US3188349A - N-secondary-alkyl-2-(3-hydroxyphenyl)-2-ethyl-alkylamines - Google Patents

N-secondary-alkyl-2-(3-hydroxyphenyl)-2-ethyl-alkylamines Download PDF

Info

Publication number
US3188349A
US3188349A US94131A US9413161A US3188349A US 3188349 A US3188349 A US 3188349A US 94131 A US94131 A US 94131A US 9413161 A US9413161 A US 9413161A US 3188349 A US3188349 A US 3188349A
Authority
US
United States
Prior art keywords
phenyl
ethyl
butylamine
methoxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US94131A
Inventor
Krohs Walter
Ther Leopold
Vogel Gerhard
Ott Heinrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Application granted granted Critical
Publication of US3188349A publication Critical patent/US3188349A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

  • the present invention provides new phenyl-alkylamines of the formula in which 0R represents the hydroxy group, the methoxy, ethoXy or benzyloxy group, R represents an alkyl group containing 1 to 4 carbon atoms and R and R are 'alkyl groups containing '1 to4 carbon atoms or together'with the adjacent central carbon atom are members of a saturated alicyclic ring system containing 5 to 6 carbon atoms, physiologically compatible acid-addition salts of these compounds and pharmaceutical preparations containing those new phenyl-alkylamines or the salts thereof as active ingredients.
  • the present invention further provides the preparation of phenyl-alkylamines of the Formula I according to methods Which may generally be applied for the preparation of such compounds.
  • the products obtained according to the invention are precious medicaments which While being Well tolerated are distinguished especially by valuable analgesic properties.
  • the compounds may be obtained, for example, by (a) reducing primary amines of the Formula II R10 z s in which OR, and R have the meanings given above, in the presence of ketones of the Formula III in which R, has the meaning given above and R represents an alkyl group containing 1 to 4 carbon atoms or an :alkylene group containing 2 to 4 carbon atoms, or (b) reacting primary amines of the Formula II With esters of the Formula IV a an ⁇ R; (IV) in which R and R have the meanings given above and X represents an inorganic or organic acid radical, if desired in the presence of an acid-binding agent, or (c) heating primary amines of the Formula II in the presence of alcohols of the Formula V v v LEO-05 R4 in which R, and K, have the meanings given above, with an excess amount of Raney nickel, or (d) reducing alcohols of the Formula V-I R2 (CH2OH R01 1H5 (VI) in which OR, and
  • the alkyl radicals R R and K may be equal or different, straight chained or branched. There may be mentioned, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec.butyl radicals.
  • the substituent 0R may be in any desired position of the phenyl nucleus.
  • amines of the Formula II may be used, for example: I
  • l-zetones of the Formula III there may be used, for example, the following compounds: acetone, methylethylketone, methyl-propyl-ketone, methylbutyl-ketone, methylisopropyl-ketone, methyl-isobutyl-ketone, diethyl-ketone, dipropyl-ketone, methyl-vinyl-ketone, isopropylidene-acetone (mesityloxide), cyclo-pentanone, cyclo-hexanone.
  • the amines to be used as starting substances may favorably be prepared by hydrogenation of the correspondingly substituted cyanides in the presence of catalysts of the 8th Group of the Periodic System.
  • the cyanides may be prepared by reacting the correspondingly substituted benzylcyanides with sodium amide and alkyl halides in a solvent immiscible with water. If the radical R represents an ethyl group, it is possible to introduce both radicals in a single operation stage into the substituted benzyl-cyanide, by reaction of 2 mols of sodium amide with two mols of ethyl-halide.
  • the substituted benzyl-cyanides are obtained in two stages, by introducing, for example, into the corresponding benzyl cyanide with the aid of one mol of sodium amide and one mol of ethyl-bromide at first an ethyl group and subsequently, again with the aid of sodium amide, for example by means of isopropyl-bromide, the isopropyl group.
  • the hydroxy group in the phenyl nucleus is in para-position, the starting substances suitable for the process may likewise be obtained from the non-substituted benzylcyanide.
  • phenyldiethyl-acetonitrile from benzyl-cyanide by means of two mols of sodium amide and two mols of ethyl-bromide.
  • 4-nitrophenyl-diethyl-acetonitrile which may be reduced at -30 C. by means of nickel catalysts under a gauge pressure of 1G-20 atmospheres of hydrogen in order to obtain 4-aminophenyl-diethyl-acetonitrile.
  • the reduction of the starting substances thus obtainable may be eifectedin the presence of ketones of the Formula III, for instance, catalytically with the aid of metals of the 8th Group of the Periodic System, preferably with palladium catalysts and an excessive amount of ketone as solvent, at a temperature of 50 C. and under a low or an elevated gauge pressure of hydrogen up to 50 atmospheres.
  • the excessive ketone is not hydrogenated to yield the corresponding carbinol and may be recovered.
  • palladium there can likewise be used nickel catalysts (Raney nickel). It is likewise possible to carry out the reduction by means of nascent hydrogen, for instance aluminum amalgam and alcohol, sodium amalgam, lithium-aluminium-hydride or sodium boron hydride.
  • the reduction may, furthermore, be carried out by electrolysis.
  • esters of inorganic or organic acids of the Formula IV may be reacted with esters of inorganic or organic acids of the Formula IV.
  • esters of inorganic or organic acids of the Formula IV There may be used for example: isopropyl-iodide, sec. butyl-bromide, 3-bromopentane, Z-bromo 3 methyl-butane, 2-bromo-4-methylpentane, cyclopentyl-bromide, cyclohexyl-bromide, p-toluene-sulfonic acid isopropyl-ester, diisopropyl-sulfate.
  • This reaction is suitably performed by heating the reactants in an appropriate solvent, for instance ethanol, propanol, benzene, toluene or xylene at temperatures between and 130 C.
  • the heating period depends on the temperature and the reactivity of the ester component and amounts, in general, to 2 to 20 hours.
