DE1543693A1 - Alkanolamine derivatives and processes for their preparation - Google Patents

Description

DR.-ING. H. FINCKE -1h A ^ fvH'S no ..

DiPL.-iNG. H. BOHR 10 ^ 0030 MOLLERSTR

Dipl- ₁ NG.S.SrAEGER _{Be aehreibu ng} May 25? 96β

to patent application v * v, * Imperial Chemical Industries Limited, London, S.W.1.,

concerning:

Alkanolamine derivatives and processes for their preparation

The priority of filing in Great Britain on 8/8/1965 and 11.5. .196.6 has been used

The invention relates to new alkanolamine derivatives that act as ß-adrenergic blocking agents and thus for Treatment or prophylaxis of cardiac artery diseases such as angina pectoris and irregular heartbeat, as well as for the treatment of hypertension and pheochromocytoma in humans.

According to the invention, new alkanolamine derivatives of the formulaί

/ ~ \ -0. CH ₂ . CHOH. CH ₂ .HE ¹ B ²

and their aldehyde condensation products, their esters as well as their salts created, where E. a hydrogen

p
atom or an alkyl radical, E an alkyl, hydroxyalkyl

or cycloalkyl radical and S? represents an alkyl radical with 2 or more "carbon atoms or a haloalkyl, cycloalkyl or alkenyl radical.

For the purposes of the invention, the above definition of the alkanolamine derivatives should also include all possible stereoisomers and Include mixtures thereof.

^ω If E ^{1 represents} an alkyl radical, this / can be an alkyl radical with a maximum of 6 carbon atoms, such as, for example, the methyl, to, ethyl or isopropyl radical.

- * If E ^{2 represents} an alkyl or hydroxyalkyl radical, this can be, for example, one with a maximum of 10 carbon atoms, such as ** e.g. methyl, ethyl, n-propyl, isopropyl, sec-butyl , tert-butyl, 1-methyloctyl or 2-Hydro3ty-1,1-dimethylethyl radical. BATH ORIGINAL

2 'p
If B or E- ^ represents a cycloalkyl radical, this can, for example, be a cycloalkyl radical with a maximum of 6 carbon atoms, such as, for example, the cyclopentyl radical.

If Br represents an alkyl radical with 2 or more carbon atoms, this can, for example, be an alkyl radical with at least 2 and at most 10 carbon atoms, such as, for example, the ethyl, isobutyl or n-heptyl radical. be.

If E "^ is a halogen alkyl radical, this can E.g. an alkyl radical with a maximum of 10 carbon atoms that carries one or more fluorine, chlorine or bromine atoms, such as e.g. with the 2,2-dichloro-1,1-dif} .uoroethyl radical.

7th

If Br represents an alkenyl radical, this can, for example, be an alkenyl radical with a maximum of 6 carbon atoms, such as, for example, the alkenyl radical.

Under the term "aldehyde condensation products" are intended For the purposes of the invention, the oxazolidine derivatives of the formula:

0. KS ²
OHE ^

2 -5 and their salts will end, where E and E "^ die Have o.a. meanings and E ^ a hydrogen atom or a Represents alkyl or aryl radicals, and these of the alkanol amine derivatives according to the invention of the above formula are derived in which E is a hydrogen atom.

If E ^ "represents an alkyl or aryl radical, this can to e.g. an alkyl or aryl radical with a maximum of 10 carbon atoms, such as the isopropyl or phenyl radical.

O- Suitable esters of the alkanolamine derivatives can be e.g.

2l O-esters, those of saturated or unsaturated aliphatic *** ■ Carboxylic acids with, for example, at most 20 carbon atoms, such as; α »acetic acid, palminic acid, stearic acid or oleic acid, or O-esters derived from an aromatic carboxylic acid e.g. with a maximum of 10 carbon atoms, such as benzoic acid,

come. & ΐ £ * λ "~ - * - '* ~ .

BAD ORIGtNAL

As examples of the salts of the alkanolamine derivatives or £? the esters derived therefrom or the aldehyde condensation products can be salts derived from inorganic acids, ^ ₁ - such as hydrochlorides, hydrobromides, phosphates, or <- ° sulfates, or salts derived from organic acids, such as

for example oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, ß-haphthoates, adipates or 1,1-methylenebi8- (2-hydroxy-3-3iaphthoate), or salts from acidic synthetic resins such as sulfurized polystyrene resins such as ⁿ Zeo ~ Karb ^H 225 (e.Vz.) originate, mention. Relatively insoluble salts such as 1,1-methylene-bis- (2-hydroxy-3-naphthoates) have the advantage that they allow the salt to stay in the blood for a longer period of time when it is used as a medicine.

The following can be mentioned as specific examples of the new alkanolamine derivatives: 1- (2- (2,2-dichloro-1,1-difluoroethoxy) phenosy) -3-isopropylamino-2-propanol, 1- (2-ethoxyphenoxy) ~ 3 -i sopropylamino-2-propanol, 1- (2-ethoxyphenoxy) 3-tert-butylamino-2-propanol, 1- (2-ethoxyphenoxy) -3-n-propylamino-2-propanol, 1- (2 -Aetho: xyphenoxy) -3-cyclopentylamino-2-propanol, 1- (2-ethoxyphenoxy) -3- (2-hydro2y-1,1-dimethylethylamino) -2-propanol, 1- (2-ethoxyphenoxy) -3- methylamino-2-propanol, 1- (2-AlIyI oxypheno: xy) -3-isopropylamino-2-propanol, 1- (2-allyloxyphenoxy) -3-tert-butylamino-2-propanol, 1- (2-n -Heptyloxyphenoxy) -3-isopropylamino-2-propanol, 1- (2-isobutoxypheno3q5r) -3-isopropylamino-2-propanol, 1- (2-0yclopentylo3qyTt> henoxy) -3-isopropylamino-2-propanol and 1- (2 -0yclopentyloxyphenoxy) -3-cyclopentylamino-2-propanol and their aldehyde condensation products, their esters and their salts. Of these compounds, the following are particularly favorable: 1- (2-Aethoxypheno: xy) -3-isopropylamino-2-propanol, 1- (2-Aethoxyphenoxy) -3-tert. -butylamino-2-propanol _t 1- (2-allyloxyphenoxy) -3-isopropylamino-2-propanol, 1- (2-allyloxyphenoxy) -3-tert. -butylamino-2-

«, Propanol and 1- (2-isobutoxyphenoxy) -3-isopropylamino-2- ^ propanol and its salts.

