DE2540552A1 - CYCLOALKYL DERIVATIVES OF 1-ARYLOXY-3-AMINO-2-PROPANOLS - Google Patents

Description

PFENNING -MAAS - SEILER MEINIG - LEMKE - Mockery

8000 MÖNCHEN 40 SCHLEISSHEIMERSTR. 299

25 508

American Cyanamid Company, Wayne, New Jersey, V.St.A. Cycloalkyl derivatives of 1-aryloxy-3-aminO-2-propanols

The invention relates to new cycloalkyl derivatives of 1-aryloxy-3-amino-2-propanols of the formula I

OCH ₀ CHCH ₉ NHR

² I.

OH

AY

wherein

R cycloalkyl with 3 to 11 carbon atoms, 1-adamantyl, Means exo-2-norbornyl or 1- indanyl,

A for alkylene with 1 to 3 carbon atoms or vinylene stands,

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Y carbamoyl, N-cyclohexylmethylcarbamoyl, Ν, Ν-dimethylcarbamoyl, Cyano, amino, hydroxy, morpholine or a radical of the formula

NCHo-C-N

C ₂ H ₅

^C 2 ^H 5

is,

and the acid addition salts and the hydrates of these compounds.

The invention also relates to new cycloalkyl derivatives of 1-aryloxy-2-amino-2-propanols of the formula II

CH ₀ CHCH ₀ NHR ² I ² OH

(II)

(CH ₂ ) ₂ Y

directed,
wherein

R is cyclohexylmethyl, if Y is carbamoyl, and in which R is isopropyl if Y is cyclohexylcarbamoyl or cyclohexylmethylcarbamoyl,

and the acid addition salts and hydrates of these compounds.

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FRG - 3 -

The invention also relates to ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate, the acid addition salts thereof and the hydrates thereof, and on o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid, the acid addition salts thereof, the hydrates thereof and the alkali and alkaline earth salts of these compounds.

The free bases of the compounds according to the invention are generally colorless crystalline solids with characteristic Melting points, some of these compounds are also obtained in the form of oils, which are converted into crystalline acid addition salts get convicted. The bases are generally insoluble in water, but dissolve in organic solvents, such as methanol, ethanol, isopropanol, N, N-dimethylformamide, damsel methyl sulfoxide or chloroform. They form with a number of salt-forming of organic and inorganic compounds acid addition salts. The production of the corresponding acid addition salts takes place by mixing the free organic base with an equivalent amount of acid, advantageously in one neutral solvent. Acids suitable for this purpose are, for example Hydrochloric acid, hydrobromic acid. Phosphoric acid, sulfuric acid, citric acid, fumaric acid, Acetic acid, ascorbic acid or gluconic acid. The salts obtained are generally in water and lower alkanols such as methanol. The o-C3 ~ cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid comes in a substantially neutral zwitterionic form and can either, as indicated above, acid addition salts or also form alkali and alkaline earth salts. The latter salts are formed by reacting with a equivalent amount of a corresponding hydroxide or carbonate, such as sodium, potassium, lithium, calcium or magnesium hydroxide or carbonate. For the invention Purposes are the organic free bases and zwitterions, their non-toxic acid addition salts and alkali and alkaline earth salts equivalent. The inventive

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Compounds have at least one asymmetric carbon atom, and the invention therefore also relates to them the racemic mixtures and the optically active isomers with the absolute D and L configurations.

The cycloalkyl derivatives of 1-aryloxy-3-amino-2-propanols according to the invention of the formulas I and II given above can be prepared by a compound of formula

(' μ OCH ₂ X

in which A and Y have the meanings given in the definition of the compounds of the formula I or in which A has the meaning given in the definition of the compounds of the formula II -CH ₂ CH ₃ -, with the proviso that, if the substituent Y is amino stands, this radical is protected by a corresponding group in a suitable manner, either by a hydrogenolytically removable group, such as the carbobenzyloxy group, the hydrogenolytically removable protective group can then be removed, for example by catalytic hydrogenation, such as hydrogenation in the presence of a palladium Charcoal catalyst in an inert diluent or solvent, such as methanol, ethanol or aqueous ethanol, where the elimination can be accelerated or completed by the presence of an acid catalyst such as hydrochloric acid or oxalic acid, or by a hydrolyzable protective group such as an alkanoyl group with up to 10 carbon atoms or a e aroyl group, such as the benzoyl group, whereby these protective groups after the reaction has been carried out by hydrolysis in the presence of a base such as ammonia, a

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Lower alkylamine, an alkali hydroxide such as sodium hydroxide, or an alkaline earth hydroxide such as calcium hydroxide, in a diluent or solvent such as water, methanol or
Ethanol, and where X is for

-CH CH ₂ or -CHOHCH ₂ Z

(or a mixture of such compounds in which X has both meanings), and Z is halogen, alkyl sulfonate or aryl sulfonate, such as methanesulfonate or p-toluenesulfonate,
means, with an amine of the formula RNH ~, wherein R is the
given above for the compounds of formulas I and II
Has meanings.

The reaction can take place at ambient temperature or at elevated temperatures
Temperature, such as 50 to 120 ⁰ C, are carried out. One can work at atmospheric pressure or at elevated pressures with heating in a closed reaction vessel. The reaction can be carried out with an amine of the formula RNH ₂ , wherein R is the
given above for the compounds of the formulas I and II
Has meanings in excess or in an inert diluent or solvent, such as methanol or isopropanol,
be performed.

The starting material required for the above process _f wherein X

is CH CH ₂ or -CHOHCH ₂ Z, or

which is a mixture of these two compounds can be prepared by reacting the corresponding phenol with an epihalohydrin, such as epichlorohydrin, in the presence of a
Base, such as an alkali hydroxide, for example sodium hydroxide, or an alkaline earth hydroxide, for example calcium hydroxide, or an amine, for example piperidine, in a diluent or solvent such as methanol or ethanol,

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or reacting in excess epichlorohydrin in the absence of a further solvent, at ambient temperature or at 75 to 110 ⁰ C.

The starting material for the above process in which the substituent X of the formula -CHOHCH ₂ Z is alkyl sulfonate or aryl sulfonate can be obtained by adding a glycol in which Z is hydroxy, with the proviso that Y is not hydroxy or amino is reacted with an alkylsulfonyl halide, an arylsulfonyl halide or an anhydride of the corresponding sulfonic acid, such as p-toluenesulfonyl chloride or methanesulfonic anhydride, in a solvent such as pyridine at ambient temperature. The glycols listed above can be prepared by reacting the corresponding phenol with 2,3-epoxypropan-1-ol or 3-chloro-1,2-propanediol in the presence of a base of the type mentioned above in an inert solvent such as ethanol, or by Hydrolysis of a compound of the formula

OCH ₂ CH-CH ₂

you CH

with an acid such as dilute hydrochloric acid in one inert solvent, v / ie water or ethanol or a mixture in the. The starting material for the above process is prepared by reacting a suitable phenol of the type described above with the acetonite of 3-chloro-1,2-propanediol in the presence of a base such as sodium hydroxide in a solvent such as methanol or ethanol.