  • the amine of the Formula II may be used in excess and a solvent immiscible with water may be used.
  • the corresponding amine salt formed in the course of the reaction is generally obtained in a crystalline form and may be removed after cooling by filtering with suction or by shaking out the reaction solution by means of water, whereupon the desired reaction product may be isolated as a salt by distilling off the solvent or by shaking out the solvent with the aid of acids.
  • a second mol of the amine there may be used in order to bind the acids formed, likewise other basic compounds, for instance sodium bicarbonate, anhydrous sodium carbonate or tertiary amines such as triethylamine or diethylaniline.
  • the reaction may likewise be carried out without using solvents by heating both reaction components to temperatures between 80 and 130 C., it being favorable to use the amine in a bimolar excess.
  • Another method of carrying out the process according to the invention consists in heating amines of the formula II in the presence of alcohols of the Formula V with an excessive amount of Raney nickel for a prolonged period of time, e.g., 15 hours, at temperatures of IOU-120 C.
  • alcohols of the Formula VI can be reacted with primary amines of the Formula VII, advantageously by beating them with an excessive amount of Raney nickel in order to obtain the desired products. It is suitable to add an excessive amount of the corresponding amine which then simultaneously serves as a solvent.
  • halogen compounds of the Formula VIII with amines of the Formula IX.
  • the reaction is performed, in principle, under the same reaction conditions as described above.
  • the benzylgroup may subsequently be split off by hydrogenation, favorably in an organic solvent, such as methanol, in the presence of noble metal catalysts.
  • the halogenated hydrocarbons of the Formula VIII may be prepared, for instance, by reducing the corresponding phenyl-dialykyl-acetic acids with lithium-aluminium-hydride in ethereal solution and treating the phenyl-dialkyl-ethanols thus obtained with concentrated hydrobromic acid at temperatures between 80 and C.
  • a further possibility of preparing the products according to the invention consists in reducing aldehydes of the Formula X, for instance 3-methoxy-phenyl-diethyl-acetaldehyde, in the presence of amines of the Formula IX. It is recommendable to carry out the reduction catalytically while using catalysts of the 8th Group of the Periodic System and in the presence of a solvent, for instance, methanol.
  • the aldehydes used as starting substances may be obtained, for example, from the corresponding carbinols by oxidation with selenedioxide.
  • amides of the Formula IX may be converted in the usual manner by reduction with lithium-aluminiumhydride into the desired products.
  • amides there may be mentioned, for instance, 3-methoxy-phenyl-diethyl-acetic acid-isopropylamide, 3-methoxy-phenyl-diethyl-acetic acid-sec. butylamide, 4-methoxy-phenyl-diethyl-acetic acid-sec. butylamide.
  • the products obtained according to the process of the present invention can be converted into the corresponding acid addition salts by treatment with inorganic or organic acids.
  • inorganic acids such as hydrohalic acid, particularly hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, amido-sulfonic acid.
  • organic acids enter into consideration: acetic acid, propionic acid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid, furnaric acid, sorbic acid, citric acid, aceturic acid,
  • aspartic acid aspartic acid, p-amino-benzoic acid, salicylic acid and -ethylenediamine-tetracetic acid.
  • the products obtained according to the invention are precious medicaments which, While being well tolerated,
  • the analgesic activity was examined in Swiss albino mice according to a modification of the method of Wolff- Hardy-Goodell (J. Clin. Invest. 19 (1940) 659).
  • This method was modified in such a way that by a process of all or nothing certain criteria were found in order to ascertain the percentage of animals reacting on the test. Thus, relatively exact relations of dosis efficiencies could be found.
  • butyl- -(3'-'hydroxyp-henyl)-2-ethyl-butylamine-(1) proved to be 7 to 8 times stronger than the known 1-phenyl-2,3-dimethyl-4-dimethylamino-pyrazolone-(S) and upon oral application two times stronger than the known 1-methyl-4-phenyl-piperidino-4-carboxylic acid ethyl-ester as regards analgesic ac-
  • the above-mentioned compound when applied in amino-propane according to the method by Ther shows a distinctly sedative activity and an antipyretic eflfeot in the case of artificially produced fever in rabbits.
  • the compounds are preferably administered in the form of drages or tablets, each tablet "containing from 5 to milligrams thereof as active ingredients.
  • Example 1 N isopropyl 2 (3' methoxyphenyl) 2 ethylbutylarnine-( l): 20 grams of 2-(37-me-thoxy-phenyD-2- ethyl-butylamine-(l) are shaken in 100 grams of acetone with palladium as catalyst and hydrogen under a weak superatmospheric pressure at 50 C., until hydrogen is no more absorbed, or hydrogenated at 50 C. under a hydrogen pressure of 50 atmospheres gauge. After separation from the catalyst and elimination of the excessive acetone by distillation there is obtained the N-isopropyl-2-(3'- methoxy-phenyl) -2-ethyl-butylamine( 1 in quantitative yield. A hydrochloride is formed which melts at 129 C.
  • the same compound is obtained by heating 2-(3'- -methoxy-phenyl)-2-ethyl-butylamine-(1) for 15 hours with excessive isopropanol and a great amount of Raney nickel, or by reacting 1- brorno-2-(3-rnethoxy-phenyl)-2- ethyl-butane in boiling xylene with isopropylamine.
  • the 1bromo-2-(3'-methoxy-phenyl)-2 ethyl-:butane is obtained by treating m-methoxyphenyl-diethylacetic acid 'in ethereal solution with lithium-aluminum-hydride and 'reaction of the carbinol obtained with concentrated hydrobromic acid. 7
  • the 2 (3 methoxy phenyl) 2 ethyl butylamine- (1) :boiling at 145-152 C. under a pressure of mm. of mercury used as starting substance is obtained by hydrogenation of (3-methoxy-phenyl)-diethyl-acetonitrile (B.P. 128-130 C. under a pressure of 4 mm. of mercury) which is formed from 3-methoxy-benzylcyanide by reaction with 2 mols of sodium amide and 2 mols of ethylbromide.