According to a further feature of the invention, a method 2 ^ for the preparation of the Alka ^ olaicinderivate according to the invention * "* suggested that that consists of a halogen compound go of the formula:

-Q, CH .OHOH.OH "Z BAD OBIOINAL

■ ζ

where Z represents a halogen atom and Br has the above meaning, is made to react with an AmIn of the formula: HHE E, where E and E have the above meanings,

Z can suitably be, for example, a chlorine or bromine atom. The reaction can advantageously be accelerated by supplying heat or to be brought to completion, and it can also be in an inert diluent or solvent, such as e.g. methanol.

According to a further feature of the invention, a Process for the preparation of the alkanolamine derivatives proposed according to the invention, which consists in that an epoxy of the formula:

0 (f VV.O.GH OH -

where Br has the above meaning, is made to react with an amine of the formula: HER Έ, where E ¹ and E have the above meanings.

This reaction with the epoxy can be carried out appropriately Heat supply accelerated or brought to a conclusion and it can also be used in an inert diluent or solvent, such as methanol or ethanol, take place.

According to a further feature of the invention, a Process for the preparation of the alkanolamine derivatives proposed according to the invention, which consists in that a Compound of the formula:

where Br has the above meaning, with a compound of the formula:, 0

Z.CH ₂ .CHOH.CH ₂ .HE ¹ E ² or CH ₂ - CH.CH ₂ .NE ¹ E ²

f "L

where E, E and Z have the meanings given above, is made to react. _{ßAD 0RmHAL}

The last-mentioned reaction can expediently take place in the presence of an acid-binding agent, such as, for example, sodium hydroxide. On the other hand it can be an alkali metal

vj- derivative of the phenol reactant, such as the sodium

^1-0 or potassium derivative, can be used as a starting material. The reaction can be carried out in an inert diluent or solvent, such as, for example, ethanol, and it can be accelerated or brought to a conclusion by supplying heat.

According to a further feature of the invention, a Process for the preparation of those of the alkanolamine derivatives

according to the invention, in which R represents a hydrogen atom, suggested that a compound of the formula:

L ^ XT ΟΈΤ / ΎΕΓ / TtT "KTD * D S ¹ « OXIq · νΠνΠ · OH λ Il Xt Xi

OR ⁵

where R and R ^ have the meanings given above and R * 'a through Hydrogenolysis represents removable radical, or a salt of such a compound is subjected to hydrogenolysis will.

Ή / can be useful, for example, the benzyl radical. The hydrogenolysis can be effected, for example, by catalytic hydrogenation in the presence of, for example, a palladium-on-charcoal catalyst in an inert diluent or solvent, for example ethanol. The hydrogenolysis is preferably effected in the presence of an acid catalyst such as hydrochloric acid.

According to a further feature of the invention, a Process for the preparation of those of the alkanolamine derivatives

Λ
according to the invention, in which R is a hydrogen atom and

R ^{2 represents} a radical of the formula: -CHR ⁶ R ?, where R ^{6 is} a hydrogen atom or an alkyl radical and R 'is an alkyl or hydroxyalkyl radical, or where R and R' are connected to the adjacent carbon atom in such a way that a Cycloalkyl radical is proposed, which consists in that an amino derivative of the formula:

* ° « > Q. CH ₀ . CHOH. CH ₀ . HH ₀

^ where Br the ο. a. Has meaning with a carbonyl compound cd of the formula B .CO.B, where E and S? ^ ₆ ο.a. Meanings

^ j. have brought under Eeduzierbedingungen the reaction ^ o is.

Suitable reducing conditions are established by the presence of hydrogen and a hydrogenation catalyst, e.g. Platinum, in an inert diluent or solvent and / or in an excess of that used as starting material Carbonyl compound when E of this compound is an alkyl radical. Also be expedient Reduction conditions by the presence of an alkali metal borohydride, e.g. sodium borohydride, in an inert Diluents or solvents, for example ethanol or aqueous methanol, and / or in an excess created the carbonyl compound used as the starting material.

Said amino derivative can also be used within the scope of the invention are formed in the reaction mixture itself. This can e.g. by reducing the corresponding α-diazoketone, α-azido ketones, α-hydroxyiminoketones, α-hatroketones, α-nitro alcohol, cyanohydrins or acyl cyanide.

According to a further feature of the invention, a Process for the preparation of the alkanolamine derivatives according to Invention proposed, which consists in that an amino derivative of the! Formula ϊ

1 -5
where E and Br have the meanings given above, or an ester or salt of such a compound with a compound

2 2

of the formula: EY is brought to Eeaktion, where EY co
ο represents a reactive ester which is derived from an O ₀ alcohol of the formula E OH, where E has the above meaning ^ω .

^ Y can conveniently, for example, be the chlorine or bromine or iodine atom, * ° the toluene-p-sulfonyloacyradical or an E & dical of the formula: -OSO ₂ OE ² , where B ^{2 is} the oai «d« utuag, represents. A particularly suitable compound of Jormel II is isopropylbroeid. BATH ORIGINAL

co The reaction may conveniently in the presence of a base, for example an inorganic base ^ », for example, sodium carbonate, ro and in the presence of a diluent or solvent m, as can be performed, for example, ethanol. The reaction may zweckmäesig ^x ~ at elevated temperature, for example between 100 and 200 * 0, beiepielsweie at about 130 * 0, take place.