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- "7 -

The invention also relates to a method for production of cycloalkyl derivatives of 1-aryloxy-3-amino-2-propanols of the formula I and II given above, by reaction of a phenol of the formula

in which A and Y have the meanings given above for the compounds of the formula I or in which the substituent A is the radical -CH-CH-- indicated for the compounds of the above formula II, with a compound of the formula

Z-CH ₂ CHOHCk ₂ KHR or CH ₃ CHCH ₂ NHR,

wherein Z has the meaning given above and R has the same meanings as given above for the compounds of formulas I and II. This process can be carried out in the presence an alkali hydroxide such as sodium hydroxide or an alkaline earth hydroxide such as calcium hydroxide in an inert Solvents such as methanol or ethanol can be carried out at ambient temperature or at 50 to 100.degree.

According to the invention, a process for the preparation of cycloalkyl derivatives of 1-aryloxy-3-amino-2-propanols is also disclosed Above given formulas I and II created, which consists in the fact that a compound of formula III

OCH ₂ CHCH ₂ NH ₂ OH

(HD;

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wherein A and Y are those given above for the compounds of formula I. Have meaning with a carbonyl compound, such as a cycloalkanone with 3 to 11 carbon atoms, 1-indanone or 2-norbornanone, in the presence of a suitable reducing agent, such as hydrogen, or a hydrogenation catalyst, for example platinum or palladium, in an inert solvent, such as ethanol or methanol, or an alkali borohydride such as sodium borohydride in a suitable solvent such as Methanol or Kthanol, implemented. If the substituent A is vinylene or if the ketone

Is 1-indanone, the process is of course carried out using alkali borohydride. If the substituent Y is amino, then this group is of course, as indicated above, provided with a non-hydrogenolysable protective group. To synthesize compounds of the formula II, a compound of the formula III in which A is -CH ₂ CH ₂ - is used either with acetone, if Y is cyclohexylcarbamoyl or cyclohexylmethylcarbamoyl, or with cyclohexanecarboxaldehyde, if Y is carbamoyl, in the method described above Wise implemented.

Those given above and used as the starting material for the above Compounds of the formula III used in said processes can be prepared by adding a compound of the formula

OCH ₂ X,

in which the substituents X, Y and A have the meanings given above, in a known manner, are reacted with ammonia.

Another process for the preparation of the compounds of the formula I consists in reacting compounds of formula III, wherein A and Y are the same as above for the compounds

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of the formula I have given meanings, with a halide, an alkylsulfonyloxy or an arylsulfonyloxy derivative of a cycloalkane having 3 to 11 carbon atoms, with 1-adamantyl, 1-norbornyl or 1-indanyl halides or with alkylsulfonates or arylsulfonates in the presence of an acid-binding agent, such as sodium carbonate, in an inert solvent such as methanol or ethanol, at ambient temperature or at 50 to 100 ^° C. The synthesis of compounds of the formula II is carried out by reacting a compound of the formula III in which A is -CH ₂ CH ₃ -, with an isopropyl halide or sulfonate, such as isopropyl bromide, if Y is cyclohexylcarbamoyl or cyclohexylmethylcarbamoyl, or with a cyclohexylmethyl halide or sulfonate, such as cyclohexylmethyl p-toluenesulfonate, if Υ is carbamoyl, in the manner indicated above.

The cycloalkyl derivatives of 1-aryloxy ~ 3-amino-2-propanols according to the invention of the formulas I and II given above can be prepared by hydrogenolysis of a compound of Form IV

OCH ₂ CHCH ₂ NRR 'H

(IV)

wherein A, Y and R have the meanings given above for the compounds of the formulas I and II, with the proviso that A does not stand for vinylene and R does not stand for 1-indanyl, and furthermore R ^{1 is} a hydrogenolysable protective group, such as the benzyl group, which can be split off with hydrogen and a suitable catalyst, such as platinum or palladium-on-carbon, under the specified conditions.

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The starting material for the above process can be prepared by reacting a compound of the formula

OCH ₂ X,

in which A, Y and X have the meanings given above, with an amine of the formula RR ¹ NH ₇ in which R and R ^{1 have} the meanings given above for the corresponding compounds of the formulas I and II, under the conditions described for this reaction, if the amine has the formula RNH ₅ , or by reacting a suitable phenol of the formula

in which A and Y have the meanings given above for the compounds of the formulas I and II, with a compound the formula

Z-CH ₂ CHOHCh ₂ NRR ¹ or CH ₃ CHCH ₂ NRR ¹ ,

in which R has the meanings given above for the compounds of the formulas I and II, under the conditions described for this reaction, the radical -NRR ^{1 being} replaced by the radical -NHR.

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- ti -.

The alkanolamines of the formulas I and II according to the invention can be prepared by adding a compound of formula V

OCH ₂ -CH-CH ₂

C ₆ H ₅

wherein A, Y and R have the meanings given above for the compounds of formulas I and II, hydrolyzed with an acid such as acetic acid or hydrochloric acid, at ambient temperature or at 50 to 110 ⁰ C.

The starting material for the above process can be prepared by using the alkali salt of an appropriate Phenol of the type described above, where the substituent Y is suitably protected, if Y is amino, with a compound of the formula

. ^C 6 «5

wherein Z has the meaning given above and R has the meanings given for the compounds of formulas I and II, in an inert solvent, such as ethanol, at ambient temperature or at 70 to 110 ⁰ C.

Another method of making compounds of the Formula V consists in that 'a compound of the formula

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OCH ₂ X,

wherein A and Y have the meanings given above and X is

~ "CH

CH

stands, and where the substituent Y is protected accordingly, if Y is amino, with a compound of the formula

CH = N-R,

in which R has the meaning given above for the compounds of the formulas I and II, in the absence or in the presence of an inert solvent, such as benzene or 1,2-dimethoxyethane, at 70 to 110 ^° C.

According to the invention, a process for the preparation of the alkanolamines according to the invention is also provided, which consists therein that one is a compound of the formula

OCH ₂ CH-CH ₂

I I

0 N-R,

Il

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wherein A, Y and R have the meanings given above for the compounds of the formulas I and II, with a base such as an alkali hydroxide, for example potassium hydroxide, or an alkaline earth metal hydroxide, for example calcium hydroxide, in an inert solvent such as water, methanol or ethanol or Combinations of these, at ambient temperature or at 50 to 90 ^° C. under conditions in which there is no hydrolysis of the substituent Y, if this substituent Y is carbamoyl, alkoxycarbonyl or cyano.

The starting material required for the above process can be Manufacture by making a compound of the formula

y- OCH ₂ CH-CH ₂ ,

YA

wherein A and Y have the meanings given above (with the proviso that the substituent Y is protected in the manner described if Y is amino, and that this substituent Y is also protected accordingly if Y is hydroxy) with an isocyanate of the formula RNCO, in which R has the meaning given above for the compounds of the formulas I and II, using a lithium bromide tributylphosphine oxide complex or a lithium bromide hexamethylphosphoramide complex as a catalyst in an inert solvent, such as benzene or xylene, at temperatures from 80 to 140 ⁰ C implements.