  • N isopropyl 2 (3' methoxy phenyl) 2 ethylbutylamine-(l): 20 grams of 2-(3'-methoxy-phenyl)-2- ethyl-butylamine-(l) are heated with 1 mol of diisopropyl-sulfate for 3 hours to 100 C. There is obtained in good yield the N-isopropyl-2-(3'-methoxy-phenyl)-2- ethyl-butylamine-(l) whose hydrochloride melts at 129 C.
  • Example 3 N sec. butyl 2 (3" methoxy phenyl) 2- ethyl-3-methyl-butyl-amine 1): 20 grams of 2-(3'-methoxy-phenyl) -2-ethyl-3-methyl-butylaminee( 1) are hydrogenated with 100 grams of methyl-ethyl-ketone as described in Example 1 (b). There is obtained in quantitative yield the N-sec. butyl-2-(3'-methoxy-phenyl)-2- ethyl-3-methyl-butylamine-(1) whose maleinate melts at 88 C.
  • N isopropyl 2 (3 hydroxy phenyl) 2 ethyl 3 methyl-butylamine-(l); melting point of the hydrochloride: 177 C.;
  • the 2 (3 methoxy phenyl) 2 ethyl 3 methylbutylamine-(l) boiling at 148153 C. under a pressure of 12 mm. of mercury and serving as starting material is obtained in the following manner: 3-methoxy-benzylcyanide is reacted with 1 mol of sodium amide and 1 mol of ethyl-bromide whereby (3-methoxy-phenyl)-ethylacetonitrile boiling at 151152 C. under a pressure of 10 mm. of mercury is obtained.
  • butyl 2 (3' methoxy phenyl) 2 ethyl-3-methyl-pentylamine-(1): 20 grams of 2-(3'-Inethoxy-phenyl)-2-ethyl-3-methyl-pentylamine-( 1 are hydrogenated with methyl-ethyl-ketone as described in Example 1 (b). There is obtained in quantitative yield the N sec. butyl 2 (3 methoxy phenyl) 2 ethyl 3- rnethyl-pentylamine-(l) Whose maleinate melts at 108 C.
  • the methyl group is separated from the 3-methoxy compounds described in Examples 4 (a) to (d) by boiling with hydrobromic acid of 48% strength with reflux and formation of the corresponding hydroxyphenyl derivatives.
  • hydrobromic acid 48% strength with reflux and formation of the corresponding hydroxyphenyl derivatives.
  • N isopropl 2 (3' hydroxy phenyl) 2 ethyl 3- methyl-pentylamine-(l); melting point of the rnaleinate: 155 C.;
  • the 2 (3 methoxy phenyl) 2 ethyl 3 methylpentylamine-(l) boiling at 173177 C. under a pressure of 11 mm. of mercury and serving as starting substance is obtained by hydrogenation of (3-methoxy-phenyl)-ethylsec. butyl-acetonitrile boiling at 143-445 C. under a pressure of 2.5 mm. of mercury which is obtained from (3- methoXy-phenyl)-ethyl-acetonitrile by reaction with sodium amide and sec. butyl-bromide.
  • Example 5 N sec. butyl 2 (4' methoxy phenyl) 2 ethylbutylamine-(l) 20 grams of 2-(4-methoxy-phenyl)-2- ethyl-butylarnine-(l) are hydrogenated with methyl-ethyl ketone as described in Example 1 (b). There is obtained in quantitative yield the N-sec. butyl-2-(4-methoxy-phenyl)-2-ethyl-butylamine-(1) whose maleinate melts at 132 C.
  • the same compound is obtained by catalytic hydrogena- 9 tion of anisyl-diethyl-acetaldehyde in the presence of sec. butylamine.
  • the 2 (4' methoXy-phenyl)-2-ethyl-butylarnine-(1) serving as starting substance and showing a boiling point of 118-128 C. under a pressure of 4 mm. of mercury is obtained by catalytic hydrogenation of (4-rnethoxy-pl1enyD-diethyl-acetonitrile showing a boiling point of 127- 129 C. under a pressure of 3 mm. of mercury, which is obtained by reaction of 4-methoXy-benzyl-cyanide with 2 mols of sodium amide and two mols of ethyl-bromide.
  • butyl-2-(4-hydroXy-phenyl)-2-ethyl-butylamine-(1) is obtained whose hydrochloride melts at 158 C.
  • the 2 (4' hydroxy-phenyl)-2-ethyl-butylarnine-(1) used as starting substance is obtained by catalytic hydrogenation of (4-hydroxy-phenyl)-diethyl-acetonitrile showing a melting point of 71 C.
  • the latter may be prepared from (4-arnino-phenyl)-diethyl-acetonitrile of a melting point of 113 C. by diazotation and boiling down.
  • Example 7 N-sec. butyl 2-(3'-ethoxy-phenyl)-2-ethyl-butylamine- (l): 20 grams of 2(3'-ethoxy-phenyl)-2-ethylbutylamine-(1) are hydrogenated in 100 grams of methylethyl-ketone with palladium as catalyst as described in example 1 (a). The mixture is then treated up. There is obtained in quantitative yield the N-sec. butyl-2-(3'- ethoxy'phenyl) -2-ethyl-butylarnine- 1 whose hydrochloride melts at 81 C.
  • the 2-(3'-ethoxy-phenyl)-2-ethyl-butylamine-(1) serving as starting substance is obtained in the following manner: 3-hydroxy-benzyl-alcohol in alkaline solution with diethylsulfate gives the S-ethoxy-benzyl-alcohol which in benzenic solution by treatment with concentrated hydrobromic acid at 50 C. forms 3-ethoxy-benzyl bromide. From this compound there is obtained by reaction with potassium cyanide the S-ethoXy-benzyl-cyanide.
  • butyl-2-(3'-hydroxy-pheny1)-2-ethyl-butylamine- (1) 20 grams of 2-(3-benzyloxypheny1)2-ethyl-butylamine-(1) are hydrogenated in 100 grams of methylethyl-ketone with palladium as catalyst as described in Example 1 (a) and worked up. There is obtained in 10 quantitative yield N-sec. butyl-2-(3-hydroxy-pheny1)-2- ethyl-butylamine-(l) whose hydrochloride melts at 165 C.
  • the 2 (3'-benzyloxy-phenyl)2-ethylbutylamine (1) serving as starting substance is obtained in the following manner: B-hydroxy-benzyl alcohol is reacted with benzylbromide in order to obtain 3-benzyloXy-benzyl-alcohol which at 50 C. in benzenic solution and when treated with concentrated hydrobromic acid is converted into the 3-benzyloxy-benzyl-bromide. The latter compound is converted by means of potassium cyanide into the 3- benZyloxy-benzyl-cyanide.
  • a member selected from the group consisting of phenylalkylamines of the formula R3 R3 +-OHzNH-Ofi HO can ⁇ a, in which R is an alkyl group containing 1-4 carbon atoms, and R and R are members selected from the group consisting of alkyl groups containing 14 carbon atoms and together with the adjacent carbon atom form an alicyclic saturated ring system containing 5-6 carbon atoms, and the salts of these compounds with physiologically compatible acids.
  • N isopropy1-2-( 3-hydroxy-phenyl)-2-ethyl-3-methyl-butylarnine- 1) 4.
  • N isopropyl-Z-(3-hydroxy-phenyl)-2-ethyl-3-methyl-pentylamine-( 1 5.
  • N-sec. butyl-2-(3'-hydroXy-phenyl)-2-ethyl-3-methyl-pentylamine- 1 References Cited by the Examiner UNITED STATES PATENTS Mndzhoyan et al., Chemical Abstracts, vol. 54, page 10910 (1960).

