BE727243A - - Google Patents

Description

  

   <Desc / Clms Page number 1>
 



  "Novel pbenoxyalkylamine derivatives and their preparation" The present invention relates to amino etbersoxides
 EMI1.1
 and their salts, which have valuable therapeutic properties, the processes by which they are prepared and the pharmaceutical compositions which contain them.



   The invention relates to substituted derivatives of
 EMI1.2
 3,5-dialkox-yphenoxyal'.kylamines which correspond to the general formula 1:

 <Desc / Clms Page number 2>

 
 EMI2.1
 in which Z is a lower alkoxy radical, such as, for example, a methoxy or ethoxy radical;

   R1 is a hydrogen atom or a lower alkyl radical, such as for example a methyl radical; and
R2 and R3 are identical or different substituents, chosen from the class comprising the hydrogen atom, alkyl radicals branched or not, aralkyl radicals branched or not on the alkyl chain and substituted or not on the aromatic ring, the aryloxyalkyl radicals branched or not on the alkyl chain and substituted ¯¯ or not on the aromatic nucleus, cycloalkyl radicals, branched or branched hydroxylated alkyl radicals ,.



   The invention also relates to the salts of the above derivatives.



   The 3,5-dialkoxyphenoxyalkylamine derivatives according to the invention can in fact be salified with mineral acids, such as hydrogen chloride, hydrogen bromide, sulfuric acid, or with organic acids, such as 'acetic acid,. propionic acid, succinic acid., citric acid, tartaric acid.



   By the expression “branched or branched alkyl radicals”, as used in the present description, is meant alkyl radicals having from 1 to 8 carbon atoms, such as for example the methyl, ethyl, n-propyl, iso radicals. -proyl, n-butyl, iso-butyl, sec-butyl, ter-butyl, n-pentyl, iso-pentyl, sec-pentyl, n-hexyl, iso-hexyl, n-heptyl, 1-methylh @ xyde, 1 , 4-dimethylpentyl.



   By the expression "aralkyl radicals' branched or not on the alkyl chain and substituted or not on the aromatic ring", as used in the present description, is meant radicals corresponding to the following formula (II):

 <Desc / Clms Page number 3>

 
 EMI3.1
 in which W and X are identical or different substituents chosen from the class comprising the atony of hydrogen, branched lower alkyl radicals - or not, the hydroxy radical and the radicals -
 EMI3.2
 branched or unbranched lower alKOxy .-; - R.4 -is an atom -â-'xydageneor a methyl radical; and n can take -the -values- -included.5- l!:!: .--, == zero and 2;

   these are, for example, the radicals P -, phenethyl: 3le, p # p # methox¯vpbéne-thyle, # -3, 4-rIicëthoxyphënétïayl, 1-methyl-2- # nény.lethyl, 3-p -metîoxypTéry.propri-e, 4 p-crëthoxyp'éxy.but ē¯. ¯
By the expression "aryloxyalkyl radicals branched or not on the alkyl chain and substituted or not su = the aromatic ring.
 EMI3.3
 qne ", as used in the p - ésertedescrintio-n. one should understand the radicals corresponding to the following formula (IIII)
 EMI3.4
 
 EMI3.5
 in which W, X, R and n have the meanings given above, such as for example the radicals -phenoxyethyl, 1-methyl-? pî.enox ethyl, 3-phenoxypropyl, p # o # methylp'henoxyëthyle '-, - ra-rethyi-pheno,. "3r-ethyl,' 1-p-methylphenoxy-yethyl, t3-o-methoxyphenoxyethyl, f3-1P-metho- -xyphenoy-yét'hyl, Pp-retlio3cyphenoxyethyl.

   P-35-diEêt'hoxyphenoxy-ethyl, 1-methyl-2-o-methylphenoxyethyli, I-methyl-2- "m-methylphenoxy- -txye t - = methyh = g = -méthyphenoxyéthy3.e, I-methy 1 . - 2-o-methoxyphé :: noxyethyl, I-methyl-2-m-methoxyphenaxethyl, I-methyl-2-p-metho, .y-. Phenoxyethyl, 1-methyl-2-j3, -di.méthatyphenoxyy- ethyl, 3- (3.5dimethoxyphenoxy) -propyl.



  By the expression "cycloalkyl radicals" as used in the present description, it is meant the saturated cyclic radicals comprising from 3 to 6 carbon atoms, as by

 <Desc / Clms Page number 4>

 example the radicals cyclcpropyle, cyclopentyle, cyclohexyle.
By the expression - branched hydroxylated alkyl radicals ¯ or non-4 as used in the present description, is meant the alkyl radicals comprising from 2 to 8 carbon atoms and a hydroxyl function.

   such as for example the 2-hydroxy- radicals
 EMI4.1
 ethyl, 3-hydroX'JPropyl * 1,5-imethyl-5-hydroxyhexyl,
A subject of the present invention is also a process for the preparation of compounds of general formula I in which R1 is an alkyl group, a process in which a
 EMI4.2
 reacting a reactive derivative of an aliphatic ketone with / 3,5-dialkoxyphenol; the derivative obtained is condensed with a primary amine, the radical of which is a radical al.ipnaiJe, arylaliphatiJe4 aryloX} Taliphatic or aliphatic 'hy <3roxylé ,, cose d4ìni p = -ecedemma; t; the compound is reduced and the compound of formula I is isolated.



   The reactive derivative of a cetane used in this process is a derivative of formula (IV);
 EMI4.3
 
 EMI4.4
 where Y is an atona 2s''rLs such '7.i-w'. vs. ° ', a; ¯ = x of chlorine, ue b = e-or- of ic5e or -a radical ûsR'- Ytx sē; ,, "Tj'i'sa.ß, F au -.F ,: 12 1¯1! :: Cîlv0; tt "'Q and R-' -! N nto:! T": lyj = çn3 "± ::: J; t: radical, 31: yl'3 inf- ......... Ji: #ii ato: r; d # h:; 3 = cqLn. * #adical àll; yl; inf- '3: 4 :: S-; lr ::: fZ "". i = iâ or #:;' ::; 0.



  The êé = 1; .é r8C é'rz = 3 9 ^: 'ß ¯ .... .î'., Is preferably: â? ^, 3a <à = 1-Yé - r & ant3 * è lZ2c &to; .1e and. dz # s this case, B is? an a'.uCi.'¯ cal methyl
The reaction of a reactive derivative of acetone with
 EMI4.5
 , ¯âL '' .. t - 2? s :: Y "é -P # a. forms ¯ '" ...' "9a d '¯i: # ¯ i â e.'.". s .. a ,. ¯¯ c, ..: $ ^ '. S', i -2-pr.:Ef3pne i reaction H dà = 1 # "é r = active from ear 3 '? E <: a 1 r 'AâSil ¯r.' Phenol 'fprma the 3,5 - :; ië r-Éin ^ - "a'? Se.



  It's reactions are. realized. a3ntageusernent in a solvent or diluent inert under the operating conditions used,
 EMI4.6
 for example calf, inffrieubs alcohols, such as n! c: t'hanctl.; \ l * <* t'ha # nol, isoproganol, or hydrocarbons, <onyxe 'benzene or toluene,.: or-. aliphatic ketones again, like acetone, - the

 <Desc / Clms Page number 5>

 methyl ethyl ketone.



   The molar ratio of 3,5-dialkoxyphenyl and of the reactive derivative of an aliphatic ketone is preferably chosen in the region of 1/1. The reaction is carried out at room temperature or at a temperature above room temperature, for example between 15 and 125 C.



   The reaction can be made faster or more complete by adding a basic compound to the reaction mixture. Basic compounds suitable for this purpose are, for example, hydroxides, alkoxides or carbonates of alkali or alkaline earth metals - when the solvent used is water, an alcohol or a ketone and alkali metals when the solvent -used is a hydrocarbon. The proportion of the basic compound used is between 50 and 200 moles per 100 moles of the phenol.