According to a further feature of the invention, a Process for the preparation of oxazolidine derivatives of Suggested ilkanolamine derivatives according to the invention, which consists in that a compound of the formula:

.0H0H, CH ₂

OR ⁵

where R and Br have the above meanings, or a salt of such a compound is reacted with an aldehyde of the formula: E OHO, where R has the above meaning.

This reaction can be carried out in a diluent or solvent, e.g..! ethanol, benzene, toluene or xylene, and optionally carried out in the presence of a catalyst, e.g. hydrochloric acid, acetic acid or iodine, and accelerated by supplying heat or to be brought to a conclusion. The water formed during the reaction can by azeotropic distillation with an appropriate reading medium, e.g. benzene, toluene, or xylene, as an entrainment agent or by means of a dehydrating agent, e.g. anhydrous potassium carbonate.

According to a further feature of the invention, a method for the preparation of alkanolamines is star after Invention proposed, which consists in that the corresponding alkanolamine derivative or a salt thereof with

an acylating agent is reacted. <o

u> Examples of suitable acylating agents can be found in o> saturated or unsaturated aliphatic carboxylic acids ^ or halides derived from aromatic carboxylic acids - * or anhydrides, such as acetyl chloride, acetic anhydride «Ο or benzoyl chloride, mention. The acylation can be carried out in one * ° diluents or solvents that are used in the Use of an acid anhydride as an acylating agent the acid from which the anhydride originates can be expedient. BATH ORIGINAL

oo If R represents a hydrogen atom, it must

^ Alkanolamine derivative used in the form of a salt thereof ο

<y ~> are used to prevent acylation of the nitrogen atoms

Will be LO.

The invention is explained in more detail below with the aid of exemplary embodiments, purely by way of example, wherein all quantities are based on weight.

example 1

A mixture of 4- parts of 1-chloro-3- (2- (2,2-dichloro-1,1-difluoräthoxy) phenoxy) -2-propanol and 28 parts of isopropylamine is heated for 10 hours in a faded Gefass to 120 ⁹ C . After cooling and opening the vessel, the contents are filtered and the filtrate is evaporated to dryness on a steam bath. The solid residue is recrystallized from ethyl acetate. This gives 1- (2- (2,2-dichloro-1,1-difluoroethoxy) phenoxy) -3-isopropylamino-2-propanol hydrochloride as white needles, mp 152-153 * 0.

The 1-chloro-3- (2- (2,2-dichloro-1,1-difluoroethoxy) phenoxy) -2-propanol is prepared as follows: A mixture of 12.8 parts of 2- (2,2-dichloro-1 , 1-difluoroethoxy) phenol, 25 parts of epichlorohydrin and 0.05 part of piperidine is heated on a steam bath for 16 hours. The excess epichlorohydrin is evaporated off under reduced pressure, namely under a pressure of 40 mm of mercury, and the residue is distilled under vacuum. The result is a colorless oil, bp 122 125 ^e C at 0.1 mm pressure. A solution of this oil in 75 parts of chloroform is shaken twice with 55 parts of concentrated hydrochloric acid and twice with 50 parts of water, dried and then filtered, whereupon the chloroform is distilled off. The residue consists of 1-chloro-3- (2- (2,2-dichloro-1,1-difluoroethoxy) phenoxy) -2-propanol.

JJ 2- (2,2-dichloro-1,1-difluoroethoxy) phenol is produced as follows:
- «ο

• v. 220 parts of catechol are dissolved in a solution of 100 parts of sodium hydroxide granulate in 600 parts of water and 200 parts of dioxane. The solution is added with stirring at 5 ° C, brought. At this temperature, a solution of 170 parts of 1,1-difluoro-1,2,2-trichloroethane in 20 g parts of dioxane is added dropwise over 5 hours. The mixture

BAD ORlGiNAU

fo is stirred for 16 hours at 20 ⁰ C and then acidified with concentrated ^ hydrochloric acid until the pH is below 5 $ .The mixture is then steam distilled until the distillate to no trace of oil is visible. The lower oily layer * ~ is then separated, dried and filtered. The oil is then subjected to fractional distillation, under reduced pressure. The result is a larger fraction as a colorless oil, Sdp.73-80 ° C at 3 mm pressure, Smp.7 ^e C consisting of 2- (2,2-dichloro-1,1-difluoräthoxy) is phenol.

Example 2

A solution of 15 parts of 1-chloro-3- (2-ethoxyphenoxy) -2-propanol in 14 parts of isopropylamine is 10 hours in a closed vessel heated to 110 ° C. The-surplus Isopropylamine is distilled off from the mixture, under reduced pressure, and the residue is in Dissolved parts of an aqueous 2N hydrochloric acid solution. The acidic solution is extracted twice with 50 parts of ether, and the extracts are disregarded. The acidic solution is made by adding an aqueous 10N sodium hydroxide solution alkalisieert, and the basic solution is extracted 3 times with 50 parts of chloroform. The summarized Chloroform extracts are washed with water, dried over anhydrous magnesium sulfate and then distilled to remove the chloroform. The residue is recrystallized from petroleum ether (bp 60-80 ° C.). Consequently 1- (2-ethoxyphenoxy) -3-isopropylamino-2-propanol, melting point 87-88 ° C., is obtained.