Description

United States Patent Claims. (of. 26il570.8)
The present invention provides new phenyl-alkylamines of the formula in which 0R represents the hydroxy group, the methoxy, ethoXy or benzyloxy group, R represents an alkyl group containing 1 to 4 carbon atoms and R and R are 'alkyl groups containing '1 to4 carbon atoms or together'with the adjacent central carbon atom are members of a saturated alicyclic ring system containing 5 to 6 carbon atoms, physiologically compatible acid-addition salts of these compounds and pharmaceutical preparations containing those new phenyl-alkylamines or the salts thereof as active ingredients.
The present invention further provides the preparation of phenyl-alkylamines of the Formula I according to methods Which may generally be applied for the preparation of such compounds.
The products obtained according to the invention are precious medicaments which While being Well tolerated are distinguished especially by valuable analgesic properties.
The compounds may be obtained, for example, by (a) reducing primary amines of the Formula II R10 z s in which OR, and R have the meanings given above, in the presence of ketones of the Formula III in which R, has the meaning given above and R represents an alkyl group containing 1 to 4 carbon atoms or an :alkylene group containing 2 to 4 carbon atoms, or (b) reacting primary amines of the Formula II With esters of the Formula IV a an \R; (IV) in which R and R have the meanings given above and X represents an inorganic or organic acid radical, if desired in the presence of an acid-binding agent, or (c) heating primary amines of the Formula II in the presence of alcohols of the Formula V v v LEO-05 R4 in which R, and K, have the meanings given above, with an excess amount of Raney nickel, or (d) reducing alcohols of the Formula V-I R2 (CH2OH R01 1H5 (VI) in which OR, and R have the meanings given above, with primary amines of the Formula VII a HzN-Cfi Ri (VII) in which R, and R, have the meanings given above, or (e) reacting compounds of the Formula VIII a Hz-Hal R10 C2115 (VIII) in which OR, and R have the meanings given above and Hal represents a chlorine, bromine or iodine atom, with amines of the Formula IX R4 in which R, and R have the meanings given above and R represents a hydrogen atom or the benzyl group, if desired in the presence of an acid-binding agent and, in case R represents a benzyl group splitting oif the latter hydrolytically, or (f) reducing aldehydes of the Formula X Ilia R10 zHs in which 0R and R have the meanings given above, in the presence of amines of the Formula VII, or (g) reducing carboxylic acid amides of the Formula XI in which 0R R R and R have the meanings given above, with lithium-aluminum-hydride in order to obtain the amines of Formula I, and if in the products obtained according to the invention CR represents the methoxyor ethoxy-group, converting these in usual manner into the hydroxy group, or if 0R represents the hydroxy group, converting the latter, if desired, into the methoxy or ethoxy group, or, if 0R represents the benzyloxy group, splitting oil? the benzyl radical, if desired, by catalytic hydrogenation.
The alkyl radicals R R and K, may be equal or different, straight chained or branched. There may be mentioned, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec.butyl radicals. The substituent 0R may be in any desired position of the phenyl nucleus.
It is most advantageous for the preparation of the products according to the invention to react amines of the Formula II with ketones of the Formula 111.. As amines may be used, for example: I
2- (2-, 3 or 4'-hydroxy-phenyl) -2-ethyl-butylamine-( 1 2-(2'-, 3'- or 4'-hydoXy-phenyl) -2-npropyl-butylamine 2- (2, 3 or 4hydroxyphenyl) 2-is0propyl-butylamine-( 1 2- (2'-, 3 or 4'-methoxy-phenyl)-2-ethyl-butylamine-(1), 2-(2'-, 3'- or 4-methoxy-phenyl)-2-n-butyl-butylamine- 2-(2'-, 3'- or 4'-methoxy-phenyl)-2isobutyl-butylamine- 2-(2'-, 3'- or 4'-methoxy-phenyl)-2n-propyl-butylamine- 2-(2'-, 3'- or 4'-methoxy-phenyl)-2-isopropyl-butylamine- 2-(2'-, -3'- or 4'-ethoxy-phenyl)-2-methyl-butylamine-(l),
2-(2-, 3'- or 4-ethoxy-phenyl)-2-ethyl-butylamine-(1),
2-(2'-, 3'- or 4'-ethoxy-phenyl)-2-ethyl-butylamine-(1),
2-(2-, 3'- or 4-benzyloxy-phenyl)-2-n-butyl-butylamine- 2-(2'-, 3'- or 4'-benzyloxy-phenyl)-2-isobutyl-butylamine,
2-(2-, 3'- or 4'-benzyloxy-phenyl) -2isopropyl-butylamine-(1) and 2-(2'-, 3 or 4-benzyl0xy-phenyl)-2-methyl-butylamine- As l-zetones of the Formula III there may be used, for example, the following compounds: acetone, methylethylketone, methyl-propyl-ketone, methylbutyl-ketone, methylisopropyl-ketone, methyl-isobutyl-ketone, diethyl-ketone, dipropyl-ketone, methyl-vinyl-ketone, isopropylidene-acetone (mesityloxide), cyclo-pentanone, cyclo-hexanone.
The amines to be used as starting substances may favorably be prepared by hydrogenation of the correspondingly substituted cyanides in the presence of catalysts of the 8th Group of the Periodic System. The cyanides may be prepared by reacting the correspondingly substituted benzylcyanides with sodium amide and alkyl halides in a solvent immiscible with water. If the radical R represents an ethyl group, it is possible to introduce both radicals in a single operation stage into the substituted benzyl-cyanide, by reaction of 2 mols of sodium amide with two mols of ethyl-halide. If the radical R ditfers from ethyl, the substituted benzyl-cyanides are obtained in two stages, by introducing, for example, into the corresponding benzyl cyanide with the aid of one mol of sodium amide and one mol of ethyl-bromide at first an ethyl group and subsequently, again with the aid of sodium amide, for example by means of isopropyl-bromide, the isopropyl group. If the hydroxy group in the phenyl nucleus is in para-position, the starting substances suitable for the process may likewise be obtained from the non-substituted benzylcyanide. For instance, there may be obtained phenyldiethyl-acetonitrile from benzyl-cyanide by means of two mols of sodium amide and two mols of ethyl-bromide. By nitration with nitric acid and sulfuric acid there is obtained from the last-mentioned compound the 4-nitrophenyl-diethyl-acetonitrile which may be reduced at -30 C. by means of nickel catalysts under a gauge pressure of 1G-20 atmospheres of hydrogen in order to obtain 4-aminophenyl-diethyl-acetonitrile. From the latter there is obtained after diazotation and boiling the 4-hydroxy-phenyldiethyl-acetonitrile from which the 2-(4-hydroxyphenyl)- 2-ethyl-butylamine-(l) is formed by catalytic hydrogenation. a
The reduction of the starting substances thus obtainable may be eifectedin the presence of ketones of the Formula III, for instance, catalytically with the aid of metals of the 8th Group of the Periodic System, preferably with palladium catalysts and an excessive amount of ketone as solvent, at a temperature of 50 C. and under a low or an elevated gauge pressure of hydrogen up to 50 atmospheres. When operating according to this method, the excessive ketone is not hydrogenated to yield the corresponding carbinol and may be recovered. Instead of palladium there can likewise be used nickel catalysts (Raney nickel). It is likewise possible to carry out the reduction by means of nascent hydrogen, for instance aluminum amalgam and alcohol, sodium amalgam, lithium-aluminium-hydride or sodium boron hydride. The reduction may, furthermore, be carried out by electrolysis.