Another process for the preparation of the alkanolamines according to the invention consists in that a compound of the formula

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OCH ₀ CCH ₀ NRR ', ² Il ² O

in which A, Y _r R and R 'have the meanings given for the compounds of the formula IV, reacted with an alkali borohydride, such as sodium borohydride, in an inert solvent, such as ethanol or methanol, at ambient temperature.

The starting material for this process can be prepared by adding a compound of the formula

OCH ₂ CCH ₂ Z 0

in which A and Y have the meanings given above and Z is bromine or chlorine (with the proviso that the substituent Y is appropriately protected in the manner described, if Y is amino, and that compounds of the above type are excluded are, if Y, morpholine or the remainder of the formula

-CN, NCH ₀ CN (C ₀ Hc) _o / 2 "2 5 2

/
0 N / 0

means) with an amine of the formula RNH ₂ or the formula RR ¹ NH, where the substituents R and R ^{1 have} the meanings given above for the compounds of the formulas I and II, in an inert solvent such as ethanol, in the presence of an acid binder, such as sodium carbonate, at temperatures of 60 to 90 ⁰ C converts. The starting material required for this process can be prepared by using a ketone of the formula

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OCHoCCHo

² S ■

wherein A and Y have the meanings given above, under conditions in which the substituent Y is not impaired, with bromine or chlorine, although compounds of the above type are excluded if A is vinylene. That Starting material for the above process can be prepared by using a phenol of the formula

Oh

X /

YA

wherein A and Y have the meanings given above (with the proviso that the substituent Y corresponds in the manner indicated is protected if Y is amino, and that compounds of the above type are excluded if Y Morpholinyl or the remainder of the formula

means) with a halogen acetone, such as bromoacetone or chloroacetone, in an inert solvent such as methanol or Ν, Ν-dimethylformamide, in the presence of an acid binder, such as potassium carbonate, is reacted at ambient temperature or at 50 to 100 ⁰ C.

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Another process for the preparation of the alkanolamines of the invention of the formulas I and II is that one Compound of formula

OCH ₀ CHCH-NR, 2, 2,

/ ^d

OH NO

wherein A, Y and R are the same as above for the compounds of the formulas I. and II have given meanings, using a base such as ammonia, or an alkali hydroxide such as sodium hydroxide, hydrolyzed under mild conditions that do not alter the Y group. The raw material for this Process can be prepared by adding a compound of the formula

CH ₂ CHO

in which A and Y have the meanings given above, with a compound of the formula RN (NO) CH ₃ , in which R is the same as in the compounds

of the formulas I and II has the meanings mentioned, under Adol condensation conditions, for example using a base such as potassium hydroxide in an inert solvent such as ethanol at ambient temperature

or at 50 to 70 ⁰ C converts. The starting material required for this process can also be obtained by reacting a suitable one

Phenol with a haloacetaldehyde, such as chloroacetaldehyde, with in the manner described for the condensation of haloacetone with phenols.

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In certain reactions of the alkanolamines according to the invention protective groups are of course required as they are

3 4
Substituents R and R of the compounds of the formula VI

OCH ₂ CHCH ₂ NRR ³

OR ⁴ < ^VI >

represent, in which A, Y and R have the meanings given above for compounds of the formulas I and II and the Substituents R and R can be identical or different hydrolyzable or hydrogenolyzable protective groups, such as they are listed above for the protection of the substituent Y in formula I, if this substituent Y is amino. Optional

3 4
the substituents R and R can also be linked to one another, so that both the oxygen atom and the nitrogen atom are protected by a single protective group. A protective group of this type can, for example, be a radical of the formula

_β .CHR, where R is hydrogen or alkyl or aryl

with up to 10 carbon atoms, as for isopropyl or phenyl, so that an oxazölidine ring is formed together with the neighboring oxygen and nitrogen atoms. This protecting group can be removed by, for example, the compound in the presence of an acid such as a mineral acid, for example hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, in a suitable solvent such as water or ethanol, at ambient temperature or at 50 to. 100 ⁰ C hydrolyzed.

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The invention also relates to a method for production of compounds of the formula

OCH CHCH ₉ NH-R OH

A-Y

wherein R is cycloalkyl with 3 to 11 carbon atoms, cyclohexylmethyl, Is exo-2-norbornyl, 1-adamantyl or 1-indanyl, A is alkylene having 1 to 3 carbon atoms or vinylene and Y is carbamoyl, cyclohexylcarbamoyl, Ν, Ν-dimethylcarbamoyl, Cyclohexylmethylcarbamoyl, hydroxyl, amino, cyano, carboxyl, Alkoxycarbonyl, morpholine or a radical of the formula

0 ο

Il

-CN N-CH -CN ' ^{Δ J}

^C 2 ^H 5

means that there is a compound of the formula

OCH ₀ CCH ₉ NHR. 0

wherein A, Y and R have the meanings given above, reduced with an alkali borohydride such as sodium borohydride.

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The invention is also directed to a process for the preparation of alkanolamines of the formulas I and II, which consists in converting a compound of the formulas I or II, in which Y is a functional group, into another compound in which Y is a means other functional group. For example, a compound of the formula I in which Y is cyano can be converted to the corresponding compound of the formula I in which Y is carbamoyl, in the presence of an alkali hydroxide, such as sodium hydroxide, and in the presence of 6 to 12% hydrogen peroxide, if the Alkanolamine residue is suitably protected in the manner described, in a diluent or solvent, such as water, at temperatures of 50 to 100 C _r oZex In the presence of a sulfonated polystyrene resin,

such as IRA * ' -40O- (OH) resin, in a diluent or solvent such as water, at an elevated temperature, for example at reflux temperature, or in the presence of an acid such as hydrochloric acid or the complex of boron trifluoride and acetic acid in one Diluents or solvents, such as water, hydrolyzed at an elevated temperature, for example at reflux temperature.

A compound of the formula I in which Y is cyano can into the corresponding compound of the formula I in which Y is amino, for example using hydrogen in Presence of a catalyst such as platinum oxide in a suitable solvent such as ethanol (provided that A does not represent vinylene), or with a metal hydride, such as Lithium aluminum hydride, in an inert solvent such as benzene, at an elevated temperature, for example at the reflux temperature, be reduced.

Ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate can be prepared by reacting the corresponding alkyl or aryl esters, such as n-hexyl-p-p-cyclohexylamino ^ -hydroxypropoxy) hydrocinnamate, with ethanol in the presence of an acid,

609813/104

such as p-toluic acid, at ambient temperature or at 50 to 100 ⁰ C.

A compound of the formula I in which Y is alkoxycarbonyl can be converted into the corresponding compound of the formula I in which Y is carbamoyl by reacting with amines of the formula NHRR ¹ , in which R has the meaning given for the compounds of the formulas I and II and R ^{1 has the} above meaning, can be converted into a suitable solvent, such as ethanol, at ambient temperature or at 50 to 100.degree.