   The reaction mixture, after optional addition of water, is extracted with a solvent immiscible with water, for example an ether-oxide, an ester, a hydrocarbon or a halogenated derivative of a hydrocarbon.
 EMI5.1
 



  The solvent is vaporized and the.-G, 5-'ial.so:. = Pséno: j-2¯ prop3Done is separated by distillation, fractionated.



  The condensa-ic-i of 1- (3.5-ialko-eoxy) -2-popanones with a primary amine whose radical is an aliphatic, arr.aliphatic, arylo1aliphatic or aliphatic 1? YàoJ; yl radical, as defined previously, is represented by the relation:
 EMI5.2
 in which R2 and Z have the meanings already given .---
 EMI5.3
 This condensation is carried out advantageously -.> - nt, either in the absence of solvent, or in a solvent inert in the ccndi-

 <Desc / Clms Page number 6>

 operations, such as for example lower alcohols, such as methanol, ethanol, isopropanol, or a hydrocarbon such as petroleum benzine.



   The molar ratio of 1- (3,5-dialkoxyphenoxy) -2-propanone and of the primary amine is preferably chosen close to
1/1.



   The reaction is carried out at a temperature close to room temperature or above room temperature, for example between 0 and 125 C.



   The product formed and known as Schiff's base need not necessarily be isolated in all cases and the reaction mixture can be catalytically reduced.
The catalyst used for the reduction can be a prereduced precious metal salt, such as, for example, platinum oxide or palladium chloride: this catalyst can also be a less noble metal, for example nickel known under the name of. Raney nickel.



  The pressures at which reductions take place satisfactorily depend on the nature of the catalyst.



     Thus., In the presence of the aforementioned precious metals, the useful pressure is between and atmospheres, although in the presence of Raney nickel, the useful pressure is between 3 and 150 atmospheres.



   In all cases, the catalytic hydrogenation is carried out at temperatures near or above the ambient temperature, for example at temperatures between 20 and 150 C.



   After hydrogenation, the separated solution of the catalyst is preferably vaporized in vacuo and the product of general formula II is obtained in the residue.



   Alternatively, the compounds of general formate I, in which R1 is a hydrogen atom, can be obtained by oxy-

 <Desc / Clms Page number 7>

 
 EMI7.1
 Periodic dation of 1- (3,5-dialkoxyphenoxyJ-2,3-dihydroxypropanes> the aldehyde obtained is treated without further purification with a primary amine, as described previously, for 1e> -1 / <à3,5-oeii4lkoyyphenoxy) - 2-propanones.



   The oxidation reaction is advantageously carried out in a dilute solution of sulfuric acid saturated in --1- (3,5-
 EMI7.2
 dialkoxyphenoxy) -2,3-dihydroxypropane The oxidizing agent is a period of sodium or potassium. The molar ratio between the oxidizing agent and the diol is preferably chosen to be close to 1/1.



   The reaction is carried out at a temperature close to or lower than room temperature, for example between -5 and -40 C
The reaction product is extracted from the aqueous phase.
 EMI7.3
 with the aid of a suitable solvent which is not suitable for water, for example, cools diethyl ether or benzene. The extraction solvent after vaporization, preferably in a vacuum, leaves the aldehyde as residue, which can be reacted as such with an amine
 EMI7.4
 primary as previously described for 1- (3,5-dîaDioxypr.éno}} - 2-propanones, and the Schiff bases cM-smes can be made to the axis la Eaniârs described.? r '<2c: c ! a'ent ..



  The solution containing 1 <= product of 13 r.fe'tioa is separated from the catalyst and is' sporised to prefer: this in the vice: the product of general formula I is contained in the xesidu In-variant, the compounds of general forsRiIe I , in which R1 is a tnethyl group and R 2 and R3 are all <2euT: α-hydrogen atoms, can be prepared by reduction of 1- (3,5-dial.oxvphenoxy) -2-propanonoxiBes to ia3-ie 1 'h; .dmre àoe lithium alamipi; 1n in the presence of a solv-nt oa'un. A suitable diluent, generally inert under the opqzfltiirresptilized conditions, for example ethers- {saturated cyclic or acyclic oxides, such as etheir # diethyliqae, tetrathydrofuraïaate.



   The reducing agent is taken in excess of the equivalence of the oxime. The reaction is carried out at a temperature

 <Desc / Clms Page number 8>

 ture between 0 and 70 C. The reaction mixture is then treated so as to destroy the excess of reducing agent and to release 1 $ amine of general formula I which is isolated by extraction with a
 EMI8.1
 solvent immiscible with water, cosase for example an eth, r = oxide.

   an ester, a hydrocarbon, a halogen derivative of a hydrocarbon, and by vaporization of this solvent preferably in a vacuum-
Compounds of general formula I in which R1 'R2 and R3 are all hydrogen atoms can be prepared by reacting a reactive derivative of acetonitrile with a 3,5-
 EMI8.2
 ., '3a.Tc benfs'f 1-th nitrile obtained is reduced to an amine and the compound of general formula 1 is isolated.
 EMI8.3
 



  The reactive derivative of aeetonitrile used in this process is preferably a halogenated derivative, such as, for example, chloroacetonitrile, bromoacetonitrile, iodoacetonitrile. The reaction of the reactive derivative of acetonitrile with a 3t 5 c: .. a'oxy¯ phenol forms a 3.5-dialkoxyphenoxyacetonitrile. This reaction is advantageously carried out in a solvent or diluent which is inert under the operating conditions used, for example. water. Sal-
 EMI8.4
 lower cools such as tethanol, ethanol, isopropanol, or hydrocarbons such as benzene or toluene, or aliphatic ketones such as acetone, methyl ethyl ketone.
 EMI8.5
 



  The molar ratio of 3,5-dialkc, xyphenol and of the reactive derivative of acetonitrile is preferably chosen in the region of 1/1.



   The reaction is carried out at a temperature near or above room temperature, for example a temperature between 15 and 125 C.
 EMI8.6
 The reaction is faster or more characterized by adding a basic compound to the reaction mixture. Basic compounds suitable for this purpose are, for example, alkali metal hydroxides, alkoxides or carbonates or
 EMI8.7
 alcal.no terror The proportion used for the basic compound is cor-
 EMI8.8
 r-, ortian used to comprise between 50 and 200 moles per 100 moles of the phenol.

   The 3,5-di-

 <Desc / Clms Page number 9>

 Alkoxyphenoxyacetonitriles are isolated, for example, by extraction with a solvent immiscible with water, such as, for example, an ether-oxide, an ester, a hydrocarbon, a halogen derivative of a hydrocarbon and by vaporization of this solvent. The residue is distilled off in vacuo and the 3,5-dialkoxyphenoxyacetonitriles are obtained which crystallize.



   They can be further purified by crystallization from suitable solvents. such as lower alcohols such as methanol, ethanol, isopropanol or their mixtures with water.



   3,5-Dialkoxyphenoxyacetonitriles can be catalytically reduced. The catalyst used is for example the nickel known under the mon de nockel of Raney. The solvent used for this catalytic reduction is advantageously a solvent which reacts with the primary amine formed, as it is formed, such as, for example, acid anhydrides, such as acetic anhydride, propionic anhydride. The useful pressure to carry out the operation is between 1 and 50 atmospheres and the temperature is close to or higher than ambient temperature, for example a temperature between 15 and 150 C.



   The solution containing the acylated product of the reduction * that is to say an acylated 3,5-dialkoxyphenoxyethylamine. is separated from the catalyst by filtration, the excess acid anhydride is hydrolyzed and the acylated 3,5-dialkoxyphenoxyethylamine is separated by extraction with a water-immiscible solvent, as by example an ether-oxide, an ester, a hydrocarbon, a -halo- and hindered derivative of a hydrocarbon, / by vaporization of this solvent.



   The residue is subjected to hydrolysis, preferably hydrolysis. acid, for example by heating under reflux an aqueous solution of a strong mineral acid, such as sulfuric acid, hydrochloric acid.



   The product of general formula I is isolated by bringing the pH of the reaction mixture of the hydrolysis to a pH greater than 8 by adding an aqueous solution of an alkali hydroxide, then by extracting with a solvent immiscible in l. 'water, like an ether-oxide,

 <Desc / Clms Page number 10>

   an ester, a hydrocarbon or a halogenated derivative of a hydrocarbon, vaporizing this solvent and distilling the residue in vacuo.



