydrobromic acid were refluxed together being refluxed with stirring for 3 hours the precipitated for 5 hours. The solution was cooled and filtered to give 2.8 dibenzylamine hydrobromide was removed. The solution 60 g. of the acid hydrobromide as a white solid M.P. 186.5- was evaporated to dryness and treated with ether. 2.8 g. 188. Recrystallisation from water and drying at 100/ of an insoluble solid were removed by filtration and HCl 12 mm. gave colourless prisms, M.P., 188-90° C. gas was passed through the filtrate to precipitate 22.1 g. (d) 5-(1-hydroxy-2-isopropylaminoethyl)-salicylic acid of the product. When recrystallised from methanol/ethyl hydrobromide.-A solution of 2.9 g, of 5-(N-benzyl-N- 3. acetate 18.0 g. of a white solid M.P. 174-176 were 65 isopropylglycyl)-salicylic acid hydrobromide in 50 ml. of obtained. ethanol was reduced in an atmosphere of hydrogen in the (b) al-Dibenzylaminomethyl - 4 - hydroxy-m-xylene presence of 0.5 g. of 10% palladium on charcoal catalyst. o,a - diol-10 g. of 5 - (N,N-dibenzylglycyl)-salicylic Hydrogen uptake was complete after 23 hours. acid methyl ester hydrochloride were basified with sodium The solution after removal of catalyst, was evaporated bicarbonate solution and extracted into ether. The ethe 70 under reduced pressure to give 2.61 g. of an amber syrup real solution was dried over MgSO4 and evaporated. The which, when triturated with ethyl acetate and ether, gave basic residue in 100 ml. of dry tetrahydrofuran was added 1.95 g. of the product as a white solid M.P. 164-166. to a suspension of 1.74 g. of lithium aluminum hydride Recrystallisation from methanol/ethyl acetate gave in 500 ml. of dry tetrahydrofuran. A white gelatinous colourless prisms M.P. 165-166 after being dried at 100 / precipitate formed which partially dissolved on heating. 75 12 mm.

8,732,300 21 22 EXAMPLE 35 The solid, however, could not be recrystallised. 144 mg. of the product, M.P. 54-60, was obtained. Preparation of 3-5-(2-tert-butylamino-1-hydroxy)ethyl 2-hydroxyphenyl-ethanol EXAMPLE 36 (a) 3 - (8-acetoxyethyl)-4-hydroxyacetophenone 5 Preparation of oil-tert-butylaminomethyl-o'-diphenyl-4- A solution of 15.0 g of 3-(o-hydroxyphenyl)-ethanol in hydroxy-xylene-a,c-diol hydrochloride 120 ml. of 40% w./w. boron trifluoride-acetic acid con A solution of phenyl magnesium bromide in ether plex was heated with stirring at 65 for 16 hours, during (45%, 50 ml.; slight excess of ca. 5 mole equivalents) which time the colour became pale-brown. The solution O was added in a thin stream to a stirred solution of 5-(2- was cooled and treated with hydrated sodium acetate, then tert-butylamino - 1 - hydroxyethyl)salicylic acid methyl with water, and the mixture was extracted three times ester (5.0 g.) in dry tetrahydrofuran (200 ml.). The mix with ether. The combined ethereal extracts were dried ture was refluxed overnight (15 hours), cooled and poured over anhydrous sodium sulphate and evaporated to give onto ice cold saturated ammonium chloride solution. 23 g. of the product as a brown oil. 15 The organic layer was separated, washed with saturated (b) 4-acetoxy-3-(6-acetoxyethyl)acetophenone. A ammonium chloride solution, dried over sodium sulphate, mixture of 23.0 g of 3-(6-acetoxyethyl)-4-hydroxyaceto and evaporated. As thin layer chromatography (silica phenone, 8.2 g of acetyl chloride, 46 g. of anhydrous po cyclohexane-ethyl acetate, 3:1) indicated the presence tassium carbonate and 500 ml. of ethyl methyl ketone was of a non-basic impurity, the crude oil was dissolved in refluxed with stirring for 4 hours. The solids were then fil 20 ethyl acetate (25 ml.) and treated with a slight excess tered off and the solvent was evaporated to give an Orange of ethereal hydrogen chloride with cooling. The precipi oil, which was chromatographed, using 600 g. of silica tate was filtered off and dried to give oil-tert-butylamino gel. Eluting with 20% ethyl acetate in benzene gave 15 g. methyl - or - diphenyl - 4 - hydroxy-m-xylene-a,c-diol, of the required product as a mobile straw-coloured oil. hydrochloride, 6.3 g (78.3%) M.P. 180-190, with (c) 4-acetoxy-3-(B-acetoxyethyl)phenacyl bromide 25 decomposition. 