A compound of the formula I in which Y is alkoxycarbonyl, can be converted into the corresponding compound of the formula I in which Y is hydroxy, in the presence of a Metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran at ambient temperature or reduce at reflux temperature.

A compound of the formula I in which Y is carboxyl can be converted to the corresponding compound of the formula I in which Y denotes alkoxycarbonyl, for example by reaction with a lower alkanol, which is normally used as a solvent serves, in the presence of an acid such as p-toluenesulfonic acid, at ambient temperature or elevated temperature, for example at reflux temperature, are esterified. Ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate can thus by reacting p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid with the process described above Ethanol can be produced in the presence of anhydrous hydrogen chloride.

A compound of the formula VI in which Y is carboxy can be converted into the corresponding compound of the formula VI in which Y represents carbamoyl or N-substituted carbamoyl through

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Reacting the corresponding acid chloride with ammonia, cyclohexylamine, Cyclohexylmethylamine, dimethylamine or

in an inert solvent such as benzene at ambient temperature or elevated temperature, but preferably below room temperature. The corresponding acid chloride can be prepared from the corresponding compounds of the formula VI, in which Y is carboxyl, by reaction with an acid halide, such as thionyl chloride or oxalychloride, in an inert solvent such as benzene, at ambient temperature or at an elevated temperature, such as at 50 to 100 ⁰ C. The corresponding compounds of the formula VI in which Y is carbamoyl or N-substituted carbamoyl can then be converted into the corresponding compounds of the formulas I or II by splitting off the protective groups R and R in the manner described.

A compound of the formula I in which Y is carboxyl can lead to the corresponding compound of the formula I in which Y is Hydroxy stands, with a metal hydride, such as lithium aluminum hydride, in an inert solvent such as tetrahydrofuran, reduced at ambient temperature or at reflux temperature will.

A compound of the formula VI in which Y is carbamoyl can form a compound of the formula VI in which Y is cyano stands, using dehydrating agents such as phosphorus pentachloride, thionyl chloride or Ν, Ν'-dicyclohexylcarbodiimide, in the presence or absence of an inert solvent such as benzene at an elevated temperature, for example at reflux temperature, are dehydrated.

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_ OO

A compound of the formula I in which Y is carbamoyl or morpholinylcarbonyl can be converted to the corresponding ' Compound of the formula I, in which Y is amino or morpholinyl, with a metal hydride, such as lithium aluminum hydride, reduce in an inert solvent such as tetrahydrofuran at ambient temperature or at reflux temperature.

A compound of the formula I in which Y is carbamoyl or N-substituted carbamoyl can be hydrolyzed to the corresponding compound of the formula I in which Y is carboxyl by treating the former with a base such as sodium hydroxide in a diluent or solvent, such as water, at an elevated temperature, such as reflux temperature, or in the presence of an acid such as phosphorus,
hydrolyzed.

such as phosphoric acid, at an elevated temperature, such as 50 to 100 C,

A compound of the formula VI in which Y is amino can be converted into a compound of the formula VI in which Y is hydroxy, be converted by treating the former with nitrous acid in an inert diluent or solvent, such as aqueous Acetic acid, at 0 to 10 C or at ambient temperature.

From a compound of the formula VI in which Y is halogen, such as bromine, or alkylsulfonyloxy, such as methanesulfonyloxy, or an arylsulfonyloxy, such as p-toluenesulfonyloxy, a compound of the formula VI, in which Y is cyano, can be prepared by the former is reacted with a metal cyanide such as potassium cyanide, in a diluent or solvent such as ethanol or water, at ambient temperature or at 50 to 100 ⁰ C.

The starting materials for the above process can be made from compounds of the formula VI, in which Y is hydroxy, can be prepared by reacting the latter with a halogenating agent such as

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Phosphorous tribromide, or an alkylsulfonyl halide or -anhydride, such as methanesulfonyl chloride or methanesulfonyl anhydride, or an aryl sulfonyl halide, such as p-toluenesulfonyl chloride, in a solvent such as pyridine at ambient temperature.

A compound of the formula VI in which Y is halogen, such as bromine, or alkylsulphonyloxy, such as methanesulphonyloxy, or arylsulphonyloxy, such as p-toluenesulphonyloxy, can be converted into a compound of the formula VI in which Y is amino, by converting the former with ammonia in a closed reaction vessel at ambient temperature or at 50 to 100 ° C. or with an alkali phthalimide such as potassium phthalimide under conditions suitable for the Gabriel synthesis, for example in an inert solvent such as N, N-dimethylformamide, at ambient temperature or at 50 to 100 ⁰ C with subsequent cleavage of the phthaloyl group with an amine, such as hydrazine, in an inert solvent such as ethanol, at ambient temperature or at 50 to 100 ⁰ C, and subsequent heating with an acid such as hydrochloric acid, in a solvent such as Acetic acid, at 50 to 100 C.

The invention is further directed to a process for the preparation of alkanolamines of the formulas I and II, in which a compound of the formula I or II, wherein A is vinylene, with hydrogen and a catalyst, such as palladium-on-carbon, in an inert Solvent, such as methanol, is reduced at ambient temperature or at elevated temperature, such as 50 to 100 ⁰ C, at atmospheric or elevated pressure.

Compounds of the formulas I and II in which A is vinylene can be prepared by reacting an aldehyde Formula VII

6 098 1 3/10 40

CHO

- 24 -.

OCH ₂ CHCH ₂ NHR OH

(VII)

in which R has the meanings described for the compounds of the formulas I and II, with a compound of the formula WCH ₂ CO ₃ H, in which W is cyano, carboxy, carbamoyl or N-substituted carbamoyl, such as N-cyclohexylcarbamoyl, N-cyclohexylmethylcarbamoyl or

-CON NCH ₂ CON (C ₃ H ₅ ) ₂

, in the presence of a base, such as piperidine, in a diluent or solvent such as pyridine, at an elevated temperature such as 80 to 110 ⁰ C. Ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate can be prepared by this method by reacting a compound of the formula VII in which R is cyclohexyl with ethyl hydrogen malonate to give ethyl p- (3-cyclohexylamine ^ -hydroxypropoxy) cinnamate, and this compound can then be hydrogenated by the process described above.

Another process for the preparation of compounds of the formulas I and II, in which A is vinylene, consists in that a compound of the above formula VII with a compound of the formula WCH ₂ PO (OR) -, in which W has the above meaning with the proviso that W does not represent carboxy and R denotes alkyl with up to 6 carbon atoms, such as ethyl, under conditions suitable for a Wittig reaction, for example in the presence of a base such as sodium hydride, in a diluent or solvent, such as 1,2-dimethoxyethane, converts at ambient temperature.