According to another favorable method of carrying out the process according to the invention amines of the Formula II may be reacted with esters of inorganic or organic acids of the Formula IV. There may be used for example: isopropyl-iodide, sec. butyl-bromide, 3-bromopentane, Z-bromo 3 methyl-butane, 2-bromo-4-methylpentane, cyclopentyl-bromide, cyclohexyl-bromide, p-toluene-sulfonic acid isopropyl-ester, diisopropyl-sulfate.
This reaction is suitably performed by heating the reactants in an appropriate solvent, for instance ethanol, propanol, benzene, toluene or xylene at temperatures between and 130 C. The heating period depends on the temperature and the reactivity of the ester component and amounts, in general, to 2 to 20 hours. In order to bind the acids that have formed during the reaction the amine of the Formula II may be used in excess and a solvent immiscible with water may be used. The corresponding amine salt formed in the course of the reaction is generally obtained in a crystalline form and may be removed after cooling by filtering with suction or by shaking out the reaction solution by means of water, whereupon the desired reaction product may be isolated as a salt by distilling off the solvent or by shaking out the solvent with the aid of acids. Instead of a second mol of the amine there may be used in order to bind the acids formed, likewise other basic compounds, for instance sodium bicarbonate, anhydrous sodium carbonate or tertiary amines such as triethylamine or diethylaniline. The reaction may likewise be carried out without using solvents by heating both reaction components to temperatures between 80 and 130 C., it being favorable to use the amine in a bimolar excess.
Another method of carrying out the process according to the invention consists in heating amines of the formula II in the presence of alcohols of the Formula V with an excessive amount of Raney nickel for a prolonged period of time, e.g., 15 hours, at temperatures of IOU-120 C.
According to a further method of operation alcohols of the Formula VI can be reacted with primary amines of the Formula VII, advantageously by beating them with an excessive amount of Raney nickel in order to obtain the desired products. It is suitable to add an excessive amount of the corresponding amine which then simultaneously serves as a solvent.
Furthermore, it is possible, to react halogen compounds of the Formula VIII with amines of the Formula IX. The reaction is performed, in principle, under the same reaction conditions as described above. When starting from amines containing a benzyloxy group, the benzylgroup may subsequently be split off by hydrogenation, favorably in an organic solvent, such as methanol, in the presence of noble metal catalysts.
The halogenated hydrocarbons of the Formula VIII may be prepared, for instance, by reducing the corresponding phenyl-dialykyl-acetic acids with lithium-aluminium-hydride in ethereal solution and treating the phenyl-dialkyl-ethanols thus obtained with concentrated hydrobromic acid at temperatures between 80 and C.
A further possibility of preparing the products according to the invention consists in reducing aldehydes of the Formula X, for instance 3-methoxy-phenyl-diethyl-acetaldehyde, in the presence of amines of the Formula IX. It is recommendable to carry out the reduction catalytically while using catalysts of the 8th Group of the Periodic System and in the presence of a solvent, for instance, methanol. The aldehydes used as starting substances may be obtained, for example, from the corresponding carbinols by oxidation with selenedioxide.
Finally, amides of the Formula IX may be converted in the usual manner by reduction with lithium-aluminiumhydride into the desired products. As such amides there may be mentioned, for instance, 3-methoxy-phenyl-diethyl-acetic acid-isopropylamide, 3-methoxy-phenyl-diethyl-acetic acid-sec. butylamide, 4-methoxy-phenyl-diethyl-acetic acid-sec. butylamide.
For the preparation of products in the formula of which 0R represents the h droxy group, it is of advantage first to prepare the corresponding methoxy-, ethoxyor benzyltion. mice excited by administration of l-phenyl-Z-methyloxy-compound. The methoxyand ethoxy-compounds may be dealkylated in the usual manner, for instance by heating with hydrogen chloride, hydrogen bromide, alu- 'minium chloride or pyridin-hydrochloride in order to obby catalytic hydrogenation with corresponding ketones and palladium as catalyst, the benzyl group is simultaneously split ofi. If the radical R: as
is however, introduced according to another method, for
instance by reaction with esters of the Formula IV, in the case of which the benzyloxy group does not react, the benzyl group is split oil? in a second stage by hydrogenation by means of noble metals as catalysts.
On the other hand, it according to one of the abovedescribed methods of operation there are obtained products in the formula of which R represents the hydroxy group, the latter can be converted into the methoxyor ethoxygroup by methylation or ethylation in the usual manner, forinstance with dimethyl-sulfate or diethyl-sulfate in an alkaline solution.
The products obtained according to the process of the present invention can be converted into the corresponding acid addition salts by treatment with inorganic or organic acids. For the salt formation may be used, for example, inorganic acids such as hydrohalic acid, particularly hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, amido-sulfonic acid. As organic acids enter into consideration: acetic acid, propionic acid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid, furnaric acid, sorbic acid, citric acid, aceturic acid,
aspartic acid, p-amino-benzoic acid, salicylic acid and -ethylenediamine-tetracetic acid.
The products obtained according to the invention are precious medicaments which, While being well tolerated,
- are distinguished by valuable analgesic properties.
The analgesic activity was examined in Swiss albino mice according to a modification of the method of Wolff- Hardy-Goodell (J. Clin. Invest. 19 (1940) 659). When applying this method a number of albino mice were given the preparation subcutaneously or orally and the period of time in which the animals reacted on the thermal irritation was examined prior to and after the administration of the products. This method was modified in such a way that by a process of all or nothing certain criteria were found in order to ascertain the percentage of animals reacting on the test. Thus, relatively exact relations of dosis efficiencies could be found. Upon subcutaneous administration the N-sec. butyl- -(3'-'hydroxyp-henyl)-2-ethyl-butylamine-(1) proved to be 7 to 8 times stronger than the known 1-phenyl-2,3-dimethyl-4-dimethylamino-pyrazolone-(S) and upon oral application two times stronger than the known 1-methyl-4-phenyl-piperidino-4-carboxylic acid ethyl-ester as regards analgesic ac- The above-mentioned compound when applied in amino-propane according to the method by Ther (Siidd. Apoth. Zeitg. 1953, page 292) shows a distinctly sedative activity and an antipyretic eflfeot in the case of artificially produced fever in rabbits.
The very excellent analgesic action of the new phenylalkylamines could also be corroborated by clinical tests.