The 1-chloro-3- (2-ethoxyphenoxy) -2-propanol used as starting material is produced as follows: A mixture of 10 parts of o-ethoxyphenol, 17 parts of epichlorohydrin and 0.01 part of piperidine is heated to 95 ° for 18 hours on a steam bath C heated. The excess ο epichlorohydrin is distilled off from the solution under reduced pressure, and the residue is dissolved in 100 parts of chloro-ω form. The chloroform solution is washed successively with> ^ 20 parts of water, 20 parts of concentrated hydrochloric acid, 20 ^ parts of water, 20 parts of a saturated aqueous sodium bicarbonate solution, 20 parts of Vaeser and then dried over anhydrous magnesium sulfate. The chloroform is distilled off under reduced pressure. This gives i-chloro-3- (2-ethoxyphenoxy) -2-propaiiol.

BATH ORIGINAL

The procedure after. Example 2 is repeated, with the difference n * difference that instead of 14! Rush isopropylamine 42 parts of _{tert-C £)} butylamine and 42 parts of methanol are used. Bas product ^? is isolated like "in Example 2, with the difference that LO the" basic oil is dissolved in 100! dents of dry ether. An essential solution of oxalic acid is added in excess and the mixture is filtered. The solid residue is recrystallized from xylene. This gives 1- (2-letho2yphenoxy) -3-tert-butylamine-2-propanol hydrogen oxalate, mp 97-99 ° 0.

Example 4

The process according to Example 2 is repeated, with the difference that instead of 14 parts of isopropylamine, 45 parts of n-propylamine and 60 parts of methanol are used. The product is isolated as in Example 2, and the residue is recrystallized from petroleum ether (bp 80-100 ° O). Thus obtained i- (2-Aethoxypheno23r) -3-n-propylamino-2-propanol, Smp.86 _T 5 to 8?, 5 ° O.

Example 5

The process according to Example 2 is repeated, with the difference that instead of 14 parts of isopropylamine, 45 parts of cyclopentylamine and 60 parts of methanol are used. The product is isolated as in Example 2, and the residue is recrystallized from petroleum ether (bp 60-80 ° 0). Thus obtained 3-cyclopentylamino-1- (2-äthoxypheno3qsr) -2-propanol, Smp.8, 5 - 88 ⁰ C.

Example 6

A mixture of 1 part 2,3-epoxy-1- (2-ethoxyphenoxy) propane, 1 part 2-amino-2-methylpropan-1-ol and 6 parts methanol is refluxed for 16 hours. The excess amine and the solvent are evaporated off and the residue is shaken with a mixture of an aqueous 2N hydrochloric acid solution and ethyl acetate. The aqueous phase is separated and alkalized _o, and the mixture is extracted 3 times with 6 parts of ethyl acetate. The combined extracts are dried and evaporated to dryness, whereupon the oily residue is dissolved in ether and an ethereal hydrogen chloride solution is added. *> The mixture is filtered and the solid residue is removed from n-butyiacetate. Thus «rhtlt sau 1- (2-

7, y, ß * p.86-90 ^# C. BAD ORIGINAL

The 2,3-epoxy-1- (2-ethoxyphenoxy) propane used as a starting material is produced as follows. A mixture of 138 parts of o-ethoxyphenol. 93 parts of epichlorohydrin, 40 parts of sodium hydroxide and 2000 parts of water are stirred for 18 hours at ambient temperature. The mixture is extracted 3 times with / 2000 parts of ethyl acetate, whereupon the combined extracts are dried and evaporated to dryness. The oily residue is distilled. This gives 2,3-epoxy-1- (2-ethoxyphenoxy) propane, bp 24-129 ° 0 at 1 mm pressure.

Example 7

The process according to Example 6 is repeated, with the difference that instead of 1 part of 2-amino-2-methylpropan-1-ol, 5 parts of a 10% strength solution of methylamine in methanol are used. The product is isolated as in Example 6, except that the oily residue from petroleum ether (Sdp.80-100 ⁰ O) is crystallized. This gives 1- (2-ethoxyphenoxy) -3-methylamino-2-propanol, mp 91-92 ° 0.

Example 8

A mixture of 4 parts of 3- (2-allyloxyphenoxy) -1-chloro-2-propanol, 10 parts of isopropylamine and 20 parts of methanol is heated to 110 ° 0 for 10 hours in a sealed tube. The excess isopropylamine and methanol are evaporated, and the oily residue is shaken with an aqueous 2N sodium hydroxide solution and ethyl acetate. The organic phase is separated off, dried and evaporated to dryness, whereupon the residue is recrystallized from petroleum ether (bp 60-80 ° 0). Thus, there is obtained 1- (2-allyloxyphenoxy) -3-isopropylamino-2-propanol, Smp.75i5-76 ⁰ C.

The 3- (2-allyloxyphenoxy) -1- • D chloro-2-propanol used as starting material is prepared as follows: ίο A mixture of 40 parts of o-allyloxyphenol, 160 parts of JJ epichlorohydrin and * tail piperidine is set to "^ ³ . »distilled off under reduced bridging, and the residue £ j is shaken with 400 parts of ethyl acetate and 200 parts of water * ° the organic phase is separated, dried and evaporated to dryness - ⁰ heated 95-10O C ^ Bas It rschüssige epichlorohydrin.. This gives 3- (2-allyloxyphenoxy) -i-chloro-2-propanol.

■ * * BADORiQiNAL

Example 9

A mixture of 2 parts of 1- (2-allyloxyphenoxy) -2,3-epoxypropane, 10 parts of tert-butylamine and 30 parts of methanol is refluxed for 4 hours. The excess amine and methanol are evaporated off, and the residue is shaken with ether and an aqueous 2N hydrochloric acid solution. The aqueous phase is separated off, made alkaline and extracted 3 times with 50 parts of ether each time. The combined essential extracts are dried and evaporated so that their volume is only a tenth of the original value. Oxalic acid essential solution is then added and the mixture is filtered. The solid residue is recrystallized from ethyl acetate. Thus, one 105-106 ⁰ is obtained 1- (2-allyloxyphenoxy) -3-tert, butylamino-2-propanol hydrogen oxalate, mp. CEL

The 1- (2-allyloxyphenoxy) -2,3-epoxypropane used as starting material can be prepared as follows: A mixture of 15 parts of o-allyloxyphenol, 9 * 3 parts of epichlorohydrin, 4 parts of sodium hydroxide and 350 parts of water is added for 6 hours Stirred at ambient temperature. The mixture is extracted with 300 parts of ethyl acetate, whereupon the extract is dried and evaporated to dryness. The oily residue is distilled. This gives 1- (2-allyloxyphenoxy) -2,3-epoxypropane, bp 115-122 ° C at 0.7 mm pressure.