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Another process for the preparation of alkanolamines of the formula I, in which A is ethylene, and Y is amino, consists in that the aldehyde of the above formula VII, in which R has the meaning given for formula I, with nitromethane in the presence of a Base, such as potassium hydroxide, in a diluent or solvent, such as ethanol, at temperatures below 25 ^° C., for example at 5 ^° C., with subsequent acidification with a mild acid, such as dilute hydrochloric acid, sodium bisulfate or 5 percent acetic acid a compound of the formula

? ^H

OCH ₂ CHCH ₂ NHR,

CH = CHNO ₂

wherein R has the above meaning, and this compound is then reacted with a reducing agent such as lithium aluminum hydride, in an inert solvent such as tetrahydrofuran, or with hydrogen or a suitable catalyst such as palladium on carbon, in a suitable diluent or solvent such as tetrahydrofuran or methanol or acetic acid, is reduced at ambient temperature or 50 to 100 ⁰ C.

Alkanolamines of the formula VI, in which Y stands for cyano, can be converted into mines of the formula

OCH ₀ CHCH ₀ NRR

OR ⁴

CH ₂ CH = NH

6098 1 3 / 10A0

3 4
wherein R, R and R have the meanings given for formula VI, with a suitable dehydrating agent such as acetic anhydride alone or in combination with sodium acetate.

For alkanolamines of the formula VI, in which Y is hydroxy, can be obtained by adding a compound of formula VIII

OCH ₀ CHCH-NRR ³

^{2 |} λ OR ⁴

ACHO (VIII).

3 4
wherein R, R and R have the meanings given for formula VI, under conditions of a Meerwein-Pondorf-Verley reduction, for example in the presence of an alkali alkoxide such as aluminum isopropoxide, in a diluent or solvent such as isopropyl alcohol, at elevated temperature, for example at Reflux temperature, reduced. The reduction can also optionally be carried out using a metal hydride such as sodium borohydride in a diluent or solvent such as ethanol at ambient temperature.

Alkanolamines of the formula VI in which Y is cyano, hydroxy, amino or morpholinyl can be prepared according to the invention by adding a compound of formula IX

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CH ₂ CHCH ₂ NRR ³

OR ⁴ . (ix),

CH = CH-CH ₂ Hal

3 4

wherein R, R and R are those indicated for the compounds of the formula VI Have meanings and Hai stands for halogen, for example bromine, is reacted with certain nucleophilic agents. A compound of the formula VI in which Y is cyano can thus be prepared by adding a compound of the formula IX with a cyanide salt, such as sodium cyanide, in the presence or absence of a promoter, such as a metal iodide, for example sodium iodide, in a diluent or solvent, such as dimethyl sulfoxide, at moderate temperatures, for example at 15 to 50 C. A connection of the formula VI, in which Y is hydroxy, can be prepared by reacting a compound of the formula IX with a Source of hydroxide ions such as aqueous sodium carbonate in a diluent or solvent such as water Ambient temperature or elevated temperature, for example at reflux temperature, hydrolyzed. A connection of the Formula VI, in which Y is amino or morpholinyl, can, for example, by reacting a compound of the Formula IX with ammonia or morpholine in a diluent or solvent such as ethanol at ambient temperature or 50 to 100 ° C can be produced.

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Compounds of the formula IX can be obtained by adding a compound of the formula

OCH ₂ CIICh ₂ NRR ³ OR *

CH = CHCH3

3 4
wherein R, R and R have the meanings given for compounds of formula VI, with a halogenating agent such as N-bromosuccinimide, in a diluent or solvent such as benzene, in the presence of a trace of a peroxide such as benzoyl peroxide, at elevated temperature, for example at reflux temperature.

The starting materials required for the above process can be prepared from propenyphenols of the formula

CH = CHCH ₃

can be prepared using the procedure described above, with the proviso that no procedures are employed may be, in which a catalytic hydrogenation is required.

Compounds of the formula VI in which Y is carboxyl can be prepared by adding a compound of the

6098 1 3 / 10A0

3 4
Formula VIII, wherein R, R and R have the meanings given for the compounds of formula VI, with an oxidizing agent such as potassium permanganate, in the presence of a base such as potassium hydroxide, in a diluent or solvent such as water, at room temperature or elevated temperature , for example at 40 to 60 ⁰ C, implemented.

Compounds of the formula VI in which Y is amino can be obtained by adding an aldehyde of the formula VIII,

3 4
wherein R, R and R have the meanings given for the compounds of the formula VI, subjecting a reductive amination with a mixture of hydrogen and ammonia in the presence of a catalyst, for example Raney nickel, at elevated pressure, for example by heating in a closed reaction vessel.

The compounds according to the invention are valuable medicaments and they are particularly suitable for treatment and prevention of cardioarrhythmia. You own a low one ß-adrenaline blocking effect (25% or less than that of dl-propanolol) and therefore do not lead to any Cardiac depression. The antiarrhythmic effectiveness of this new compounds is determined by a corresponding experiment on guinea pigs. The principle of this experiment consists in giving guinea pigs intravenous administration of the cardiac glycoside thevetin Induces cardiac arrhythmia and examines whether and for how long the respective active substance delay the onset of this cardiac arrhythmia can. For this purpose, male guinea pigs of the Hartley strain, which weigh 400 to 600 g, are first passed through untraperitoneal Injection of 1500 mg urethane per kg body weight anesthetized. Then the trachea is cannulated, towards which point The right and left jugular veins are cannulated for infusion purposes. To the To measure the heart rate of the animal, the lines are connected in such a way that they correspond to an EKG with line II.

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Thevetine dissolved in normal saline is released into the left jugular vein at a constant rate of 100 mg / kg Body weight / 0.1 ml thevetine solution / minute infused, whereby a cardiac arrhythmia occurs in the comparison animals after 14.9 + 0.9 minutes, which is reflected in the loss of the P-wave shows on the electrocardiogram and this point is taken as the end point. The active ingredient to be examined in each case (100 mg) is dissolved in 1 to 4 ml of a suitable solvent, such as normal saline solution, 25% strength 0.1 η hydrochloric acid in normal Saline solution, 25% 0.1 η sodium hydroxide in normal saline solution, 25% ethanol in normal saline, 25% propylene glycol in normal saline, a 1: 1 mixture of ethanol and Propylene glycol or a 1: 1: 1 mixture of 0.1 η hydrogen chloride acid, ethanol and propylene glycol, depending on the solubility of the particular compound used. Someone else In a number of animals, such an amount of the above solution is infused into the right jugular vein over a period of 5 minutes that that a total dose of 5, 10 or 25 mg of active ingredient per kg of body weight is obtained, with 7 to 8 minutes on it the infusion of the Thevetin solution into the left jugular vein begins. The time until the P wave disappears in this case examined group of animals is compared with the corresponding time in the comparison group. Occasionally shows the Compound certain signs of toxicity when administered at the maximum allowable dose. A connection is considered effective; if it delays the thevetine-induced loss of the P-wave by at least 20 minutes. In a representative series of tests, typical compounds according to the invention show an antiarrhythmic activity, when administered intravenously according to the procedure given in the doses shown in Table I below examined.