.with methyl-vinyl-ketone and palladium as catalyst until .t-ioned direction.
6, The compounds are preferably administered in the form of drages or tablets, each tablet "containing from 5 to milligrams thereof as active ingredients.
The rfollowing examples serve to illustrate the invention but they are not intended to limit it thereto:
Example 1 (a) N isopropyl 2 (3' methoxyphenyl) 2 ethylbutylarnine-( l): 20 grams of 2-(37-me-thoxy-phenyD-2- ethyl-butylamine-(l) are shaken in 100 grams of acetone with palladium as catalyst and hydrogen under a weak superatmospheric pressure at 50 C., until hydrogen is no more absorbed, or hydrogenated at 50 C. under a hydrogen pressure of 50 atmospheres gauge. After separation from the catalyst and elimination of the excessive acetone by distillation there is obtained the N-isopropyl-2-(3'- methoxy-phenyl) -2-ethyl-butylamine( 1 in quantitative yield. A hydrochloride is formed which melts at 129 C.
The same compound is obtained by heating 2-(3'- -methoxy-phenyl)-2-ethyl-butylamine-(1) for 15 hours with excessive isopropanol and a great amount of Raney nickel, or by reacting 1- brorno-2-(3-rnethoxy-phenyl)-2- ethyl-butane in boiling xylene with isopropylamine.
The 1bromo-2-(3'-methoxy-phenyl)-2 ethyl-:butane is obtained by treating m-methoxyphenyl-diethylacetic acid 'in ethereal solution with lithium-aluminum-hydride and 'reaction of the carbinol obtained with concentrated hydrobromic acid. 7
('b) N-sec. butyl 2-(3'-methoxy-phenyl)-2-ethyl-buty1- amine-(1): 300 grams of 2-(3 methoxy-phenyl)-2-ethylbutylamine-( 1) are hydrogenated in 750 grams of methylethyl-ketone and worked up according to the above-men- The- N-se'c. butyl-2-(3'-methoxyphenyi)-2-ethyl-butylamine-(1) is obtained in quantita tive yield. Its hydrochloride melts at 139 C.
The same compound is obtained by hydrogenating at C. '2- 3'-methoxyphenyl) -2-ethy1ibutylamine-( 1) no more hydrogen is absonbed, or by treating .3-methoxyphenyl-diethyl-acet-ic acid-sec. butylamide with lithiumaluminum hydridepor by heating to boil for 15 hours ..2-(3'-methoxy-phenyl)-2-ethy1-butanol-(1) with an exces- .sive amount of sec. lbutylamine in the presence of large amounts of Raney-nickel. There were furthermore obtained irom. 2-(3'-methoxy-phenyl)-2-ethyl-butylamine- 1 (l) by hydrogenation with the corresponding ketones:
(c) N [3" methyl butyl (2")] 2 (3' methoxyphenyl)-2-ethy1-ibutyl=amine( 1); melting point of the hy- 1 .drochloride: 132 C. (fir-om methyl-isopropyl-ketone).
(d) N [4" methyl pentyl (2")1 2 (3 methoxyphenyl)-2-ethyl-butylamine-(1); melting point of the hydrochloride: 86 C. (from methyl-isobutyl-ketone).
(e) N pentyl (3") 2 (3' methoxy phenyl) 2- e.thyl-butylamine-( 1 melting point of the hydrochloride:
118 C. (from diethyl-ketone).
( f) N cyclopentyl 2 (3' methoxy phenyl) 2- ethyl butylamine-(l); melting point of the maleinate:
128 C. (fromcyclopentanone).
(g) N cyclohexyl 2 (3' methoxy phenyl) 2 ethyl-butylamine-(1); melting point of the hydrochloride: C, (from cyclohexanone).
(h) N pentyl (2") 2 (3 methoxy phenyl) 2- ethylabutylaminei 1); melting point of the hydrochloride: 126 C. (from methyl-propyl-ketone).
By heating the 3-methoxy compounds described in Examples 1 (a) to (h) for 8 hours with hydro'br-omic acid of 48% strength with reflux, the methyl group is split olf with formation of the corresponding hydroxy phenyl derivatives. The following products were produced, for example: V
N-is opropyl-2-( 3 -hyd-r0xy-phenyl) -2-et.hyl-butyl amine- (1) melting point of the hydrochloride: 154 C.;
; N-sec. butyl-2-(3'-hydroxy-phenyl)-2-ethyl-butylamine- V 1); melting point of the hydrochloride: C.; N- ['3 "-rne'thyl-ibutyl- 2" 2-( 3 '-hydr oxy-phenyl-Z-ethylsnssgaee 7 butyI-amine-( 1 melting point of the hydrochloride: 185 C.;
N- [=4"-methyl-pentyl (2") ]-2-(3'-hydroxy-phenyl) -2- ethylbutyl-amine-( 1); melting point or" the hydrochloride: 164 C.;
N-pentyl- 3 -2- 3'-hydroxy-phenyl -2-et-hy1-butylamine- (1); melting point of the hydrochloride: 180 C.;
N- cycl op entyl-2-( 3 '-hydroxyp henyl -2-ethylb utylamine- (1); melting point of the hydrochloride: 179 C.;
N-eyclohexyl-Z- 3 -hydroxy-phenyl -2-ethyl-buty1amine- (1); melting point of the hydrochloride: 198 C.;
N-pentyl-(2" -2-( 3 'hydroxy-phenyl -2-ethyl-butylamine- (1); melting point of the hydrochloride: 167 C.
The 2 (3 methoxy phenyl) 2 ethyl butylamine- (1) :boiling at 145-152 C. under a pressure of mm. of mercury used as starting substance is obtained by hydrogenation of (3-methoxy-phenyl)-diethyl-acetonitrile (B.P. 128-130 C. under a pressure of 4 mm. of mercury) which is formed from 3-methoxy-benzylcyanide by reaction with 2 mols of sodium amide and 2 mols of ethylbromide.
Example 2 N isopropyl 2 (3' methoxy phenyl) 2 ethylbutylamine-(l): 20 grams of 2-(3'-methoxy-phenyl)-2- ethyl-butylamine-(l) are heated with 1 mol of diisopropyl-sulfate for 3 hours to 100 C. There is obtained in good yield the N-isopropyl-2-(3'-methoxy-phenyl)-2- ethyl-butylamine-(l) whose hydrochloride melts at 129 C.
Example 3 (a) N sec. butyl 2 (3" methoxy phenyl) 2- ethyl-3-methyl-butyl-amine 1): 20 grams of 2-(3'-methoxy-phenyl) -2-ethyl-3-methyl-butylaminee( 1) are hydrogenated with 100 grams of methyl-ethyl-ketone as described in Example 1 (b). There is obtained in quantitative yield the N-sec. butyl-2-(3'-methoxy-phenyl)-2- ethyl-3-methyl-butylamine-(1) whose maleinate melts at 88 C.
There were likewise obtained from 2-(3-methoxyphenyl)-2-ethyl-3-methyl-butylamine-( 1) by hydrogenation with the corresponding ketones the following compounds: I
(b) N isopropyl 2 (3 methoxy phenyl) 2- ethyl-3-methyl-butylamine-( 1); melting point of the hydrochloride: 131 C. (from acetone). 7
(c) N pentyl (2") 2 (3' methoxy phenyl) 2- ethyl-3-methyl-butylamine-(1); melting point of the maleinate: 90 C. (from methyl-propyl-ketone).
(d) N {pentyl (3") 2 (3' methoxy phenyl) 2- ethyl-3-methyl-butylamine-( 1); melting point of the fumarate: 138 C. (from diethylketone).
(e) N [3 methyl butyl (2")1 2 (3 methoXyphenyl) -2-ethyl-3-methyl-butylarnine-( 1 melting point of the fumarate: 142 C. (front methyl-isopropyl-ketone) By boiling the solution with hydrobromic acid of 48% strength under reflux the methyl group is split ofr the 3- methoxy compounds described in Examples 3 (a) to (e) with formation of the corresponding hydroxy-phenyl derivatives. The following products were prepared, for example:
N isopropyl 2 (3 hydroxy phenyl) 2 ethyl 3 methyl-butylamine-(l); melting point of the hydrochloride: 177 C.;
N-sec. butyl 2 (3 hydroxy phenyl) 2 ethyl 3 methyl-butylamine-( 1 melting point of the hydrochloride: 158 C.;
N pentyl (2") 2 (3' hydroxy phenyl) 2 ethyl- 3-methyl-butylamine-(1); melting point of the hydrochloride: 193 C.;
N pentyl (3") 2 (3' hydroxy phenyl) 2 ethyl- 3-methyl-butylamine-(l); melting pointof the hydrochloride: 164 C.;
N [3 methyl butyl (2")] 2 (3' hydroxy pheno o nyl)-2-ethyl-3-methyl-butylamine-(l); melting point of the hydrochloride: 174 C.