3.66 g. of bromine in 75 ml. of chloroform was added This material was dissolved in a small amount of tetra dropwise, over 70 minutes to a stirred solution of 6.0 g. hydrofuran, filtered and ethyl acetate (20 ml.) added and of 4-acetoxy-3-(6-acetoxyethyl) acetophenone in 75 ml. allowed to crystallise to afford 4.8 g., M.P. 186-7, with of chloroform, at room temperature. Stirring was con decomposition. tinued for a further 10 minutes then the solution Washed EXAMPLE 37 with water and dried over anhydrous sodium Sulphate. 30 Evaporation of the solvent gave 7.3 g. of 4-acetoxy-3-(B- Preparation of oil (benzyl tert-butylamino)methyl-4- acetoxyethyl)phenacyl bromide as a brown oil. hydroxy-o.8-methyl-m-xylene ox,c-diol (d) B-5-(2-benzyl-tert-butylamino-1-hydroxy)ethyl-2- hydroxyphenyl ethanol-4.3 g. of 4-acetoxy-3-(6-ace 35 (a) 4-acetoxy-3-bromoacetophenone.-A solution of toxyethyl)phenacyl bromide and 4.1 g of benzyl tert-bu 3 - bromo - 4 - hydroxyacetophenone (25 g.) in acetic tylamine were dissolved in 20 ml. of dry tetrahydrofuran anhydride (125 ml.) was refluxed for one hour. The ex and the solution was left to stand at room temperature for cess acetic anhydride was then evaporated, in vacuo to 7 days. Benzyl tert-butylamine hydrobromide was formed give a brown oil (29.2g.). and was filtered off. The filtrate was added dropwise over 40 The product was distilled at reduced pressure. 40 minutes to a stirred suspension of 1.5 g. of lithium alu minium hydride in 30 ml. of tetrahydrofuran. The tetra Yield=25.5 g. hydrofuran refluxed gently as the solution was added and BP=128-130 at 0.05 mins. a gelatinous solid precipitated. (b) 4-actoxy-2,3 - dibromoacetophenone.-40 drops Stirring was continued for 2 hours at 70, then the 45 of a solution containing bromine (15.8 g.) in chloroform mixture was cooled to 0° and 15 ml. of water was added (509 mi.) was added to a stirred solution of 4-acetoxy cautiously to the cold stirred mixture. The mixture was 3-bromoacetophenone (25.4 g.) in chloroform (800 ml.) stirred for 1 hour, then dilute hydrochloric acid was added which contained 4 drops of hydrobromic acid in acetic until the mixture was slightly acidic. The pH was ad acid. A golden-yellow colour was produced and the stirred justed to about 8 by the addition of sodium carbonate 50 Solution was warmed (40') for a few minutes. The colour solution. The mixture was filtered, and the filtrate was quickly disappeared and the temperature of the stirred extracted four times with chloroform. The combined solution was maintained at 20-23 while the rest of the chloroform extracts were washed once with water and bromine solution was added dropwise over 2% hours. dried over anhydrous sodium sulphate and the chloro The solution was washed with water (x4), dried over form was evaporated to give 1.8 g. of brown oil. 55 magnesium sulphate and evaporated to give a greenish The oil was refluxed with 500 ml. of light petroleum y" oil which suddenly crystallised to a cream-coloured (B.P. 60-80) for 10 minutes and the solution was de SO1. canted and left to stand at room temperature over-night Recrystallisation from ethanol gave the product as a to give a white solid which was filtered as a first crop. white solid, On treatment with benzene some of the remaining oil 60 dissolved. The solution was decanted, treated with char Yield-24 g. coal and evaporated to give 0.8 g. of a pale-brown oil. M.P.