The ß-adrenaline blocking effect is based on guinea pigs determined by the so-called atrial strap test. For this purpose, guinea pigs of both sexes are weighed

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400 to 600 g killed by a blow to the head. The heart is then quickly removed and placed in a bowl filled with Ringer-Locke solution, oxygen being passed through the solution. The two atria are separated from the ventricles and placed in an isolated organ bath kept ^{at a constant temperature of 30 + 1 ° C.} The force of contraction of the atria is recorded on a Grass polygraph by connecting one end of an atrium to a Grass Force Displacement Transducer (FT-03) after a tension of 1.0 g is applied. After an initial stabilization time of 10 to 15 minutes

the bath increasing amounts of isoproterenol (1 χ 10 "^ mol to

—7 —2

I χ IO moles, dissolved to 10 moles in normal saline, which

10 moles of ascorbic acid) are added, and a dose-effect curve is obtained in this way. After repeated washing of the atria, the bath is mixed in a concentration of 10 mol with the particular compound to be investigated or the ß-adrenaline blocker dl-propanolol in 10 molar solution in a suitable Solvents, such as distilled water, normal saline,

II to 15% strength 0.1 η hydrochloric acid in distilled water or normal saline, 11 to 15% ethanol in distilled Water or normal saline or 11 to 15% propylene glycol in distilled water. Be 15 minutes later repeated the experiments with isoproterenol. The dose-response curve of isoproterenol in the presence and in the absence of the particular active ingredient to be investigated is on semi-logarithmic paper applied with seven decades. The relative potencies of the compounds tested, based on those for a 50 percent Inhibition of the isoproterenol effect compared to dl-propranolol (propranolol = 100%) required amount, emerge from the following Taelle I.

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Tabel

Compound 2- / o- (S-Cyclopropylamino ^ -hydroxypropoxy) phenyl / acetamide

2- / 0- (3-cyclobutylamino-2-hydroxypropoxy) phenyl / acetamide hydrate (4: 1)

2- / 0- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide

2- / o- (3-Cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide hydrate (8: 1) 2- / 0- (3-CycloheptylaInino-2-hydroxypropoxy) phenyl / acetamide 2- / m- (3-cyclohexylamino-2 -hydroxypropoxy) phenyl / acetamide 2- / p- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide 2 - / _ p ~ (3-cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide

o-P-Cyclopropylamino ^ -hydroxypropoxy) hydrocinnamamide hemifumarate hemihydrate

ο- (3-cyclobutylamino-2-hydroxypropoxy) hydrocinnamamide

ο- (S-Cyclopentylamino ^ -hydroxypropoxy) hydrocinnamamide hemifumurate

Anti-arrhythmic activity

on guinea pigs with thevetine infusion

Dose time (mini to
(mg / kg, disappearance of the
iv) P waves

15.0

10.0

40.0 + 5.3

15.0 23.6 ± 2.0 15.0 34.0 + _ 5.0 18.3 34.5 + 0.3 15.0 31.0 + 11.2 10.0 23.9 + _ 2.7 10.0 31.0 + _ 6.2 17.7 22.8 + 0.3 10.0 35.0 J ₁ 6.3 9.6 33.9 + 4.6

36.9

1.7

β-blocker activity

Percent of dl-propranolol

5 3

24 3

14 24

10

in

cn cn

JN)

Table I (continued) link

o- (B-Cyclohexylamino - ^ - hydroxypropoxy) hydrocinnamamide hemifumarate

N-Cyclohexylmethyl-o- (S-cyclohexylamino - ^ - hydroxypropoxy) hydrocinnamamide

4- / o- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamoyl / -N, N-diethy1-1-piperazine acetamide dihydrochloride

o- (3-Cycloheptylamino-2-hydroxypropoxy) hydrocinnamamide hemifumarate

o- (3-Cyclooctylamino-2-hydroxypropoxy) hydrocinnamamide hemifumarate

o- (3-Cyclononylamino-2-hydroxypropoxy) hydrocinnamamide hemifumarate

o- (3-Cyclodecylamino-2-hydroxypropoxy) hydrocinnamamide hemifumarate

o- (3-Cycloundecylamino-2-hydroxypropoxy) hydrocinnamamide-hemi fumarate sesquihydrate

o- / 2-Hydroxy-3- (exo-2-norbornylamino) propoxy / hydrocinnamamide hemifumarate

Anti-arrhythmic activity

on guinea pigs with thevetine infusion

dose
(mg / kg,
iv) Time (min.) Until
Disappearance of
P waves ± 1.5 10.0 39.4 2.8 2.8 20.0 1.6 6.1 21.9 ± 4.8 10.0 40.2 + 2.7 .10.0 44.8 + _ 7.0 15.0 39.5 + _ 6.6 15.0 49.7 + 6.1 15.0 27.1 + 4.5 25.0 33.2

ß-blocker activity

Percent of dl-propranolol

10

14th

6 KJ

17th

Tabel

(Continuation)

link

O- / 3- (1-Adamantylamino) -2-hydroxypropoxy / hydrocinnamamide hemifumarate hydrate and hydrochloride hemihydrate

o- / 2-Hydroxy-3- (indanylamino) propoxy_ / hydrocinnamamide

o- | 3 - / ^ (cyclohexylmethyl) amino / -2-hydroxypropoxy? -hydrocinnamamide

N-Cyclohexyl-o- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamamide

N-Cyclohexylmethyl-o- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamamide

m- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamamide

p- (3-Cyclopentylamino-2-hydroxypropoxy) cinnamamide

p- (3-Cyclopentylamino-2-hydroxypropoxy) hydrocinnamamide hydrochloride

p- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamamide hemifumarate Antiarrhythmic activity

on the guinea pig
with Thevetin Infuslon

Dose time (min.) To
(mg / kg, disappearance of the
iv) P waves

10.0
10.0

8.2

25.0

29.9
31.1

2.7
2.3

37.1 + 7.7

15.0 28.4 + 2.6 5.0 25.3 + 5.7 4.0 27.6 ± ² ' ⁴ 25.0 21.4 + 2.5 15.0 32.2 + 1.8 15.0 43.0

24.4 + 1.4

ß-blocker activity

Percent of dl-propranolol

16

15 24

5 8

10

Table I (continued)

cx> ο cc

link

I - /? - (3-aminopropyl) phenoxy _ / - 3-cyclohexylamino-2-propanol

1-Cyclohexylamino-S-Zo- (3-morpholinopropyl) phenoxy _ / -2-propanoi

o- (S-Cyclohexylamino - ^ - hydroxypropoxy) hydrocinnamonitrile hydrochloride

ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate

1-Cyclohexylamino-S-Zo- (3-hydroxypropyl) phenoxy-2-propanol hemifumarate

1-Cyclohexylamino-S-Zp- (3-hydroxypropyl) phenoxy / -2-propanol hemifumarate

o- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid hydrochloride

2- / 0- (3-Cyclopropylamino-2-hydroxypropoxy) phenyl / -N, N-dimethylacetamide hydrochloride

Anti-arrhythmic activity

on guinea pigs ff. with Thevetin infusion

Dose time (min.) To
(mg / kg, disappearance of the
iv) P waves

1O, O

9.5

28.4 + 0.9

21.5 + 2.3

9.1 23.0 + 1.2 10.0 30.1 + 1.1 4.7 33.8 + 4.2 25.0 24.4 + 2.0 15.0 20.8 + 3.6 15.0 24.7 + 7.5

ß-blocker activity

Percent of dl-propranolol

25th

24

The invention is further illustrated by the following examples.