The 2 (3 methoxy phenyl) 2 ethyl 3 methylbutylamine-(l) boiling at 148153 C. under a pressure of 12 mm. of mercury and serving as starting material is obtained in the following manner: 3-methoxy-benzylcyanide is reacted with 1 mol of sodium amide and 1 mol of ethyl-bromide whereby (3-methoxy-phenyl)-ethylacetonitrile boiling at 151152 C. under a pressure of 10 mm. of mercury is obtained. Starting from this sub stance there is obtained with 1 mol of sodium amide and 1 mol of isopropyl-bromide the (3-methoXy-phenyl)- ethyl-isopropyl-acetonitrile boiling at 127128 C. under a pressure of 1.5 mm. of mercury which, upon hydrogenation yields the 2-(3'methoxy-phenyl)-2-ethyl-3-methylbutylamine- 1 Example 4 (a) N sec. butyl 2 (3' methoxy phenyl) 2 ethyl-3-methyl-pentylamine-(1): 20 grams of 2-(3'-Inethoxy-phenyl)-2-ethyl-3-methyl-pentylamine-( 1 are hydrogenated with methyl-ethyl-ketone as described in Example 1 (b). There is obtained in quantitative yield the N sec. butyl 2 (3 methoxy phenyl) 2 ethyl 3- rnethyl-pentylamine-(l) Whose maleinate melts at 108 C.
The following compounds were likewise obtained from 2 (3' methoxy phenyl) 2 ethyl 3 methyl pentylamine-(l) by hydrogenation with the corresponding ketones:
(b) N isopropyl 2 (3' methoxy phenyl) 2- ethyl 3 methyl pentylamine (1); melting point of the maleinate: 93 C.;
(c) N pentyl (2) 2 (3 methoxy phenyl) 2- ethyl-3-methyl-pentylamine-(1); melting point of the hydrochloride: 187 C.;
(d) N [3 methyl butyl (2")] 2 (3' methoxyphenyl) -2-ethyl-3-methyl-pentylamine-( 1); melting point of the fumarate: C.
The methyl group is separated from the 3-methoxy compounds described in Examples 4 (a) to (d) by boiling with hydrobromic acid of 48% strength with reflux and formation of the corresponding hydroxyphenyl derivatives. For example, the following products were obtained:
N isopropl 2 (3' hydroxy phenyl) 2 ethyl 3- methyl-pentylamine-(l); melting point of the rnaleinate: 155 C.;
N sec. butyl 2 (3' hydroxy phenyl) 2 ethyl 3- the hydrochloride: 176 C.;
N pentyl (2) 2 (3' hydroxy phenyl) 2 ethyl- 3-methyl-pentylamine-(1); melting point of the hydrochloride: 197 C.;
N [3" methyl butyl (2")] 2 (3' hydroxy phenyl)-2-ethyl-3-methyl-pentylamine-(1); melting point of methyl-pentylamine-(l); melting point of the hydrochloride: C.;
The 2 (3 methoxy phenyl) 2 ethyl 3 methylpentylamine-(l) boiling at 173177 C. under a pressure of 11 mm. of mercury and serving as starting substance is obtained by hydrogenation of (3-methoxy-phenyl)-ethylsec. butyl-acetonitrile boiling at 143-445 C. under a pressure of 2.5 mm. of mercury which is obtained from (3- methoXy-phenyl)-ethyl-acetonitrile by reaction with sodium amide and sec. butyl-bromide.
Example 5 N sec. butyl 2 (4' methoxy phenyl) 2 ethylbutylamine-(l) 20 grams of 2-(4-methoxy-phenyl)-2- ethyl-butylarnine-(l) are hydrogenated with methyl-ethyl ketone as described in Example 1 (b). There is obtained in quantitative yield the N-sec. butyl-2-(4-methoxy-phenyl)-2-ethyl-butylamine-(1) whose maleinate melts at 132 C.
The same compound is obtained by catalytic hydrogena- 9 tion of anisyl-diethyl-acetaldehyde in the presence of sec. butylamine.
From N sec. butyl 2 (4' methoXy-phenyl) 2- ethyl-butylamine-(l) there is obtained, by boiling with hydrobromic acid of 48% strength, the N-sec. butyl-2-(4'- hydrcXy-phenyl)-2-ethyl-butylarnine-(l) whose hydrochloride melts at 158 C.
The 2 (4' methoXy-phenyl)-2-ethyl-butylarnine-(1) serving as starting substance and showing a boiling point of 118-128 C. under a pressure of 4 mm. of mercury is obtained by catalytic hydrogenation of (4-rnethoxy-pl1enyD-diethyl-acetonitrile showing a boiling point of 127- 129 C. under a pressure of 3 mm. of mercury, which is obtained by reaction of 4-methoXy-benzyl-cyanide with 2 mols of sodium amide and two mols of ethyl-bromide.
Example 6 N-sec. butyl-2-(4'-hydroxy-phenyl)-2-ethyl-butylamine- 1) 2- (4'-hydroXy-phenyl -2-ethyl-butylamine-( 1 melting at 122 C. is hydrogenated in the presence of methylethyl-ketone and palladium as catalyst, whereby N-sec.
butyl-2-(4-hydroXy-phenyl)-2-ethyl-butylamine-(1) is obtained whose hydrochloride melts at 158 C.
The 2 (4' hydroxy-phenyl)-2-ethyl-butylarnine-(1) used as starting substance is obtained by catalytic hydrogenation of (4-hydroxy-phenyl)-diethyl-acetonitrile showing a melting point of 71 C. The latter may be prepared from (4-arnino-phenyl)-diethyl-acetonitrile of a melting point of 113 C. by diazotation and boiling down.
Example 7 N-sec. butyl 2-(3'-ethoxy-phenyl)-2-ethyl-butylamine- (l): 20 grams of 2(3'-ethoxy-phenyl)-2-ethylbutylamine-(1) are hydrogenated in 100 grams of methylethyl-ketone with palladium as catalyst as described in example 1 (a). The mixture is then treated up. There is obtained in quantitative yield the N-sec. butyl-2-(3'- ethoxy'phenyl) -2-ethyl-butylarnine- 1 whose hydrochloride melts at 81 C.
The 2-(3'-ethoxy-phenyl)-2-ethyl-butylamine-(1) serving as starting substance is obtained in the following manner: 3-hydroxy-benzyl-alcohol in alkaline solution with diethylsulfate gives the S-ethoxy-benzyl-alcohol which in benzenic solution by treatment with concentrated hydrobromic acid at 50 C. forms 3-ethoxy-benzyl bromide. From this compound there is obtained by reaction with potassium cyanide the S-ethoXy-benzyl-cyanide. By reaction with the birnolar amount of ethyl-bromide with 2 mols of sodium amide in benzenic solution it furnishes the 3-ethoXy-phenyl diethyl-acetonitrile from which there is obtained by catalytic hydrogenation with Raney nickel and a solution of methanol and ammonia the 2-(3'-ethoxyphenyl) -2-ethyl-butylamine-( 1) Example 8 N-sec. butyl-2-(3'-hydroxy-pheny1)-2-ethyl-butylamine- (1): 20 grams of 2-(3-benzyloxypheny1)2-ethyl-butylamine-(1) are hydrogenated in 100 grams of methylethyl-ketone with palladium as catalyst as described in Example 1 (a) and worked up. There is obtained in 10 quantitative yield N-sec. butyl-2-(3-hydroxy-pheny1)-2- ethyl-butylamine-(l) whose hydrochloride melts at 165 C.
The 2 (3'-benzyloxy-phenyl)2-ethylbutylamine (1) serving as starting substance is obtained in the following manner: B-hydroxy-benzyl alcohol is reacted with benzylbromide in order to obtain 3-benzyloXy-benzyl-alcohol which at 50 C. in benzenic solution and when treated with concentrated hydrobromic acid is converted into the 3-benzyloxy-benzyl-bromide. The latter compound is converted by means of potassium cyanide into the 3- benZyloxy-benzyl-cyanide. The bimolar quantity of ethyl-bromide in benzenic solution and 2 molts of sodium amide are caused to act on this compound, whereby the 3-benzyloXy-phenyl-diethyl-acetonltrile is formed from which the 2-(3'-benzyloxy-phenyl-2ethyl-butylamine-(1) is formed by catalytic hydrogenation with Raney nickel as catalyst and a solution of methanol and ammonia.
We claim:
1. A member selected from the group consisting of phenylalkylamines of the formula R3 R3 +-OHzNH-Ofi HO can \a, in which R is an alkyl group containing 1-4 carbon atoms, and R and R are members selected from the group consisting of alkyl groups containing 14 carbon atoms and together with the adjacent carbon atom form an alicyclic saturated ring system containing 5-6 carbon atoms, and the salts of these compounds with physiologically compatible acids.
2. N-sec. butyl 2-(3'-hydroXy-phenyl)-2-ethyl-butylamine-(l).
3. N isopropy1-2-( 3-hydroxy-phenyl)-2-ethyl-3-methyl-butylarnine- 1) 4. N isopropyl-Z-(3-hydroxy-phenyl)-2-ethyl-3-methyl-pentylamine-( 1 5. N-sec. butyl-2-(3'-hydroXy-phenyl)-2-ethyl-3-methyl-pentylamine- 1 References Cited by the Examiner UNITED STATES PATENTS Mndzhoyan et al., Chemical Abstracts, vol. 54, page 10910 (1960).
Weston et al., Jour. Amer. Chem. Soc.," vol. 65, pages 674-7 (1943).
CHARLESB. PARKER, Primary Examiner;
W. B. KNIGHT, L. ZITVER, IRVING MARCUS,
JOSEPH P. BRUST, Examiners.