-73-78 This was dissolved in ethanol and addition of water gave a whitish solid. Further recrystallization from aqueous (c) 4' - acetoxy - 3' - bromo - 2 - benzyltert.butyl ethanol gave a second crop of product as a pure-white 65 amino acetophenone.-A solution of 4 - acetoxy - 2,3'- solid. The total yield of the product was 265 mg., M.P. dibromoacetophenone (8.5 g.) and benzyl, tert-butylamine 133-34.5 C. (8.3 g) in dry methyl ethyl ketone (120 ml.) was re (e) B - 5 - (2 - tert-butylamino - 1 - hydroxy)ethyl fluxed for 2% hours. Crystals of benzyl, tert.butylamine 2 - hydroxyphenylethanol. 211 mg. of 6-5-(2-benzyl hydrobromide were deposited and these were filtered after tert - butylamino - 1 - hydroxy-ethyl-2-hydroxyphenyl 70 the mixture had been cooled. Evaporation gave an orange ethanol was hydrogenolysed at room temperature in 30 oil which was treated with ether to precipitate more hy ml. of ethanol over 10% palladium catalyst on charcoal. drobromide. This was filtered and the ether solution was Hydrogen uptake ceased in 30 minutes. The catalyst was evaporated to give the product as an orange oil which filtered off and the filtrate was evaporated to give a was used directly, without further purification. greenish-yellow oil, which solidified after deep freezing. 75 Yield=11.5 g. 3,732,300 23 24 (d) ox-benzyltertbutylaminomethyl - 3 - bromo-a-hy Recrystallisation from tetrahydrofuran ether gave 0.8 g. droxy-p-cresol-4 - acetoxy-3'-bromo-2-benzyltertbutyl of a 3-dimethyl - 4 - hydroxy-al-isopropylaminomethyl-m- aminoacetophenone (11.5 g.) in ethanol (50 ml.) was xylene-ox, a3-diol, o-benzoyl-benzoate M.P. 162-4. added dropwise over 5 minutes to a suspension of sodium borohydride (6 g.) in ethanol (70 ml.). The tempera EXAMPLE 39 ture was kept at 30-40' and a vigorous effervescence Preparation of 5-1-hydroxy-2-(1-methyl-2-phenoxy occurred during the addition. The solution was left to ethyl)amino)ethylsalicylamide stand at room temperature overnight, then water Was (a) 5-(1-hydroxy-2-((1-methyl-2-phenoxyethyl)aminol added and the ethanol was evaporated. The product was ethyl}salicyclic acid methyl ester.-5-[(2-amino-1-hy extracted into ether (x10) at pH 12 and the combined 10 droxy)ethylsalicylic acid methyl ester hydrochloride ethereal extracts were washed with water, dried over an (2.53 g.) in methanol (60 ml.) was basified by the addi hydrous sodium sulphate and evaporated to give an tion of methanolic sodium methoxide (25 ml. containing orange oil. 0.24 g. of sodium; 1 mol.) and was added to 1-phenoxy Treatment with hot equeous ethanol (charcoal) then 2-propanone (1.53 g; 1 mol.; redistilled B.P. 74/0.7 cooling gave a crystalline solid, which was recrystallised 5 mm.). The mixture was hydrogenated in the presence of from aqueous ethanol three times, giving the required prehydrogenated 10% PdO/C catalyst (1 g.) suspended product as an off white solid. in methanol (25 ml.). Uptake of hydrogen was complete Yield=2.3 g. within 25 hours. M.P.s 139-140.5 The solution was filtered and evaporated, and the re 20 sulting oil was separated from sodium chloride and a (e) a-I(benzyltertbutylamino)methyll - 3 - bromo-or trace of unchanged primary amine by washing with water hydroxy-p-cresol-(1.135 g.) in dry T.H.F. (20 ml.) was and extracting into ether (150 ml.). The ether was dried added dropwise over 40 minutes under nitrogen to a MgSO4) and evaporated to give the crude ester as an stirred solution of n-butyllithium in ether (.9 N, 13.8 ml.). oil (2.7 g.. An orange, milky precipitate was produced and some 25 (b) 5-1-hydroxy-2-(1-methyl-2-phenoxyethyl)amino) heat was given out during the addition. The mixture was ethyl)-salicylamide. The crude ester of (a) (2.70 g.) was gently refluxed for 10 minutes, then left at room tem dissolved in methanol (20 ml.) and ammonia solution perature for 1 hour. d. 0.880 (20 ml.) and allowed to stand in a stoppered Acetaldehyde (0.52 g., 4 moles) in ether (15 ml.) was flask for five weeks. added dropwise, over 5 minutes to the stirred mixture, 30 whereupon most of the solid was dissolved. The solution The solution was evaporated and the residual oily solid was further refluxed for 45 minutes then poured into in methanol (7 ml.) was chromatographed on a column water. Ammonium chloride was added and the product of silica (25 g.) in ethyl acetate. - was extracted with ether (three times). The combined Elution with ethyl acetate gave the following fractions ethereal extracts were washed with saturated brine solu 35 (a) 50 ml. TLC SiO/MeOH 2 spots Rf 0.7 and Rf 0.9 tion, dried over anhydrous sodium sulphate and evap (b) 650 ml.: 1 spot Rf 0.7 orated on a rotary evaporator, without using heat, to give (c) 2 spots Rf 0.30 and 0.70 a brown oil, yield 1.1 g. - Chromatography of 150 mg. of this crude product on Fraction (b) was evaporated to give a friable solid silica gave 50 mg. of an oil which failed to crystallise. 40 (ca. 0.60 g.) which was crystallised from benzene to give An NMR of this material indicated that it contained white crystals of the amide. (260 mg.)2 M.P. 126.5- some of the required diol. The doublet at y 8.6 due to 128.5 C, the methyl of the side chain -CH(OH) CH3 was readily EXAMPLE 40 identified. Soluble tablets, suitable for sub-lingual administration, EXAMPLE 38 45 containing 1 ml. of active ingredient, present as the Preparation of o,3-dimethyl-4-hydroxy-3-isopropylamino sulphate methyl-m-xylene-a,c-diol 1 mg. tablet, 10,000 (a) 4-benzyloxy-al-(N-benzyl - N - isopropylamino) Formula mg. tablets, g. methyl-c3-dimethyl-m-xylene-ox,a-diol-A solution of 50 of-t-butylaminomethyl-4-hydroxy-m-xylene 1.5 g. of 2-benzyloxy-4-2-N-benzyl,N-isopropylamino-1- ala-diol sulphate- 1.2 20.0 Granular mannitol--- 870 870.0 hydroxyethyl benzoic acid, methyl ester in 50 ml. of Magnesium stearate-- 0.9 9.0 tetrahydrofuran (50 ml.) was treated with an excess of Stearic acid.------0.9 9.0 methyl magnesium bromide in 50 ml. of ether and stirred Total.------90.0 900, 0 at room temperature overnight. The mixture was poured 55 on to saturated ammonium chloride solution and the organic layer separated, filtered through cotton wool, and evaporated to dryness to yield a gum. Method Trituration of a portion of this gum with dilute hy The four ingredients are mixed together, and the mixed drochloric acid gave a water insoluble salt, which was powder is compressed on a suitable tablet machine fitted recrystallised from tetrahydrofuran-ethyl acetate to give 60 with 4' normal concave punches, to produce tablets of colourless crystals of 4-benzyloxy-al-(N-benzyl N-iso the correct weight. propylamino) methyl-ox3-dimethyl-m-xylene-a,c-diol, hy EXAMPLE 41 drochloride M.P. 174.5-175. . (b) as - dimethyl-4-hydroxy-al-isopropylaminomethyl Tablets suitable for oral administration. m-xylene-ox,a-diol-A solution of 1.2g. of 4-benzyloxy 65 al-(N - benzyl-N-isopropylamino) methyl-ox3-dimethyl-m- 1 Img. tablet (as base), 10,000 xylene-a,03-diol in 10 ml. of methanol was added to Formula mg. tablets, g. 0.2 g of pre-reduced 10% palladium on carbon in 10 ml. a-t-butylaminomethyl-4-hydroxy-m- of methanol and hydrogenated until uptake of hydrogen 70 xylene-oza-diol sulphate.-- 1.2 2. Calcium sulphate dihydrate- 88.2 882. ceased. The catalyst was filtered off and the filtrate evap Maize starch------24.0 240. orated to leave 0.9 g, of a pale yellow gum. Amijel------6.0 60. The gum was dissolved in ether and treated with an Magnesium stearate.------0.6 6. ethereal solution of o-benzoyl benzoic acid to afford 1.08 Total.------120.0 1, 200, g. of a crystalline salt M.P. 161-162. 