Example 10

The process according to Example 9 is repeated, with the difference that instead of 10 parts of tert-butylamine, 10 parts Diethylamine can be used. The product is isolated as in Example 9. This gives 1- (2-allyloxyphenoxy) -

_{3-diethylamino-2-propanol-r} hydrogen oxalate, Smp.83-85 ° 0th co

to example 11

JJ A mixture of 2 parts 1-chloro-3- (2-n-heptyloxyphenoxy) - -J 2-propanol, 10 parts of isopropylamine and 20 parts of methanol -i is in a sealed tube at 110 ° C for 12 hours heated. The excess Amiη and methanol are evaporated, and the residue is mixed with 30 parts of an aqueous 2N sodium hydroxide solution and 150 parts of ethyl acetate shaken. The organic phase is separated off, dried and evaporated to dryness. The residue is made from petroleum

BATH ORIGINAL

. 3-l6opropylei ^ j | * ^ - (2-n-lieptyloiyptienox3r) -2-propaiiol, / fj m.p. 77 ^e C.

LO The 1-0hlor-3- (2-n-hept "yl-

* ~ oocyphenoxy) -2 ** propanol can be produced as follows: £ β will be 55 ώΐΐθ catechol in a solution of 12 {dents Sodium dissolved in 350 parts of anhydrous methanol, whereupon the Hieöüüung is heated to reflux. One Solution of 90 parts of n-heptyl bromide in 90 parts of anhydrous Methanol is added over 1 hour and the resulting solution is refluxed for a further 3 hours heated. The methanol is evaporated and the residue is shaken with 300 parts of ether and 100 parts of water. The organic phase is separated off, dried and evaporated to dryness. The oily residue is distilled. This gives o- (n-heptyloxy) phenol, b.p. 117-122 ° G at 0.8 mm pressure,

A mixture of 20 parts of o- (n-heptyloxy) phenol, 100 parts of epichlorohydrin and 1 part of piperidine is heated for 16 hours to 95 "10O ⁰ G. The excess of epichlorohydrin is evaporated, and the residue is treated with 400 parts of ethyl acetate and 80 parts of water The organic phase is separated, dried and evaporated to dryness, giving 1-chloro-3- (2-n-heptylo3yphenoxy) -2-propanol.

Example 12

The process according to Example 11 is repeated, with the difference that instead of 10 parts of isopropylamine, 10 parts n-propylamine can be used. The residue is recrystallized from petroleum ether (boiling point 80-100 ° 0). Thus receives one 1- (2-n-heptyloxypheno3qsr) -3-n-propylamino-2-propanol, M.p. 83 ° G,

Example 13 _t

The process according to Example 11 is repeated, with the difference that instead of 10 parts of propylamine, 10 parts of tert-butylamine are used. The product is like ^ isolated in Example 11, with the difference that the DAE ~> rückstlndllehe basic oil in 40 parts waeserfreien% iethere resolved "is worftu? an itheric (tealetu * - ^m solution is added) DicIUeohung is filtered, and the fixed piece of work is made up of the law.

Thus, 1- (2-n-heptylpi7phenoxy) -5-tert.-but7le »ino-

2-propanol-hydrogea-o3tsaat _r aj ^; 126 * 0. bad original

A mixture of 2.35 parts of o-Isobutoxyphenol, 12 ropes epichlorohydrin and 0.01 part of piperidine is heated 18 hours 4H- to 90-100 ⁰ C. The excess epichlorohydrin is distilled off under reduced pressure and the oily residue is dissolved in 50 parts of chloroform. The chloroform solution is washed successively with 20 parts of an aqueous HN hydrochloric acid solution, 20 parts of water, 20 parts of an aqueous sodium bicarbonate solution and 20 parts of water and then dried over anhydrous magnesium sulfate. The chloroform is distilled off under reduced pressure. Thus, 1 -Chlor-3- (2-isobut03ypheno3cy) -2-propanol.

A mixture of 12 parts of isopropylamine with this product is heated for 10 hours in a sealed Gefass to 100 ⁰ C. The product is isolated as in Example 1, and the residue is recrystallized from petroleum ether (bp 60-80 ° C.). This gives 1- (2-isobutosypheno: xy) -3-isopropylamino-2-propanol, m.p. 84-85 ° C.

Example 15

A mixture of 11 parts of 1-chloro-3- (2-cyclopentyloxyphenoxy) -2-propanol, 100 parts of isopropylamine and 200 parts of methanol is ^{heated to 110 °} C. for 12 hours in a closed bore. The excess 1 minute and methanol are evaporated, and the residue is shaken with 100 parts of an aqueous 2N sodium hydroxide solution and 100 parts of ethyl acetate. The organic phase is separated off, dried and evaporated to dryness, whereupon the oily residue is dissolved in ether. Oxalic acid essential solution is added and the mixture is filtered. The solid residue is recrystallized from n-butyl acetate. This gives 1- (2-Cyclopentyloayphenox7) -3-iaopropylamino-2-propanol hydrogen oialate,