   Alternatively, the 3,5-dialkoxyphenoxyacetronitriles can also be reduced with lithium aluminum hydride in the presence of a suitable solvent or diluent generally inert in the compounds. operating conditions used, for example acyclic and cyclic ethers-oxides, such as diethyl ether, tetrahydrofuran. The reducing agent is taken in excess of ---- compared to the nitrile equivalence.



   The reaction is carried out at a temperature between 0 and 70 C. The reaction mixture is then treated so as to destroy the excess of reducing agent and to release the amine of the general formula. I which is isolated in the manner described above.



   The products of general formula I according to the invention can be purified by a suitable method, such as fractional distillation, optionally in vacuum, crystallization, countercurrent distribution, absorption.



   The salts of the compounds of general formula I can be obtained from the corresponding free bases by treating a solution of this base in a suitable solvent, for example: an ether-oxide such as diethyl ether; a lower alcohol such as methanol, ethanol, isopropanol; an aliphatic nitrile such as acetonitrile; the water; or mixtures thereof, by a solution of an acid in a suitable solvent. The desired salt is isolated by filtration, decantation or evaporation of the reaction medium.



   The compounds in accordance with the invention and their salts can contain one or more asymmetric centers. In the course of their preparations, a mixture of stereoisomers is obtained, which can be separated into separate racemic mixtures. Each racemic mixture can be resolved into two optically active isomeric compounds, also in accordance with the invention, by applying the methods commonly used for this purpose.



   The compounds of general formula I and their salts are

 <Desc / Clms Page number 11>

 , interesting by their pharmacodynamic properties. According to the invention, it has been shown that some of these derivatives enjoy significant antispasmodic and spasmolytic properties of the anticholinergic and musculotropic type.



   A subject of the present invention is also pharmaceutical compositions which contain as active constituents one or more compounds of general formula I, alone or with other active substances, in admixture with a suitable pharmaceutically acceptable vehicle.



   These compositions can be solid compositions, such as bare or coated tablets, cachets, capsules, dispersible powders. or suppositories, or liquid compositions for oral use or for use by injection.



   Solid compositions for oral use can be prepared by mixing one or more compounds according to the invention, for example with milk sugar, powdered sugar, starch, talc. Compositions for anal use may be prepared by incorporating one or more compounds according to the invention, for example in cocoa butter or another suitable vehicle, such as derivatives of mono-, di- and triglycerides of saturated fatty acids.



   Liquid compositions for oral use can be prepared, for example, by dissolving one or more compounds in accordance with the invention and in addition a stabilizing or anti-oxidant substance, such as, for example, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate in distilled water, or distilled water with the addition of ethanol, glycerin, flavored syrups, liquid compositions for use by injection can be prepared by dissolving one or more compounds in accordance with to the invention in 1-distilled water, optionally in the presence of a stabilizing or antioxidant agent, and optionally of another hydroxylated liquid, for example glycerin or pharmaceutically acceptable glycols.

 <Desc / Clms Page number 12>

 



   The present invention is further illustrated, but not limited by the following preparation examples, in which parts are parts by weight.



   Examples 1-10 provide for the use of the process in which a reagent of an aliphatic ketone is reacted with
 EMI12.1
 3. 5-diarxoiryphenol (ruz = lower alkyl in formula II. Examples 1 and 2 relate more particularly to the preparation of starting propanones. EXAMPLE 1
 EMI12.2
 1- 3 5-imethoxJ heno -2-rovanone 61.6 parts of 3,5-imétiao ;; yphenol, 12.8 parts of anhydrous potassium carbonate and 30 part of acetone are brought to reflux and are added over eight hours, alternately and by
 EMI12.3
 dez 'J; a: tités cited? S6- of a solution of 37.3 parts of,' c:.?!: '. r: c'; tcne to ;;:;.: '1s 30 parts of' acetone- ec. of 102 parts of carbon in ar7riyere.

   The reflux: is still maintained 15 hours, 15 .s'3lc'tion ect! * Acetone is vaporized. The residue of evaporating i '? R! taken up by 150 parts of - ,: enzène est la = é à 'l'eau-, sediê'e't 1- lJe:; z * ia # esf r> .spo = .isé¯ The rézi <u scuz reduced pressure : ± #., Im> 1-0> - :: - 3p - ;: j ± 7'r} ':': 1 '? "": "?: -:' :; (: 'J7j -2- f.;: p3 :::: S -: e # u ## = start of #? ô-; ds; La '' 4o.ri = t is sc? 2e la io ## = lig7l4âe incolcre.



  -P? Int debJi3ition; 165'-153 "under fan Hg Melting point, t;: 197-198" 'C Melting paint: 172-173 C EXEMP @ E2
 EMI12.4
 1-é3 ì-dié? HvJrTw = hénoJii)) - 2-o = 'opanone L, 1-! 3,5-diétnoxypbénoJ'Y) -2-propanone is obtained by the process described in example no 1, with a 76% yield of the theory and is in colorless crystalline form after cisO - / - tallization with petroleum benzine.
 EMI12.5
 - Boiling point: 175-1800 under 5 tam Ho

 <Desc / Clms Page number 13>

 - Melting point 47-48 C
 EMI13.1
 - 2.4-diniErophenµlhydrazone, melting point: 182-183 "C - Semicarbazone, Melting point:

   155-157 C EXAMPLE 3
 EMI13.2
 3- 3 5-Dftetho-aerao -2-iso ro I-aina rooane hydrochloride 21 parts of 3- (3, 5-dimethoxyphé? Oxyj-2-propane) and 6.5 parts of 2-aminopropane dissolved in 220 parts of 'Ethanol are added-1 part of the catalyst 10% palladium on adsorbent carbon and hydrogenated at 48 C at atmospheric pressure.



  The amount of hydrogen absorbed is 92% of theory after 9 hours.



   The catalyst is filtered off, the alcohol is evaporated off in vacuo and the residue is taken up in 200 parts of isopropanol and acidified with excess anhydrous hydrogen chloride.



  The precipitate formed is filtered off and crystallized with isopropanol. The
 EMI13.3
 1- (3,5-Dimethoxy-phenoxy) -2-isoprnpyiaminapropane hydrochloride is thus obtained in a yield of 66% of theory and is in the form of colorless crystals. - Melting point: 140-141 VS
 EMI13.4
 - D53? perchicricue in anhydrous acetic acid calculated for C'l 4,289.8; found: 292.1 Determination of total nitrogen, calculated: -4.801%; - troà # é: 4. Î6
Following the procedure of Example 3 above, the following products were also prepared:
 EMI13.5
 1- (3,5-dimethoxvzhén =) - 2-metb - ,,, Ia-.iinopropane hydrochloride - Melting point: 124 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI13.6
 C12HoNCIC3, po: molecular ids ce 261; 8; found: 263.9 Determination of total nitrogen calculated: s 5.3;

   found: 5.32% 'h'hâarh dra de L- 3 --d.tht' hezo --eth 3aninc ro ane Melting point: 136-137 C - Perchloric content in anhydrous acetic acid, calculated for

 <Desc / Clms Page number 14>

 
 EMI14.1
 C13D22D3C1, Molecular Weight: 275.8; found s'?: r, 5 - Determination of total nitrogen, calculated: 5.08%; Found: 5.07% 1- (3,5-Dimethoxyphenoxy) -2-n-propvlaminopropane hydrochloride.