Example 1 2- / o- (2,3-epoxypropoxy) phenyl / acetamide

A solution of 273 ml of epichlorohydrin in 175 ml of ethanol is stirred over a period of one hour with a solution of 48.44 g of o-hydroxyphenylacetamide / Annals 313, 79 (1900] _ / and 35 ml of 10 η sodium hydroxide in 700 ml of absolute The mixture is left to stand at room temperature for 4 days, the mixture is filtered and the filtrate is evaporated under reduced pressure to a colorless oil, the oil obtained is dissolved in methylene chloride and the solution is washed with water and then dried over magnesium sulfate . After filtration, the solution obtained and evaporation under reduced pressure to obtain 34.53 g of colorless crystals, melting at 97 and 103 ⁰ C. recrystallization from ethyl acetate and then from ethanol leads to 2- / o- (2,3 -Epoxypropoxy) phenyl / acetaraid colorless in the form of crystals melting at 100 to 1Ο2 ⁰ C.

Example 2 2-Ip- (3-Cyclopropylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 15.0 g of 2- / o- (2,3-epoxypropoxy) phenyl / acetamide and 15.0 g of cyclopropylamine in 250 ml of isopropanol is heated to reflux temperature for 4 hours and then evaporated under reduced pressure to give a colorless syrup receives. By crystallization of this syrup from ether-ethyl acetate to obtain 16.3 g of colorless crystals, melting at 90 to 96 ⁰ C.

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After recrystallization from ethyl acetate, 4.7 g of 2- / o- (3-cyclopropylamino-2-hydroxypropoxy) phenyl / acetamide are obtained in the form of colorless granular crystals with a melting point of 96 to 98 ^° C.

Example 3 2- / o- (3-cyclobutylamino-2-hydroxypropoxy) phenylacetamide

A solution of 15, Og 2- / o- (2,3-epoxypropoxy) phenyl / acetamide, 15.5 g cyclobutylamine hydrochloride and 14.4 ml 10 η sodium hydroxide in 250 ml isopropyl alcohol is refluxed for 4 hours and then in filtered while still hot. A colorless syrup is obtained by evaporating the filtrate under reduced pressure. The syrup is crystallized from ethyl acetate with the aid of diatomaceous earth, yielding 13.3 g of colorless crystals of melting point 112 to 114 ⁰ C. Recrystallization from ethyl acetate resulting in 9.0 g of 2- / o- (3-cyclobutylamino-2-hydroxypropoxy) phenyl / acetamide colorless in the form of crystals, melting at 116 to 118 ⁰ C.

Example 4 2- / o- (3-Cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 15.0 g of 2- / o- (2,3-epoxypropoxy) phenyl / acetamide and 15.0 g of cyclopentylamine in 250 ml of isopropyl alcohol is heated to reflux temperature for 4 hours, after which it is allowed to stand at room temperature for 18 hours. The colorless solid obtained after evaporation of this solution under reduced pressure gives after recrystallization from ethyl acetate 17.6 g of 2- / o- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide colorless in the form of crystals, melting at 123-124 ⁰ C. .

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Example 5

2- / o- (3-Cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide hydrate (8; 1)

A solution of 10.35 g of 2- / o- (2,3-epoxypropoxy) phenyiyacetamide in 50 ml of cyclohexylamine and 50 ml of isopropyl alcohol is heated to reflux temperature for 6 hours and then evaporated under reduced pressure. In this case, one obtains 15.00 g of colorless crystals having a melting point 131-139 ⁰ C. By recrystallization from ethyl acetate-methanol to obtain 6.31 g of colorless crystals, melting at 140 to 145 ⁰ C. A further recrystallization from heptane gives 2- / op-Cyclohexylamino ^ -hydroxypropoxy) phenyl / acetamide hydrate (8: 1) in the form of colorless crystals which melt ^{at 144 to 145 ° C.}

Example 6 2- / o-p-Cycloheptylamino - ^ - hydroxypropoxy) phenyl / acetamide

A solution of 15.0 g of 2- / b- (2,3-epoxypropoxy) phenyl / acetamide and 15.0 g of cycloheptylamine in 250 ml of isopropyl alcohol is heated to reflux temperature for 4 hours, after which it is allowed to stand at room temperature for 18 hours. The obtained solution is evaporated under reduced pressure and crystallizing the colorless residue from ethyl acetate and obtained as 18.7 g of colorless crystals of melting point 129 to 131 ⁰ C. Recrystallization from ethyl acetate leads to 16.5 g of 2- / ο- (3-cycloheptylamino-2-hydroxypropoxy) phenyl / acetamide colorless in the form of crystals, melting at 132.5 to 133.5 ⁰ C.

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Example 7 m- (2,3-Epoxypropoxy) phenylacetamide

A solution of 100 ml of epichlorohydrin in 60 ml of ethanol is over a period of 15 minutes with a solution of 15.12 g of m-hydroxyphenylacetamide / piss. Pharm. Pharmacol. 20, 607 (1968) / and 10 ml of 10 η sodium hydroxide in 230 ml of absolute ethanol are added. The whole is left to stand for 8 days at room temperature, the suspension obtained is filtered and the filtrate is evaporated under reduced pressure. 23.94 g of colorless crystals are obtained as residue. The ümkristallisation from ethyl acetate yields 11.62 g of m- (2,3-epoxypropoxy) phenylacetamide colorless in the form of prisms, melting at 93 to 95 ⁰ C.

Example 8 2- / m- (3-Cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 4.14 g of m- (2,3-epoxypropoxy) phenylacetamide in 20 ml of cyclohexylamine and 20 ml of isopropyl alcohol is heated to reflux temperature for 2 hours and then evaporated under reduced pressure. 6.42 g of colorless crystals which ^{melt at 134 to 135 °} C. are obtained as residue. Which melt the ümkristallisation of ethyl acetate and then from benzene to give 2- / jr.- O-cyclohexylamino ^ -hydroxypropoxy) phenyl / acetamide in the form of white crystals at 132 to 133.5 ⁰ C. By reaction with cyclobutylamine, 2- / m- (3-cyclobutylamino-2-hydroxypropoxy) pheny] L / acetamide is obtained in a similar manner. A corresponding reaction with cyclodecylamine leads to 2- / m- (3-cyclodecylamino-2-hydroxypropoxy) phenyl / acetamide.

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- 4Ö -.