^ M.p. 189-191 ° 0.
ο

The 1-chloro-3- (2-cyclopentyl ox7ph * noiy) -2-propanol used as the starting material can be used as follows: Sin · Kitohung from 3 ropes o-Cycloptntylojgrph · »© !, 15 Parts of rpiohldrhTtlrin and 0.2 parts of piperidine are heated to 95-100 g for 16 hours. The tbtrschüiaigt Xpicalörüjirin is atgadavpft, and the Süoketand is shaken with 100 $$ !! "& Aathylacatat iM 30 Τ · ϋ · η a wleaerigen Sft-Vatritn ^ grdroxydldaung B * i. The organic material is separated off and dried

BAD ORIGJNAL

and evaporated to dryness. Thus, 1-chloro-3- (2-cyclopentyloxyphenoxy) -2-propanol is obtained as ι. _atr

CO "TO

£> Example 16

-J "The procedure of Example 15 is repeated with the

, _ Difference is that instead of 100 parts isopropylamine 100 parts tert-butylamine can be used. The resulting oxalate is recrystallized from n-butyl acetate. Thus one obtains 1- (2-0yclopentyloxyphenoxy) -3-tert-butylamino-2-propanol oxalate, m.p. 166-170 * 0 ".

Example 17

The procedure of Example 15 is repeated with the The difference is that 10 parts of cyclopentylamine are used instead of 10 parts of isopropylamine. The resulting oxalate is recrystallized from ethanol. This gives 3-cyclopentylamino-1- (2-cyclopentyloxyphenoxy) -2-propanal hydrogen oxalate, M.p. 186-187 ° 0.

Example 18

A mixture of 20 parts of 1- (2-ethoxyphenoxy) -3-isopropylamino-2-propanol, 7 parts of a 30 # aqueous bormaline solution and 600 parts of xylene are taken for 6 hours Heated to reflux, which formed in the reaction Water using a Dean and Stark water collector is withdrawn. The xylene is evaporated and the oily residue is distilled. This gives 5- (2-ethoxyphenoxymethyl) -1-isopropyloxazolidine, Bp. 135 ^ 0 at 0.2 mm pressure.

Example 19

A mixture of 5 parts of 1- (2-ethoxyphenoxy) -3-isopropylaminopropanol hydrochloride and 50 parts of acetyl chloride is refluxed for 6 hours. The excess acetyl chloride is evaporated off and the residue is shaken with 50 parts of an aqueous 2N sodium bicarbonate solution and 100 parts of ether. The organic phase C _{0 is} separated off, dried and evaporated to dryness. The oily residue is purified by thin layer chromatography on 1 mm thick plates by removing the fraction with an R -, - Vert of 0.19 using a mixture of benzene (67 vol. ) and ethyl acetate (33 Vol #) is collected as eluants, thus obtaining 1- (2-ethoxyphenoxymethyl) -2-isopropylaminoethyl acetate as an oil.

BATH

jaeispiex dsj

A mixture of 20 parts of 3-amino '' - 1- (2-äthoxyphenoxy) -2-propanol, 14 parts of isopropyl ·, 12 parts of sodium carbonate and 200 parts of ^ is .ethanol for 8 hours in a sealed Bohr to 130 ° C heated. The ethanol is evaporated off and the residue is shaken with 60 parts of an aqueous 2N hydrochloric acid solution and 200 parts of ether. The aqueous phase is separated off, made alkaline and extracted with 200 parts of ethyl acetate. The Aetfcylacetat extract is dried and evaporated to dryness (Sdp.80-100 ^e C) and the residue is recrystallized from petroleum ether *. This gives 1- (2-ethoxyphenoxy) -3-isopropylamino-2-propanol, mp 87-88 ° 0.

The 3-amino-1- (2-ethoxyphenoxy) -2-propanol used as starting material can be prepared as follows: A mixture of 2 parts of 3-chloro-1- (2-ethoxyphenoxy) -2-propanol, 10 parts of an aqueous ammonia solution (see G 0.88) and 20 parts of methanol are heated to 110 ° C. in a sealed tube for 12 hours. The excess watery Ammonia solution and the methanol are evaporated, and the residue is mixed with 30 parts of an aqueous 2N hydrochloric acid solution and 100 parts of ether shaken. The aqueous acidic solution is made alkaline and 3 times with each 100 parts of ether extracted. The essential extract is dried and evaporated to dryness. The residue is dissolved in ether, whereupon an ethereal oxalic acid solution is added and the mixture is filtered. The solid residue is recrystallized from ethanol. This gives 3-amino-1- (2-ethoxyphenoxy) -2-propanol ~ hydrogen oxalate, m.p. 148-150 ° C.

Example 21

A mixture of 3-amino-1- (2-ethoxyphenoxy) -2-propanol, 1 part sodium borohydride, 2 parts acetone and 20 parts Q ethanol is refluxed for 4 hours. The ethanol ^ is evaporated, and the residue is shaken with 30 parts of an aqueous 2N hydrochloric acid solution and 100 parts of ether, ^ The ethereal phase is separated, alkalized and extracted 3 times ^ with 100 parts of ether each time. The combined cd essential extracts are dried and evaporated to dryness, and the residue is recrystallized from petroleum ether (bp 60 80 ° C). This gives 1- (2-ethoxyphenoxy) -3-isopropylamino-2-propanol, m.p. 87-88 ° C. _{ßAD 0RlQ} , _NAL

22nd J * I34J030

There are 14 parts of o-ethoxyphenol of a solution of 4 parts Uodium hydroxide in 2000 parts of anhydrous ethanol admitted. Then 20 parts of 1- (H-benzyl-IT-isopropylamine) -2,3-epoxypropane are added in 200 parts of anhydrous ethanol are added, and the mixture is refluxed for 4 hours heated. The solution is cooled and evaporated to dryness under reduced pressure, and the residue is shaken with 500 parts of water and 1000 parts of ethyl acetate. The organic phase is separated off and dried and evaporated to dryness. The oily residue is xxxat 3- (N-Benzyl-N-isopropylamino-1- (2-ethoxypheno: xy) -2-propanol.