  - Melting point: 135-136 C - Perchloric dosage in anhydrous acetic acid, calculated for C14H24O3Ncl molecular weight 289.8; found: 289.2 - Determination of total nitrogen, calculated: 4.80%; found: 4.76%
 EMI14.2
 (3,5-dinrethoxvnhenoxy) -2-n-bt; tylaaninorropane hydrochloride - Melting point: 91-92 C - Perchloric content in anhydrous acetic acid, calculated for C15H26O3NCl. molecular weight: 303.8; found: 308.3 - Determination of total nitrogen, calculated: 4.61%; found 4.56%
 EMI14.3
 1 - (3,5-Dimethoxyphenoxy) -2- (1, 4-dimethylpentylamine) - propane hydrochloride Melting point: 160-161 C
Perchloric content in anhydrous acetic acid, calculated for
C18H32C3Ncl. molecular weight: 345.9;

   found: 351.4
Total nitrogen determination, calculated: 4.05%, found 3.99%
 EMI14.4
 1- {3,5-dimethoxc¯yphenox hydrochloride,) - 2- (1-meth = iexyiam-inoj- :: rç.nc: 2e - Melting point: 125-127 C ¯ - Perchloric determination in acid anhydrous acetic, calculated-for
 EMI14.5
 Molecular Weight C18H3203NCl -.- 345, -9; found: 349.0 - Determination of total nitrogen, calculated: 4.05%; found: 4.01% 1- (3, S-dimethoxypâenoxy) -2-c-cl ohe hydrochloride: vlatinoroane - Melting point: 174-175 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI14.6
 C17H2S03NC1. molecular weight 329.9; found: 328.9 - Determination of total nitrogen, calculated: 4.24%; find :

   9., 2L96

 <Desc / Clms Page number 15>

 EXAMPLE 4
 EMI15.1
 I-3,5-d? methaxYphenoxy) -2-isobutylaminopropane hydrochloride 42 parts of 1- (3,5-diaethoxyphenoxyj-2-propanonēet.



  15.8 parts of 1-amino-2-methylprapane dissolved in 500 parts of ethanol are added 1.5 parts of the catalyst with 10% palladium on adsorbent carbon and hydrogenated at 45 ° C. at atmospheric pressure. The theoretical amount of hydrogen is absorbed in 3.5 hours.



   The catalyst is filtered off, the alcohol is vaporized in vacuo and the residue is distilled off at reduced pressure.
 EMI15.2
 



  1- (3,5-imimethoxyphenoxxy) -2-sobutylaminopropane is obtained with a yield of 72% of theory and is in the form of an almost colorless liquid with a boiling point of 174 C at 1 mm Hg.



     -a solution of 15 parts of the previous base, in
 EMI15.3
 75 diethyl esdxsther is acidified with anhydrous hydrogen chloride. The precipitate formed, recrystallized from isopropanol, gives the hydrochloride of 3-, d3; ethoxt'Izénvxyj-2-iso'utylaminc-propane with a yield of 79% of theory and which is in the form of colorless crystals.



  - Melting point: 116-117 C - Perchloric dosage in anhydrous acetic acid, calculated for C15H26O3NC1. molecular weight: 303.8; found: 300.5
Determination of total nitrogen, calculated: 4.61% Found: 4.59% By the method of this example 4, the following product was also prepared:
 EMI15.4
 -1 {3t5-imethoxvphenoxv) -7-isopentylaminopropane hydrochloride - Melting point 101-102 C.



  - Perchloric content in acetic-anhydrous acid, calculated for
 EMI15.5
 C162 $ C3i'Cl, molecular weight: '31? d) found: 315.9 - Determination of total nitrogen, calculated: 3.47%; found: 4.39%

 <Desc / Clms Page number 16>

   'EXAMPLE 5
 EMI16.1
 Chlornvdrstte de '.-3 5-dïéthi fieéeo -2-:

   wvtar = '¯no ro ane 20 parts of l # (3.5 # di! aethcxyphenoxy} # 2 # propanone and 10.5 parts of l-aminonexane dissolved in 70 parts, of cyclohexane -is -is to reflux and l The water liberated is separated by distillation c3Z'dï.,. 'ispi3 The quantity # heori <pe c * water being removed, the solvent is evaporated and the resÍ9u is taken up in 200 parts of ethanol and adâitÍ0-TIé Soel- xart of the catalyst ¯ 1ì% palladium on ad5crbant carbon. The solution is hydrogenated at 45 C at atmospheric pressure- -pi = é # 1.qçēand the theoretical amount at. "hydrogen is absorbed in 4.5 ' hours.



   The catalyst is separated by filtration, the alcohol is
 EMI16.2
 and the residue is taken up in 25 parts of isopropariol and - 200 parts of e'e2iex: ¯and¯BC'idified with anhydrous hydrogen chloride. The precipitate formed is crystallized from isopropanol and the hydrochloride of 1- (3,5-imethoxx? HenoX1 ') - 2-n-heJlaminopropane is obtained with a yield of 61% of theory and is in the form of crystals. colorless.



  -   Fusion point. 90-92 - Perchloric content in anhydrous acetic acid calculated for
 EMI16.3
 .113Cf33C1, molecular weight: 331.9; found - 334.4 - Assay bilges 3 total nitrogen, calculated 4.22%; found: 4.19% EXAMPLE 6
 EMI16.4
 1- (3,5-imétnoxvohenoXY) -2-S-phenethylaminopropane chlorhvàrate 42 parts of 1- (3,5-dimethoxyphenoxy) -2-pr panone and 25 parts of 1-amino-2-phenylethane in solution in 450 parts 3 parts of the catalyst containing 10% palladium on adsorbent carbon are added to ethanol and hydrogenated at 45 ° C. at atmospheric pressure. The theoretical amount of hydrogen is absorbed in 9.5 hours.



   The catalyst is filtered off, the alcohol is va-
 EMI16.5
 porise and the residue is taken up in 75 parts of isopropanol and 400 parts of diethyl ether. and acidified with hydrogen chloride

 <Desc / Clms Page number 17>

 
 EMI17.1
 anhydrous. The precipitate formed is crystallized in l2isopr "'panol-and T-3.5-dir: éthtxygaêno) 2-phencthylatsrinogropane hydrochloride is obtained with a yield of 39% of theory and is in the form of colorless crystals. Melting point: 105-106 C
 EMI17.2
 - Determination per caloric iia.ns 1 "acidfLa.cétique- an..1-} ydre calculated for C3.328C3C ', molecular weight: 351.9: found: 350.3 - Determination of total nitrogen, calculated 3.98 %' find :

     3.98% EXAMPLE 7
 EMI17.3
 1-3,5-d.aetho.-yp hydrochloride: éxoxyj-2 - s-methōahénéaT- - 1 amino> opane -I- 3. S-dinethoTphPnoxy hydrochloride) -2- -mêtho- phenethylaminopropane is obtained by the process described in Example 6, with a yield of 53% of theory and is in the form of
 EMI17.4
 colorless crystals after crystallization from ilacetonitrile.



  - Melting point: 118-119 - Perchloric content in anhydrous acetic acid calculated for ------
 EMI17.5
 e20D28C4àC. , molecular weight: 381.9: found: 378.5 - Calculated total nitrogen content: 3.66% found 3.64%
By the process of these Examples 6 and 7, the following products were also prepared:
 EMI17.6
 1- (3.5-di aetho hydrochloride. ^ '' ¯enoxy j -2- $ 3. -d = aethok-yphézaéty3amino) # propanē¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ - Asicirr point ¯? ô2-Ta2, .S C - Perchloric assay in anhydrous acetic acid, calculated for C203O0 s -XCI, molecular weight: = 41i.9; found 409.5 - Determination of total nitrogen, calculated c 3, .C-:

   found 3.38% T .- (3, Sd = nethox .-, ppheno: -yj-2- (i-methyl-2 phenethyl amino) -propane hydrochloride "- -. --- - Melting point: 129-130 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI17.7
 CZOH2803NCl, molecular weight 365.9? found = 362.3
Determination of total nitrogen, calculated 3.83% found 3.82%

 <Desc / Clms Page number 18>

   EXAMPLE 8 -
 EMI18.1
 É- (3,5-Dimethoxyphenoxy) -2- (1-methyl-2-phenoxyethyl) - :: 1nopropane hydrochloride, 10.5 parts 1- (3,5-dimethoxyphenoxy) -2-propanone and 8 parts of 1-methyl-2-phenoxyethylamine are dissolved in 105 parts of ethanol and added to 0.5 part of the catalyst 10% palladium on carbon adsorbent. The solution is hydrogenated
 EMI18.2
 at 40 C at atmospheric pressure.