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF PHENYLALKYLAMINES OF THE FORMULA
US94131A 1960-03-11 1961-03-08 N-secondary-alkyl-2-(3-hydroxyphenyl)-2-ethyl-alkylamines Expired - Lifetime US3188349A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1960F0030735 DE1242240C2 (en) 1960-03-11 1960-03-11 Process for the preparation of phenylalkylamines and their acid addition salts

Publications (1)

Publication Number Publication Date
US3188349A true US3188349A (en) 1965-06-08

Family

ID=7093891

Family Applications (1)

Application Number Title Priority Date Filing Date
US94131A Expired - Lifetime US3188349A (en) 1960-03-11 1961-03-08 N-secondary-alkyl-2-(3-hydroxyphenyl)-2-ethyl-alkylamines

Country Status (4)

Country Link
US (1) US3188349A (en)
DE (1) DE1242240C2 (en)
GB (1) GB971752A (en)
NL (1) NL262294A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3422140A (en) * 1962-01-17 1969-01-14 Haessle Ab 2,3-dihydroxyphenylalkanamides
US3422141A (en) * 1962-01-17 1969-01-14 Haessle Ab 3,4-dihydroxyphenylalkanamides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2251245A (en) * 1938-10-01 1941-07-29 Gen Aniline & Film Corp Production of hydroxy alkyl amines
US2742397A (en) * 1953-06-09 1956-04-17 Commercial Solvents Corp Analgetic compositions of n-(1-methyl propyl) cyclohexylamine
US2793977A (en) * 1951-08-31 1957-05-28 Caspe Saul Compositions and method for reducing blood sugar concentration
US2884455A (en) * 1956-10-29 1959-04-28 Dow Chemical Co Propynyl phenylethylamines and their halogen acid salts

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE904536C (en) * 1942-11-29 1954-02-18 Troponwerke Dinklage & Co Process for the preparation of 1- (oxyphenyl) -2-aminobutanes with an analgesic effect
NL64412C (en) * 1943-08-18

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2251245A (en) * 1938-10-01 1941-07-29 Gen Aniline & Film Corp Production of hydroxy alkyl amines
US2793977A (en) * 1951-08-31 1957-05-28 Caspe Saul Compositions and method for reducing blood sugar concentration
US2742397A (en) * 1953-06-09 1956-04-17 Commercial Solvents Corp Analgetic compositions of n-(1-methyl propyl) cyclohexylamine
US2884455A (en) * 1956-10-29 1959-04-28 Dow Chemical Co Propynyl phenylethylamines and their halogen acid salts

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3422140A (en) * 1962-01-17 1969-01-14 Haessle Ab 2,3-dihydroxyphenylalkanamides
US3422141A (en) * 1962-01-17 1969-01-14 Haessle Ab 3,4-dihydroxyphenylalkanamides

Also Published As

Publication number Publication date
NL262294A (en)
DE1242240C2 (en) 1967-12-07
GB971752A (en) 1964-10-07
DE1242240B (en) 1967-06-15

Similar Documents

Publication Publication Date Title
US3152173A (en) Basically substituted diphenyl-methane derivatives and process for preparing them
DE1543374C3 (en) 3,4 Dihydroxyphenylalkanolamines and their acid addition salts, processes for their production and pharmaceutical preparations
US3966749A (en) Novel synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols, the pharmaceutically acceptable acid addition salts thereof and intermediate useful in the preparation thereof
US4476136A (en) Aminomethyl-5 oxazolidinic derivatives and therapeutic use thereof
Wilkinson et al. Antituberculous Agents. III.(+)-2, 2-(Ethylenediimino)-di-1-butanol1, 2 and Some Analogs
US3804899A (en) 3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof
DE2143204B2 (en) N-fluoroalkyl-phenylisopropylamine derivatives and their salts, processes for their preparation and pharmaceuticals based on them
US3188349A (en) N-secondary-alkyl-2-(3-hydroxyphenyl)-2-ethyl-alkylamines
US3225098A (en) N-substituted phenylalkylamines
Kevill et al. Synthesis of 5-substituted 1-(1-adamantyl) tetrazoles and related compounds
DE1543777C3 (en) Process for the preparation of alpha-lower alkyl-beta- (4-hydroxyphenyl) -alanines
IL32481A (en) Diphenylmethoxyethylamino derivatives,their preparation and pharmaceutical compositions containing them
US2431285A (en) Process for preparing 1-(dihydroxy-phenyl)-2-amino butanol-1 and intermediates
US3222399A (en) Cyclopentylbenzylamines
US3096244A (en) Substituted butyric acid amide and analgesia
US3213138A (en) N, n-disubstituted-n'-phenylalkyl hydrazines
Surrey et al. New Amebacides. IV. 1 The Preparation of Some N-Benzyl-N-(2-carbamylethyl)-and N-Benzyl-N-(2-cyanoethyl)-haloacetamides
EP0000013B1 (en) 4-phenyl-8-amino-tetrahydroisoquinolines, pharmaceutical compositions containing them and process for preparation of these compositions
US4820734A (en) Phenethylamine derivatives
DE1593762A1 (en) Process for the preparation of new substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes
US3481980A (en) Process and intermediates for n-(4-(2-alkylaminoalkoxy) - benzyl) - 3,4-dialkoxy benzamides
US2864863A (en) Nitro and polyamines and a process for producing these amines
EP0125046B1 (en) Process for preparing pyrimidinetrione derivatives
Tatsuno et al. Synthesis and adrenergic. beta.-blocking activity of some 1, 3-benzodioxole derivatives
US3362993A (en) Substituted benzamides and methods for their preparation