A mixture of 30 parts of 3- (N-benzyl-N-isopropylamino) -1- (2-ethoxyphenoxy) -2-propanol, 3 parts of a 10% palladium on charcoal catalyst, 30 parts more concentrated Hydrochloric acid and 1000 parts of ethanol is in a hydrogen atmosphere at ambient temperature below atmospheric Pressure shaken. The mixture is then filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is mixed with 300 parts of an aqueous 2N hydrochloric acid solution and 1000 parts of ether shaken. The aqueous phase is separated off, made alkaline and 3 times with extracted per 1000 parts of ether. The summarized essential extracts are dried and evaporated to dryness, and the residue is made from petroleum ether (bp 60-80 ° C) recrystallized. This gives 1- (2-Aetho3cyphenoxy) -3-isopropylamino-2-propanol, M.p. 87-88 ° 0.

Claims (1)

Claims 1. Alkanolamine derivatives and their aldehyde condensation products, Ί their esters and their salts, characterized in that the alkanolamine derivatives have the formula: QO. OH ₂ .CHOH. OH ₂ IF have, where B is a hydrogen atom or an alkyl radical, E is an alkyl, hydroxyalkyl or cycloalkyl radical and B ^{y is} an alkyl radical with 2 or more carbon atoms or a haloalkyl, cycloalkyl or alkenyl radical. 2. alkanolamine derivatives according to claim 1, characterized in that E is an alkyl radical with at most 6 carbon atoms. 3. alkanolamine derivatives according to claim 2, characterized in that E is the methyl, ethyl or isopropyl radical. 4. alkanolamine derivatives according to any one of claims 1-3, characterized in that B is an alkyl or hydroxyalkyl radical with a maximum of 10 carbon atoms. 5. alkanolamine derivatives according to claim 4, characterized in that 2
that E is the methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, 1-methyloctyl or 2-hydroxy-1,1-dimethyl radical. 6. alkanolamine derivatives according to any one of claims 1-3, characterized in that E is a cycloalkyl radical with at most 6 carbon atoms. <° 7 * alkanolamine derivatives according to claim 6, characterized in that cd that B is the cyclopentyl radical. ^ 6. Alanolamine derivatives according to one of claims 1-7 * characterized - * characterized in that Br is an alkyl radical with at least 2 '«> and at most 10 carbon atoms. 9. AlkanolamizuUrivate according to claim 8, characterized in that da ·· B * da · aethyl, leobutyl or n-E «ptyl radical. BATH ORIGINAL 10. alkanolamine derivatives according to any one of claims 1-7, characterized in that R * is an alkyl radical with at most 10 carbon atoms, which carries one or more fluorine, chlorine or bromine atoms. 11. Alkanolamine derivatives according to claim 10, characterized in that R ^{5 is} the 2,2-dichloro-1,1-difluoroethyl radical. 12. alkanolamine derivatives according to any one of claims 1-7, characterized in that Br is a cycloalkyl radical with at most 6 carbon atoms. 13. Alkanolamine derivatives according to claim 12, characterized in that Br is the cyclopentyl radical. 14. Alkanolamine derivatives according to any one of claims 1-7 » characterized in that R · ^ is an alkenyl radical with is at most 6 carbon atoms. 15. Alkanolamine derivatives according to claim 14, characterized in that • χ that R- 'is the allyl radical. 16. Aldehyde condensation products according to one of claims 1 to 15, characterized in that they are oxazolidine derivatives the formula: '^ "^ _{. CH 5.} CH - CH 3 ^l ■ '2 ^J 0 HR CHR ⁴ ρ jr or their salts, where R and R ^ are those in claim 1 4 have given meanings and R is a hydrogen atom or represents an alkyl or aryl radical. _o 17. Aldehyde condensation products according to claim 16, characterized ^ characterized in that R is an alkyl or aryl radical with ω is at most 10 carbon atoms,
^. X18. Aldehyde condensation products according to claim 17, characterized characterized in that R is the isopropyl or phenyl radical represents. BATH 19. Ester according to any one of claims 1-15> characterized in that it is of a saturated or unsaturated aliphatic Carboxylic acid with a maximum of 20 carbon atoms or from an aromatic carboxylic acid with a maximum of 10 carbon atoms. 20. Esters according to claim 19, characterized in that they are of acetic acid, palminic acid, stearic acid, oleic acid or benzoic acid. 21. Salts according to one of claims 1-20, characterized in that they contain hydrochlorides, hydrobromides, phosphates, sulfates, Oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, ß-naphthoates, adipates, 1,1'-methylene-bis- (2-hydroxy-3-naphthoates) or salts derived from sulfonated polystyrene resins. 22. The compounds 1- (2- (2,2-dichloro-1,1-difluoroethoxy) pheno3y) -3-isopropylamino-2-propanol and 1- (2-ethosyphenozy) -3-isopropylamino-2-propanol and the aldehyde condensation products and the esters thereof and the salts thereof. 23. The compounds 1- (2-Aethosypheno3cy) -3-tert-butylamino-2-propanol, 1- (2-Aethox ^ ^r phen ^> oxy) -3-n-propylamino-2-propanol, 1- (2 -Aetho3q5rpheno2 {y) -3-cyclopentylamino-2-propanol, 1- (2-ethoxyphenoxy) -3- (2-hydroxy-1,1-dimethylethylamino) -2-propanol, 1- (2-ethoxyphenoxy) -3- methylamino-2-propanol, 1- (2-allyloxyphenoxy) -3-isopropylamino-2-propanol, 1- (2-allyloxyphenoxy) -3-tert. -butylamino-2-propanol, 1- (2-n-heptyloxyphenoxy) -3-i-sopropylamino-2-propanol, 1- (2-isobutoxyphenoxy) -3-isopropylamino-2-propanol, 1- (2-cyclopentyloxyphenoxy) - 3-isopropylamino-2-propanol and 1- (2-cyclopentyloxyphenoxy) -3-cyclopentylamino-2-propanol and their aldehyde condensation products, their esters and their salts. J ₀ 24. 1- (2-Aethoxypheno: ^) - 3-isopropylamino-2-propanol and its salts. i ^ 25. 1- (2-Aethoxypheno3q5r) -3-tert-butylamino-2-propanol and ^ - its salts. 26. 1- (2-Allyloxypheno ^) -3-isopropylamino-2- propanol and its salts. BATH ORIGINAL its salts. 28 .. 1- (2-Iso "buto3C3rpheno3ty) -3-isopropylaniino-2-propanol and its salts. 29. Process for the preparation of the alkanolamine derivatives according to one of claims 1-15 and 21-28, characterized in that that a halogen compound of the formula; 00