   The amount of hydrogen absorbed in 17 hours is 79% of theory.



   The catalyst is filtered off and the alcohol is vaporized in a vacuum. The residue is taken up in 350 parts of ether
 EMI18.3
 diethyliqc-e- and acidified with anhydrous hydrogen chloride. The pre- - =. Pité formed is crystallized in water and the hydrochloride of 1- (3,5diméthoÀypheno -y} -2- (I-methyl-2-phenoxyethyl) aminopropane is obtained with a yield of 25% of theory and occurs as colorless crystals.



  - Melting point: 145-146 - Perchloric content in anhydrous acetic acid calculated for C20H28O4NC1. molecular weight: 381.9; found 378.2.



   Determination of total nitrogen, calculated; 3.67%: found 3.63%
By the process of this example 8, the following products were also prepared:
 EMI18.4
 1 # slorhvàraÊe de .- (325-diaêhx5.hêac -,) - 2 - zïaéro% et: ciaeiaooro'Pane - Melting point: 120-121 C - Perchloric dosage in anhydrous acetic acid, calculated for
 EMI18.5
 C - H 3, 0, NC 1, molecular weight: 367.9; found: 364.7 - Determination of total nitrogen, calculated = 3.81%; found: 3.81% 1- (3,5-Dimethoxyphenoxy) -2- (3-phenoxypropylamino) hydrochloride romane .... ¯¯¯¯¯¯¯¯¯¯¯¯ ...



   Melting point: 125-126 C - Perchloric dosage in anhydrous acetic acid, calculated for C20H28O4NC1. molecular weight = 381.9; found: 382.5 - Determination of total nitrogen, calculated 3.67% Found: 3.69%

 <Desc / Clms Page number 19>

 
 EMI19.1
 --3f5-s¯étraoxyp.ëzoxi) --- 3-o-methoxhenox - ëth Ia.no ^ csane hydrochloride - Melting point: 78-79 C Perchloric strength in anhydrous acetic acid, calculated for
 EMI19.2
 CoH2805NCl.

   H20. molecular weight 415.9; found 418.1 - - Total assote, calculated: 3.37%; found 3.36% '1-3, -d3ei-hox-y': aenoxy) -2-3-a-riethoxxypaeroxyëthyi hydrochloride = -3; !! '. i: 10DrOpane - Melting point: 114-115 C - Perchloric content in anhydrous acetic acid, calculated for C20H28O5NC1 molecular weight: 397.9: found: 397.0
 EMI19.3
 - Determination of total nitrogen, calculated: x 3.52; found: J3, E7 :. ¯ -. ¯¯¯.¯ ..



  Hydrochloride of .- 3, S-direth-zzhéracay) -2 - # - p-méthoa-ypaénoËt? NylaT; i L3 ogla? 3e - ¯ - Foint of ¯fusion: 109-110 C - Perchloric dosage in acetic acid anhydrous, calculated for
 EMI19.4
 C20H2805NCl. molecular weight: 397.9; found 393.0 - Determination of total nitrogen, calculated 3.52Y .; found: 3.53% Hydrochloride- de -3, 5-c.;. ethoxpheaoxyj -2- (3, 5-dir! ethoxyphenox gr- eth> + lamino) -propane - Melting point 107-108 C - Assay Perchloric in anhydrous acetic acid, calculated for C21H30O6NCl. molecular weight: = 427.9; proven: 423.9
 EMI19.5
 - Determination of total nitrogen, calculated: 3.27? find'-:

   3., 22 ¯¯¯ Hydrochloride of I- 3, 5-cîiet? Oxy¯ hénoxy) -2- il-ethyl-2 p-aaefhyl- -propane - Melting point: 151-152 C - Perchloric content in the anhydrous acetic acid, calculated for
 EMI19.6
 C213ûC4C1 molecular weight: 395.9? found 392.9 - Determination of total nitrogen, calculated 3.54%: found: 3.55% 1- (3,5- dimC-thoxyphenoxy) -2- (1-methyl-2-p-methox hydrochloride ¯v phenoxxqethvlamino) -propane - Du point, ion 135-136 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI19.7
 C21 $ 30C5'TCl molecular weight = - 411.9;

   find :. 408.9 - '-Dose-of total nitrogen, calculated: 3.40%: found: 3.43%

 <Desc / Clms Page number 20>

 
 EMI20.1
 Hydrochloride dc t3i- i- 3 5¯dimet3zo 'enox -2-meth Ieth 1 amin 1
Fission point: 185-186 C - Perchloric content in anhydrous acetic acid, calculated for C22H32O6NC1. molecular weight: 442.0: found: 439.2 - Determination of total nitrogen, calculated: 3.17%; find :

     3.15%
 EMI20.2
 .-3,5-Imêt'csirghéd. Hydrochloride, it} - f3- (3,5 dimetoxypénoxyjra Iasr.ine nrcoane - Melting point: 145-146 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI20.3
 C2232'Ci '' molecular weight: 442, t3; found 443.0
Determination of total nitrogen, calculated: 3.17%: found: 3.15% EXAMPLE 9
 EMI20.4
 Chlc'rhydrste ': e 1- ē.to>: é.ycr ¯-i-egth.lhe:.: Ylamino) -propane parts 1- {3,5-dié.o :: 7Pheoyl) -2 {propar .one parts l - (3,5-diôto'r: yphêr-C!: -: yl) -2 - (DEOp3none 19 parts of 2-minoe? tae are easily solved in 350 parts t .d * "H : .1! Anol. L \ .p:,: i2: .. addition 'Se 2 parts dJ: palladium catalyst law ± on char%.>; E..adrt3¯..tae .., the solution is hydrogenated to the taken-
 EMI20.5
 b. sioa m: ay- .b i2, ':.' sb, at 4S '=' C.

   The quantity .. "'.."' ... r "t" t3 of hydrogen is absorbed ea 11 E '' '. ^' ,.



  % 3 .ÂW '-: va' '. 3r is 31p2j p3r Eiltrstion and the solution' Fi, t ... ¯'¯ .... "¯ ¯ ... û <11. ±% J3 -: ti ; 7: .2 ràsà ± 1 QSk '71J àI ,, ::: rl: z -: {) n C72 :: 1Z 11 {t: - ::: '55!';.? 7.::13. :: :: t = .'-. $ ..-: '. plr 1' :: l ::::: -: 2C: ai ::.:?: J.; 3: '"l' .; : sec, Ls precipitate .... "s is crystallized 3 3.'as * st. le = 10r7drate ès 1- (3,5L ',' 3 ::. '" .-' .. L ' û3âT '"; é.unyr'n's'é :: i ..' Y¯? '..-- p ^.'" "^ pe": -: dF'CI as d - ,, :: ri ;: rt7.1x i;: co-1Dreg 3 :.] "#m '' a ^ ï'7.-r3 .... w of 13% of theory, # P.oiT: t d9 fasion: 9 -91 #. * I: nt fufi - = at 93-9i D? SLgft h sF'Sû.T ". ±: -.:1;ns 1 + acjd = anhydrous acetic calculate for i.7J $ xJVm3¯s "= oiiàa W: .L¯4.T ', ¯ à74, bone found 376.3
Determination of total nitrogen calculated: 3.74% ?. found: '3.71%
By this same process, the following product was prepared:

   
 EMI20.6
 hydrochloride ¯de .- 3 -dieto 'eox 2-n-'ha.lamitorQOan melting point: 100-101 C

 <Desc / Clms Page number 21>

 - Perchloric content in anhydrous acetic acid, calculated for
 EMI21.1
 C19H3403KC "1, molecular weight 359.9" Found:

   358.3 -Dose of total nitrogen, calculated: 3.89% found 3.89% EXAMPLE 10
 EMI21.2
 '1-t, 3,5-dim. Et'Eaoxyphenoxy} -2- 3.gdroxy-ethlrlamnopropane hydrochloride -
6.1 parts of ethanolamine and 21 parts of 1- (3.5-
 EMI21.3
 dixnciiiacra: ëuo, .-, .- 2 propaone in solution in 17 parts of ethanol are added to 0.05 part of pre-reduced platinum oxide in 7 parts of ethanol and are hydrogenated at atmospheric pressure at 21 ° C. theoretical quantity of hydrogen is absorbed in 12 hours,
The gold catalysis is separated by filtration and the solution
 EMI21.4
 Ethanoligue is added with 250 parts of ether and is acidified with anhydrous hydrogen chloride.