75 3,732,300 25 26 Method Method (1) All the ingredients except the magnesium stearate, The active ingredient, the oleic acid, 2-dimethylamino are mixed together, the mixed powder are granulated with ethanol and part of the dichlorodifluoromethane. The sus water, and the damp mass is passed through a 16 mesh pension is then diluted with the remainder of the dichloro SC difluoromethane, and the requisite quantity is filled into (2) The wet granules are dried, and then passed through aluminum aerosol containers, which are closed by a suit a 20 mesh screen. able metering valve. The containers are then pressurised (3) The dried granules and the magnesium Stearate with trichlorofluoromethane. are mixed together and compressed on a suitable tablet In the above compositions, the amount of active in machine fitted with 4' normal concave punches, to pro O gredient may be varied widely and the Sulphate may be duce the required tablets. replaced by any other salt having a pharmaceutically EXAMPLE 42. acceptable anion. An aerosol formulation, expressed in terms of a single We claim: metered dose. 15 1. A compound of the formula Formula: 100 ug. dose cx1-t-Butylaminomethyl - 4 - hydroxy-m-Xylene X CE.C.I.NER2R3 c',c-diol, ug. ------100 / Oleic acid, pig. ------10 20 Dichlorodifluoromethane, mg. ------6. / xŽ oIII, Trichlorofluoromethane, mg. ------24 Method The active ingredient, the oleic acid and part of the di chlorodifluoro-methane are mixed together. The Suspen 25 herein R is H or alkyl of 1 to 6 carbon atoms; R2 is sion is then diluted with the remainder of the dichloro or benzyl; R is H, alkyl of 1 to 6 carbon atoms or fluoromethane, and the requisite quantity is filled into alkyl of 1–6 carbon atoms substituted by lower alkoxy aluminum aerosol containers which are closed by a suit phenyl or phenoxy; and X is -CONR5Rs where R5 and able metering valve. The containers are then pressurised 30 6 are each H, alkyl of 1 to 6 carbon atoms or benzyl, with trichlorofluoromethane. or a physiologically acceptable acid addition Salt thereof. 2. The compound of claim 1 which is 5-(2-tert-butyl EXAMPLE 43 amino-1-hydroxyethyl)-salicylamide. Formula: 100 p.g. dose 3. The compound of claim 1 which is 5-(1-hydroxy ol-t-Butylaminomethyl - 4 - hydroxy-m-xylene 2-isopropylaminoethyl)-salicylamide. o,0'-diol Sulphate, pig. ------120 35 4. The compound of claim 1 which is 5-1-hydroxy Sorbitan trioleate, pg. ------120 21-methyl-2-phenoxyethyl)amino)ethylsalicylamide. Dichlorodifluoromethane, B.P.C., mg. ------61. 5. The compound of claim 1 which is 5-(1-hydroxy-2- Trichlorofluoromethane, B.P.C., mg. ------24 isopropylaminoethyl)-N-methyl salicylamide. Method The compound of claim 1 which is N-benzyl-5-(1- 40 droxy-2-isopropylaminoethyl)salicylamide. Mix together the active ingredient, sorbitan trioleate, 7. The compound of claim 1 which is 5-1-hydroxy and part of the dichlorodifluoromethane. The suspension 2: (isopropylamino)-butyl salicylamide. is then diluted with the remainder of the dichlorodifluoro ; 8. The compound of claim 1 which is 4-1-hydroxy methane, and the requisite quantity is filled into aluminum 2 (isopropylamino)ethylsalicylamide. aerosol containers, which are closed by a suitable meter 45 ing valve. The containers are then pressurised with tri References Cited chlorofluoromethane. UNITED STATES PATENTS EXAMPLE 44 Formula: 100 p.g. dose 3,536,712 10/1970 Keck et al. ------260-562 ol-t-Butylaminomethyl - 4 - hydroxy-m-Xylene 50 a,c-diol Sulphate, ug. ------120 HARRY I. MOATZ, Primary Examiner 2-dimethylaminoethanol, ug. ------26.6 U.S. C. X.R. Oleic acid B.P. 1963, ug. ------93.4 Trichlorofluoromethane, B.P.C., ng. ------24 55 260-348 R, 474, 501.1, 519, 570.5 C, 570.7, 592, 623 Dichlorodifluoromethane, B.P.C., ng. ------61 D; 424-324, 330, 316, 315, 309