cn f ~% - ° ^gh p ^{0H0H CH} ? ^Z where Z represents a halogen atom and R * has the meaning given in claim, is reacted with a 1min of the formula: HHR ¹ E, where R ^ and E ² d: Claim 1 have given meanings. 30. The method according to claim 29, characterized in that Z is a chlorine or bromine atom. 31 · Process for the preparation of the alkanolamine derivatives according to one of claims I-15 and 21-28, characterized in that that an epoxy of the formula: .CH - ^N where E has the meaning given in claim 1, with 1 2
an amine of the formula: RHR R is reacted, 1 2
where R and R have the meanings given in claim 1. to 32. Process for the preparation of the alkanolamine derivatives according to a of claims 1-15 and 21-28, characterized in that ^ a compound of the formula: where E ^ has the meaning given in claim, with a compound of the formula: BATH Z.CH ₂ .CH0H.0H ₂ .HB ⁿ R ^<ä octer CH ₂ - g 1 2 is brought to reaction, where R and R have the meanings given in claim 1 and Z in claim 29 has given meaning. 33. The method according to claim 321, characterized in that the reaction in the presence of an acid binding agent, or that an alkali metal derivative of the phenolic reactant is used as a starting material. 34. Process for the preparation of those of the alkanolamine derivatives according to claim 1, 4-15 "and. 21-28, in which R" ^{1 is} a hydrogen atom, characterized in that a compound of the formula; J ^ 0 .CH ₂ .GHOH-OH ₂ .SR ² R ⁵ where R and H * have the meanings given in claim 1 and Έ? represents a radical which can be split off by hydrogenolysis, or a salt of such a compound is subjected to hydrogenolysis. 35 · The method according to claim 34, characterized in that R ^ is the benzyl radical. 36. The method according to claim 34 or 35> characterized in that the hydrogenolysis is effected by catalytic hydrogenation in an inert diluent or solvent, 37. The method according to claim 36, characterized in that the hydrogenolysis by hydrogenation in the presence of a Palladium on charcoal catalyst and in the presence of Ethanol is effected. 38. The method according to any one of claims 34-37, characterized in that that an acid catalyst is present. _ ^ 39 · Process for the preparation of those of the alkanolamine derivatives ^ according to one of claims 1, 4-15, 21-24 and 26-28, in which • o in which R is a hydrogen atom and R is a radical of the formula: -CHR ⁶ R ' ⁷ represents, where R ^{6 is} a hydrogen atom or an alkyl radical and R 'is an alkyl or hydroxyalkyl BATH ORIGINAL represents radical or E and R 'so with the neighboring C atom are linked that a cycloalkyl radical is formed is, characterized in that an amino derivative of Formula: / ~ \ -O. CH ₂ . OHDH. CH ₂ where E ^ has the meaning given in claim 1, with 6 7 of a carbonyl compound of the formula: E .00.E 'under Eeduzierbedingungen is brought to Eeaktion, where E and E 'have the above meanings. 40. The method according to claim 39 »characterized in that the reduction conditions through the presence of hydrogen and a hydrogenation catalyst in one inert diluents or solvents are created. 41. The method according to claim 59 »characterized in that the reducing conditions by the presence of an alkali metal borohydride in an inert diluent or Solvents are created. 42. A process for the preparation of the alkanolamine derivatives according to any one of claims 1-15 and. 21-28, characterized in that that an amino derivative of the formula: , CH ₂ . CHOH. where e ' ¹ and E * have the meanings given in claim 1 have, with a compound of the formula: EY for Eeaktion is brought, where E Y is a ^ reactive ester derived from an alcohol of the formula E OH, where E ^{2 has} the meaning given in claim 1. co 43. The method according to claim 42, characterized in that ω Y the chlorine, bromine or iodine atom, or the toluene-p- ^ sulfonyloxy radical or a radical of the formula: -OSOpOE 2
~ * represents, where E has the meaning given in claim 1 te · has. _BATH 44. The method according to claim. 41 or 42, characterized in that that it is done in the presence of a baae. 45. A process for the preparation of the aldehyde condensation products according to one of .Ansprüche 1, 4-18 and 21-23, thereby
marked that a compound of the formula OE ⁵ 2 -ζ where E and B? have the meanings given in claim 1, or a salt of such a compound is brought to the reaction with an aldehyde of the formula E ^{4 CHO,}
where E has the meaning given in claim 16. 46. The method according to claim 45 *, characterized in that the water formed during the reaction by azeotropic
Distillation or with a Sntw & sserangsiP ^: ttel is removed. 47 * Process for the production of the esters according to one of the Claims 1-15 and 19-23 »characterized in that
the corresponding alkenolamine derivative or a salt thereof is reacted with an acylating agent. 48 · The method according to claim 47 »characterized in that an acid halide or an acid anhydride is used as the acylating agent. JATBfTANWXlTE . H. FINCKE, DIPU-ING. H. BOH * DIPL-ΙΝβ. S. STABGHl BATH ORIGINAL