   The precipitate is crystallized from isoprJpanol, then from acetotile and ¯ "Ig 5-. '--C., F.:'sZG3:i, -'ili'., E.'Re :: hydrochloride. ïfs.ro? ne is o'bt 3n.'a with a '':. '. ^ sa of 21% of 1a-theo = ie and appears as colorless crystals-
 EMI21.5
 Melting point: I 3 ..'-. i. ' -Dosage;:;:; e :: - of 1! Or: ic in 1. anhydrous aceti-g-ae acid, calculated for C "C: J", - "- ,,," '1 cois? molecular: 291 8 *. :: '. "¯% .i" r. t 29-4 2 1 -: {J1 - ') -') vJ!. "-" "" '' "'"' "'..t; -' ¯.J .. - .... : .v ....... ¯ '! ..:. .J; f., .. 7g -¯i..J - "' -" ",: r -. t. -r - sa-5 i.2.;. it 2zc :: .. e tOt37, c5 .. 'Lc; l'i :: 41: 2G ::';

    -rs''3: 4,791b Next, the operative sose described in is e ::: eüple To, ',: .. a. prepared the above 4 '.. T, .¯'C'Yt Hydrochloride of, -3e: cYL.'. ïiJénig,) - 2- ^ f-âfydrox ... 'TssOû ".:' la.? '.' 3o- propane
Melting point: 135-136 C
 EMI21.6
 -¯Dcs9qe perchloric acid in anhydrous acetic acid., Calculated for .. ".ç ... s e3'â ... a, -.... '; :: 1s iEi3" e,': v '305 , 3? find : . 300 "" 7.



  14D 24 '"' 4 -'' -'''- ..; ......... 1.U .. J -" "... -" - 305.3; - 306.7 '- Determination of total nitrogen, calculated: 4.58%; found: 4.59%
The following Examples 11 to 13 relate to the preparation
 EMI21.7
 ration of! lou.veaux composas '%' ,,>., - hydrogen) by the periodic oxidation of ï - f 3, 5-diaiscirlovpércy} -2, 3-di'.dxo: ypropanes, with then

 <Desc / Clms Page number 22>

 
 EMI22.1
 treatment of the aldehyde obtained with an amine, Example 11 relating to the preparation of the aldehyde under management.



  EXAMPLE II
 EMI22.2
 3 5-dîmethoxv hénoxvacétaldehyde 45.6 parts of 1- f 3, 5-di é ho.-rp'¯: enoxy) -2, ¯3-3ihv3roxypropane are dissolved in 1500 parts of water and 4 parts of concentrated sulfuric acid, 35 parts potassium perio3ate
 EMI22.3
 are added with stirring studies their complete dissolution, the
 EMI22.4
 aqueous solution is extracted with 1 "diethyl ether. After washing the extracts with 1 * ea-a and drying, the ether is evaporated and left a colorless liquid of 34 parts of. = vrs per. :: r¯ crude acetaldehyde.



  - '; r¯. = eheni., 7zraxre PF: 173-175QC 5eicarDazone PF: 139-140oC ± .LE 12 1- (3,5-diethoxphéo) hydrochloride) - 2- (1,4-dimethylpentyla! alno ) # êtTianē¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ " > 16-, 5 part <3e s ''. 2Cz: 'É''¯e'c.TC7Ctu-' t32''e.ßiCl2 in solution in 125 parts G eth * n.J1 are added 9.7 parts this t "'' 1: -: - E ::: here? gz.ri and 085 part of catalyst an palladium at .10 sr carbon SCiTTGp Ite22le is hr0éné the pressure - .. ¯..ra ^: = ß: ... '"'", a. <k .. at 40 Ûn e't 7a quantity t1oriq ¯.â a â. "" <"w .: T? Ca was absorbed, n 2 'hours., The catalyst is separated by filtration, 1- * alcohol is vaporized in a vacuum and the residue is taken up in 300 parts of diethyl eter and is acidified with anhydrous hydrochloride.



  The precipitate: formed is crystallized from water and the chlornyarate of 1-3, .- dimet: xpé-1-2- (1,4-dimet "saw3, lpnt'aaino) -ethane is obtained with lln yield ¯ of -67% of the theory and is presented 'under
 EMI22.5
 colorless crystal form
 EMI22.6
 -Melting point: = r.2Î-3.9 C
 EMI22.7
 - Perchloric content in glacial acetic acid, calculated for-

 <Desc / Clms Page number 23>

 
 EMI23.1
 C17H30031S! Cl., Molecular Weight: 33i, 9: Found 329.8 -Dose of Total Nitrogen, Calculated: 1-, 22; 5: Found 4..20
Following the procedure described in this Example 12, the following products were also prepared:
 EMI23.2
 1- (3,5-Dîmethoxyphé; ozy) -2-methvlaminoethane Cblornvdrate - Melting point: 144 C - Perchloric content in 3 = anhydrous acetic acid, calculated for
 EMI23.3
 cll! '18'D3Cl- molecular weight: 247.7? find :

   245.4 - Determination of total nitrogen, calculation -; 57 ---: 5.65%; found: 5.55% - Boiling point of the base: 151-154 C under 1 mm Hg
 EMI23.4
 C? Sic ..- 1- (3.S-dimethoXVPhenoxy} -2-ethylaminoetnane hydrate - Melting point: 141-142 C - Perchloric dosage in anhydrous acetic acid, calculated for C12H20O3NC1, molecular weight: 261.8 ; found: 258.9
Total nitrogen determination, calculated: 5.35% / found: 5.26%
 EMI23.5
 - Base boiling point; 153-157 C at 1 mm Hg ī3> 5-? I hydrochloride: etTnoxv hêno) - sonv3anoethane - Melting point: 155-156 C - 3 ^, yvst ,? perchloric acid in anhydrous acetic acid, calculated for 1 ... j "" -. l? ¯v ¯ ..) ... ,, - 1 .LI .1: '"v -. Q. malpo'ia3F -e .... G 1 ::

   tro; 1 * ê: 275.8 - 1: = s # .j.a to <1 '> zxô = e 1 = ataT, cz: 1 == rlé; 5iT08; b == oni., é = 5, Qµµ1 n ¯ ¯¯s1z¯., ... r de -â F ^ Wc, ": 3Xs: i3-i ...? - 2-is, 'r? 3iikpminothd 's1 ±.' -¯ -Melt-fusion 119-120 C -Perchloric dosage in anhydrous acetic acid, calculated for
 EMI23.6
 C13H2203 2C'- Molecular weight: r 2'5.8: found 271.2 -Dosage of total nitrogen, calculated: 5.08%; found: 5.13% Ch? oh - ,: d = ate de .- 3 5 -?.: ét? ao hër, ov --2-: ¯huviamânoëcaane Point of szan. :: -x54 C ..



  Perchloric strength in anhydrous acetic acid, calculated for e1e2403-WI, oiectia.ar weight: 289r 8; found =: 285.9 - Determination of total nitrogen, calculated: e 4.830.1 .; found: 4.84%.

 <Desc / Clms Page number 24>

 
 EMI24.1
 1- (3, S-di;: etnoX "r.Jhênoxvl-2-isohu.tvlamînoêtbane hydrochloride Melting point: 131-132 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI24.2
 C14B2403NCl. molecular weight: 2E9, S; found 287.2% sg -total nitrogen, calculate 4.33%; found: 4.76% - Base boiling point: 168-1.720C. under 2 mm Hg 'i ..': 3 <: îi: ûra: e of 1- {3.5- diéthoÀvhénoXè} -2 - he> laminoethane- - 2àsion point 116-11aoC - Perchloric content in anhydrous acetic acid, calculated for
 EMI24.3
 C1H3O3za'Cl, molecular weight: 317.9; found 316.0 - Calculated total nitrogen content: 4.41%; find :

   4.37% i- 3.5--3 hydrochloride: téTh ocyp? .Énoa-y -2- (i-nêthyihexvlaaei.no j ¯ ethanē¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ - Melting point 56-58 C - Determination of perchloric acid in acetic acid anhydrous, calculate for
 EMI24.4
 C, H 0-NCl, molecular weight: 331.9; found: 335, - Determination of total nitrogen, calculated: 4.22%; found: 4.13% 1- (3,5-aiMetholphenoÀ /) - 2-cvclohexvlaminoethane hydrochloride - Melting point: 147-148 C - Perchloric content in anhydrous acetic acid, calculated for
 EMI24.5
 ï626D31, molecular weight: 315.8? find :

   3I, D - Determination of total nitrogen, calculated - 4.440 ,,.; found 4.38% EXAMPLE 13
 EMI24.6
 I- f 3 L5-d i tëthh éaaoscy-2¯¯y3'hénêt'hYlainoethane hydrochloride 15 parts of 3.5-di: netizoxyphenoxyacëtaidëhyde and 9.7 parts of P-phenethylamine are treated as indicated in Example 12. The hydrochloride of 1--3, 5 dimethoxyphenoxr -f = phene-thylaminoethane is obtained after crystallization from water in a yield of 38% of theory and is in the form of colorless crystals.



  - Melting point: 121-122 C - Perchloric dosage in anhydrous acetic acid calculated for C18M24O3NC1, molecular weight: 337.9; found 335.6

 <Desc / Clms Page number 25>

 
 EMI25.1
 - Determination of total nitrogen, calculated 4, Z5C :; found: .4, The following Example 14 relates to the preparation of a compound according to the invention. in the formula of which R., methyl and R2 = R3 = hydrogen, by reduction of an oxime.



  EXAMPLE 14 -
 EMI25.2
 Hydrochloride: e - (3 5-ciaeth.ex, Âéc -.- ré: .é 'laminated 18 parts of 2-- 3, 5-'iaaefTio = pheno: .- r --ropanoxirsr. In solution in 7 parts The diethyl ether is added at room temperature to a solution of 4.5 parts of lithium aluminum hydride (1% lithium aluminum). The reaction is completed by heating for 1 hour at reflux. The reaction mixture is worked up, the aluminum salts are dissolved in sodium hydroxide and the ethereal phases are decanted, 1 = 1 * ees, "" dried and evaporated. The residue is distilled under reduced pressure and the 2 - (3,5 ---- dimet'hoxyphenoxy # 1-methyletnylami.ne is collected at 155-1600c- under 1 mm Hg as a colorless liquid and is obtained with a yield of 61% of theory.



   5 parts of the previous base are dissolved
 EMI25.3
 in 1. ' sodium ether and acidified with anhydrous hydrogen chloride. The precipitate obtained is crystallized from isopropanol and 2-i3.5-dimëthoaé hydrochloride: o == mt-aylethyl? amine is obtained with a yield of 89% of theory and occurs in the form of colorless crystals.



  - Melting point: 203-204 C - - Perchloric content in glacial acetic acid calculated for
 EMI25.4
 1ID18o3C1, molecular weight: t 2.7 found z 249.4 --- Determination of total nitrogen cal; cu: 1e 5.65%; found s 5. 6t6 ¯ The following examples relate to new compounds
 EMI25.5
 calves, in the formula of which R = ft 2 = R3 hydrogen, by reacting a reactive derivative of a # t.onU: .rile with a 3,5-cïiaïlçoxy¯ phenol, Examples 15 and 17 se relating to the preparation of starting nitriles.

 <Desc / Clms Page number 26>

   EXAMPLE 15
 EMI26.1
 3.

   S-dïr, éLhâhénoxyaetcrnitriie 3 & parts of 3, -dieé.ho:,. Hârto. are easily dissolved in a suspension of 26 parts of potassium carbonate in 50 parts of methyl ethyl ketone. The mixture is brought to reflux and
 EMI26.2
 is added 13 parts of c7nlafoac --zrz -1 e- "'" "
The solvent is vaporized in a vacuum and the residue is taken up in water, and the chloroform - After washing and drying, the chlorofilm phases are evaporated and the residue is distilled in
 EMI26.3
 the void.

   3.5-d.méhoxyghéez¯a.céton.-riie is collected at 164-167 C under 3 m, m is Hg in liquid form which crystallizes on cooling. - Melting point: 48-49 C EXAMPLE 16
 EMI26.4
 3, 5-Dimethohenoxx ethyiarire hydrochloride 20 parts of 3, 5-disetâox'aéecsx "acé-ontri i e and 12 par- en
 EMI26.5
 The anhydrous sodium acetate is dissolved in 120 parts acetic anhydride and two teaspoons of Raney nickel are added. The mixture is hydrogenated under a pressure of 4 kg / cm2 at room temperature.



   The catalyst is separated by filtration, the acetic anhydride is hydrolyzed and the acetylated derivative of the amine is separated by
 EMI26.6
 extractions then hydrolysis in 2-m; '-4' hydrochloric acid only at reflux. The amine is extracted with diethyl ether after basifying the aqueous phase.



   The ethereal phase after washing and drying is evaporated, the
 EMI26.7
 The sid1 is distilled in a vacuum and the 3, 5-dât'hox.ghënoxyethyl amine is collected at 154-156 C under 3 mm Hg and is obtained with a yield of 64% of theory.



   2 parts of the distillation product are dissolved in diethyl ether and acidified with anhydrous hydrogen chloride, the precipitate obtained is crystallized from isopropanol

 <Desc / Clms Page number 27>

 
 EMI27.1
 and. -3.5-diéhohér.cxyéhiami.ne hydrochloride is obtained with a yield of 95% of theory and is in the form of colorless crystals.



  - Melting point 154-155 C
 EMI27.2
 -Dc; .5age perd'nlorique in glacial acetic acid, calculated for C1t3163 '"¯ molecular weight: 233.7; tronvê" =' 235.4 .. '### - ## - # EXAMPLE 17
 EMI27.3
 3û. etlao.-aéaox-vacétoni rs.Ie 72-parts of 3,5-diethoxyphenol, 52 parts of potassium carbonate and 65 parts of taethyl ethyl ketone are brought to reflux and added with 28-parts of acetositrile in solution in 25 parts of methyl ethyl cetane- -.-. # --- * # '' "" The reaction mixture is treated CC3a, iTE described in Example 15 and 3,5-diethoxyphenaxyacetonitrile is collected at 145-1500C under 0.5 mm of Hg with a yield of 6S% of theory and crystallizes on cooling.
Fusion point:

  40-41 C EXAMPLE 18
 EMI27.4
 - (3,5-diétTioxvp'hêncx? ethylsEtine hydrochloride 29 parts of 3,5-diëhoxyg'aé: oexyacéoairüe in solution in 70 parts of diethyl ether are added 10 parts of lithium aluminum hydride in solution in 175 parts diethyl ether, at room temperature, reflected for one hour. The reaction mixture is treated with water and sodium hydroxide, the ether phase is separated, washed, dried and acidified with acid. hydrochloric anhydrous.

   The precipitate obtained is crystallized.
 EMI27.5
 Se in isoprqpanol and -3.-d.iethoxhenaxyj ethylamine hydrochloride is obtained with a yield of 72% of theory and appears in the form of colorless crystals.



   Melting point: 154-155 C
Perchloric content in anhydrous acetic acid, calculated for
 EMI27.6
 12H2oC3 "Ci, molecular weight: z 261.7; found = 264.2
Determination of total nitrogen, calculated: = 5.35%, found: 5.33%.

 <Desc / Clms Page number 28>

 



   Although various embodiments and details of embodiments have been described to illustrate the invention, it goes without saying that the latter is obviously not limited to the details given as many variations and modifications can be envisaged.

 

Claims (1)

EMI29.1 CLAIMS EMI29.2 1. Substituted derivatives of 3, S-ars oxyhéüxßa ¯ amines corresponding to the general formula: EMI29.3 EMI29.4 in which: EMI29.5 'Z is a lower alkoxy radical; is a hydrogen shad or --- n radical - "11-; r1 EMI29.6 inferior; EMI29.7 are different sstituants 2 and Ra feels different ideic sustitnts chosen in the class:. '. :: = 3 ¯ ^ ¯a' t ¯'a '= "" rW a' the 2? Bdi # water alkyls branches or no, the radicals. ^? z'c .. 'a. "S branches or not Siîi' 'r, 3¯' z = 3 ''. 3: a: '., Jt G and S 3'vS é. ß. ''.: 5 had on the ring '-¯'f': 't2' the aryloxyalkyl radicals ratified or not on * the alkyl chain and SES.ß "-¯: âS .., s': not on the 1103? Al: 7-es.: =; Dic21! X les r * adi ': 3'x -: -:': '! ::: 71st ¯â!'. =. ¯ ..; e: 3:? S 2: ra: lc :: és ':; r :, cia les s'els of 3 these dri'j' #. 5 3 = .. 33 - ^,., ¯ ...:. : 5 .ie- 2Q '.â 395 S' .. W..ih: '3' 1-3 r? Iat0 1. car'sctBZ'isss zen what the radicals arkY! 5 'âè2': y'S:. . 'ss sr the r' ': .êi ¯: .f "., at substitutes ¯! .¯" 3.'. L43 S: 3: 'the kernel r: :) ti:;: e: t 50: Jt .... e.:,. E .. :: len (.. r "'2 and / or w33 are radicals of r-" i.,. Sß' ... 3. EMI29.8 EMI29.9 in which a and X are substituents .- '' 'e.3..ôS C3I ìi' '- ¯ .rents chosen from the class C;} :: âpreha.'1t l àt':; na:: I hydrogen, the <Desc / Clms Page number 30> EMI30.1 radicals aliz - 1-es lower .rT3C ^ = - -'Q- non., the radical 3nydroQx the alkoxy radicals 3'i P = '' tï..x'S Branches or not,? -4 is a hydrogen atom where -a radical mt; 1y.le, and n can have the value of -0 inc3.as-.ï.V # sest. EMI30.2 3. Derivatives according to claim 1, characterized EMI30.3 in that the aryloxysHyl radicals branches. ' not on the alkyl chain 'and substituted for the non on the 3cya' -îT. =: ¯ which may represent R2-ei / or-R3 'are radicals of the formula: EMI30.4 EMI30.5 in which .1 ", 3 and-n knew the meaning given in the r \ EMI30.6 claim EMI30.7 4. The drifts appearing --- 1 .-? I:! - iE: ::. ;;: ':' = ':: 1q ::; i resell ÍscDàres cptiqueent active. 5. Process for the substituted 3, 5-di :: llly lCj <1? HeTIyc; "3al, = rl =.: - :: = - es?." 1é? O :: '1dat 2. icrul's -arî5 :: ': ¯ ¯ is a? roup- = alyle, ts? idi.s -qus Z, R- y - 2 CO #' - (I "'17} in which Y represents a stoss t? T ' ¯ - "^ '3.:.' .. a radical ..¯ ': 2yi-3Sar; R'sjCia1 or F, --- t-7¯'î: Sai j;': '.: é st - re2sete at a lower slkyla radical: a'3.r? or not, with: a 3,5-dialkoxyphên.ol, Gele o'btsnu est '.: Q3ns3 with UTIS 3s:' s-tL ô.z'l? = M¯ ..Ti '..'- de ja7 forz = 1 e ;; IZ' "" '2 in which RZ represents an alkyl radical, a ...' "'c'3 = c, 2y i'" Ç.'ût3 ".. alkyl, cycloalkyl or alkyl: iydr-ox31-6, te3. Ue defiai, precedas # <Desc / Clms Page number 31> EMI31.1 nent for R2 'the costpose is then reduced and the compound of formula (I) is isolated. 5. Process for the preparation of substituted derivatives EMI31.2 r3E? "'w, - E: c" .L 3; ÀÉïFaXC'3Çi aiTeS corresponded to the formula .in which RI is an atone '¯ # ,: ae, while Z, R2 and R3 have the given meaning, characterized in that one SOUi "" 2 and the 1- (3, 5-diap'oxyphenoxy) -2,3-di.ydroxy.rcpanes uses periodic oxidation, Ta3 ', iE is treated. obtained with a primary amine of the formula R2-NH2 of claim ", the compound obtained is reduced, and the compound of formula CI) is isolated. 7. Preparation process: substituted drifts EMI31.3 G'.c.-V., '-. ï r.::ß rJ: ri; '?': 2 = é, f: "c ï,.-..- ¯.S of the formula I, in which- L" '- "" "1 - a to ..... '-i \ ;;;. - and t., ..: \. 2 1 ;; :: t ....... "' -'--. all - :::::; r,;,.; s .....: ... 1.-0 :; c 'û. g ç of hydrogen, characterized in that; 4 # 'on sc: .r: "" :. e reduction, the ¯¯ - 5- "A?. ^ G': r''Si = v: lW ^ : x'3 'irc using lithius and: .a.3i's.? in the presence of a suitable solvent or diluent, and isolating therefrom the compound of iormmia (I). 8. Preparation process for the substituted derivatives EMI31.4 3,5-dialkylox''pnénsxyalKylaEii.nes of the "" '. "'" n .. :: ¯ 3 T in lacue7le q¯, z and-R .; zo ,, àmus three 1+;? j ==, 1 ==, = characterized in ¯e - ..2 -., ';; / soz: .. u' "\" ....: .'- ..: .. 5 - -> <$ --'- ;;;, "" "-, ---; '1 -'---'--" "-' = '. Ce g5'îJ makes react a = éri7é G'.A ,. .ca I ±., ......: = t ...- 'g a. = d .. 3T ± ± -' a 3 2t 5- dia.lkrfP1: é: o1. -c gUi de li! r- -. :: z .- ::. i; '": l ::; t2 ... = ::.: .-;: -: ... ¯g ::; - ketanitril-2 which is reduced to an amine, and cn es-zie --c compound of the desired formula (I) .; 9. Process for the preparation of salts of derivatives EMI31.5 substituted with 3,5-dia7kj; la%> '@ né # oxjsalE yl * = d # = es of the formula (13-, characterized in that we treat this solution Za free base in l! 11 - solvan: t-- "with a solution '..:' x ¯ a" E -t '"3¯'¯1t i3 ..'-' .ç incr- ganic in a solvent- EMI31.6 10. Use of substituted derivatives of the 3,5-dial-- 'iey3, xta "yaî'a.nas ¯ era: R (formula CI) and their salts <Desc / Clms Page number 32> EMI32.1 title of products ': 3'. ''. û: dCBtW tS no1: a ::: r # ent as edicanets having i) I "i: l?" 1 ° Li "S: T1" .3ßLSie: L3..c7.iIS and S'zGSiuOTT "I.sa, EMI32.2 these derivatives or salts being used alone or in combination with EMI32.3 .. des C, 'iu ... ^. 5 cx: ri: ... des p = 5% = iélés similar or different- 11.'. "." v ^ t'.2. ^ f3 $ i. . = 'JTi' ".: R" i8 '' 'Z: P.'IiQ'.7E'S comprising one or more substituted derivatives of y3 -. ^ ¯c: t¯ß?, JQ: îX; l. ^ '¯: Cs.G¯8 and / or one or more of their vehicles .. ^. 3.:-¯ are appropriate. ¯¯¯ ¯¯¯¯ # ¯¯ "'1"). iv, ^. î.23üX "2S7? S? - their preparation, cos- -¯c:. ---------- ..-- 121. The new ¯ev¯- -'- their - , ",. '" e1: -' à <1lOn, CO:;! 1me described above,.: 1. ^. s ..: .. x2: 1 '.: in the examples given.