Example 9 2- / p- (2,3-epoxypropoxy) phenyl / acetamide

A solution of 150 ml of epichlorohydrin in 90 ml of absolute ethanol is stirred over a period of 15 minutes with a solution of 22.6 g of p-hydroxyphenylacetamide / reports 22, 2141 (18892 / and 15 ml of 10 M sodium hydroxide in 345 ml of absolute ethanol added. Stir the solution may be for 18 hours at room temperature and then filtered them. by washing the filter cake with water are obtained 22.7 g of colorless crystals, melting at 168 ⁰ C melt. recrystallization from ethyl acetate-ethanol to give 2- / p - (2,3-Epoxypropoxy) phenyl / acetamide in the form of colorless platelets which melt ^{at 168 to 170 ° C.}

Example 10 2- / p- (3-Cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 8.00 g of 2- / p- (2,3-epoxypropoxy) phenyl / acetamide and 20.0 g of cyclopentylamine in 180 ml of isopropyl alcohol is heated to reflux temperature for 4 hours and then filtered while hot. The filter cake is washed with 20 ml of isopropyl alcohol, whereupon the combined filtrates are cooled and filtered. In this case, we obtain 8.40 g of 2- / p- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetamide colorless in the form of needles, melting at 155-158 ⁰ C.

Example 11 2- / p- (3-Cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 10.36 g of 2- / p- (2,3-epoxypropoxy) phenyl / acetamide in a mixture of 50 ml of cyclohexylamine, 50 ml

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2 5 4 η 5 5

Isopropyl alcohol and 25 ml of methanol are heated to reflux temperature for one hour and then evaporated under reduced pressure. The colorless crystals obtained are dissolved in dilute hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is mixed with sodium hydroxide, whereupon the mixture is filtered and the filter cake is washed with water. This gives 13.78 g of colorless crystals of melting point 154-155 ⁰ C. Recrystallization from ethyl acetate results in 10.12 g of 2- / p- (3-cyclohexylamino-2-hydroxypropoxy) phenyl / acetamide as colorless crystals, melting at Melting between 154 and 155 ^{° C.}

Example 12 2- / p- (3-Cycloheptylamino-2-hydroxypropoxy) phenyl / acetamide

A solution of 4.90 g of 2- / p- (2,3-epoxypropoxy) phenyl / acetamide and 5 ml of cycloheptylamine in 100 ml of isopropyl alcohol and 20 ml of absolute ethanol is heated to reflux temperature for 4 hours. By cooling and filtering, 3.84 g of colorless crystals which ^{melt at 163 to 165 °} C. are obtained. Recrystallization from ethanol yields 2.89 g of 2- / p- (3-cycloheptylamino-2-hydroxypropoxy) phenyl / acetamide in the form of colorless crystals having a melting point of 163 to 163.5 ⁰ C.

Example 13 o- (2,3-Epoxypropoxy) hydrocinnamic acid amide

A solution of 170 g of epichlorohydrin in 100 ml of ethanol is used with stirring over a period of one hour with a solution of 29.2 g of o-hydroxyhydrocinnamic acid amide / ^ Science Reports Tohoku Imp. Univ. 17, 695 (1928) _ / and a solution by

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18/5 ml of 10 η sodium hydroxide in 300 ml of ethanol are added. The whole is left to stand for 48 hours at room temperature, the mixture is then filtered to separate 9.30 g of sodium chloride and the filtrate is evaporated under reduced pressure. The colorless crystals obtained in this way are dissolved in dichloromethane, whereupon the solution is washed with 1 η sodium hydroxide and with water and then dried over magnesium sulfate. The solution obtained after filtration is evaporated under reduced pressure. 38.38 g of colorless crystals are obtained. A sample thereof is recrystallized from ethyl acetate to give o- (2,3-epoxypropoxy) hydrocinnamide obtained in the form of colorless crystals, melting at 43 to 45 ⁰ C.

Example 14

o- (3-Cyclopropylamino-2-hydroxypropoxy) hydrocinnamic acid amide

hemifumarate hemihydrate

A solution of 11.05 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 10.0 g of cyclopropylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for 4 hours and then evaporated under reduced pressure. 13.45 g of a colorless oil are obtained as residue. A solution of this oil and 2.90 g of fumaric acid in ethanol is diluted with ether, and filtering this solution gives 0.27 g of o- (3-cyclopropylamino-2-hydroxypropoxy) hydrochloric acid amide hemifumarate hemihydrate in the form of colorless crystals that melt at 95 to 97 ^{° C.}

Example 15 o- (3-Cyclobutylamino-2-hydroxypropoxy) hydrocinnamic acid amide

A mixture of 5.35 g of cyclobutylamine hydrochloride and 10.00 g o- (2,3-Epoxypropoxy) hydrocinnamic acid amide in 50 ml of ethanol and 5 ml

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1O η sodium hydroxide is heated to reflux temperature for 6 hours. The resulting mixture is filtered and the filtrate is evaporated under reduced pressure. 13.04 g of colorless crystalline residue are obtained. The residue is recrystallized from ethyl acetate and then dissolved in dilute hydrochloric acid. The cloudy solution obtained is extracted with ethyl acetate. The aqueous solution is made basic with sodium hydroxide and the resulting mixture is extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. 4,2Og obtained of a colorless crystalline residue, which melts at 125 to 128 ⁰ C.

The residue is chromatographed over silica gel using chloroform-methanol (6: 1) as the eluant, monitoring the effluent at 275 NM. The fraction corresponding to the first maximum is collected and evaporated under reduced pressure. 4.90 g of colorless crystals which ^{melt at 129 to 131 °} C. are obtained. Recrystallization of this material from ethyl acetate-methanol provided 2.05 g of O- (3-cyclo ~ butylamino-2-hydroxypropoxy) hydrocinnamide in the form of colorless crystals having a melting point of 131-133 ⁰ C.

Example 16

o- (3-Cyclopentylamino-2-hydroxypropoxy) hydrocinnamic acid amide

hemifumarate

A solution of 11.05 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 8.52 g of cyclopentylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for 4 hours and then under reduced pressure evaporated. 15.01 g of colorless oil are obtained as residue. A solution of this oil and 2.90 g of fumaric acid in hot absolute Ethanol is cooled and filtered. This gives colorless crystals, from which one recrystallises twice

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passes from ethanol to 9.73 g of O- (3-cyclopentylamino-2-hydroxypropoxy) -hydrozimtsäureamid hemifumarate as colorless crystals, melting at 170-171 ⁰ C.

Example 17

o- O-Cyclohexylamino ^ -hydroxypropoxy) hydrocinnamic acid amide hydrate (4: 1) and hemifumarate

A solution of 6.64 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide in 75 ml of cyclohexylamine is heated to reflux temperature for 6 hours and then evaporated under reduced pressure. 12.09 g of colorless oil remain as residue. This oil crystallizes on standing. The material obtained is recrystallized twice from ethanol, giving 5.21 g of o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide hydrate (4: 1) in the form of colorless crystals with a melting point of 140 to 141 ° C. A solution in hot ethanol is prepared from these crystals and 1.89 g of fumaric acid, which is then cooled and filtered. Colorless crystals with a melting point of 187 to 189 ^° C. are obtained. Recrystallization of these crystals from ethanol gives 4.60 g of o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate in the form of colorless crystals, which are at 187 to 189 ⁰ C melt. .

Example 18 N- (Cyclohexylmethyl) -o-hydroxyhydrocinnamic acid amide

A solution of 100.0 g of hydrocoumarin in 150 ml of absolute Ethanol is used over a period of 30 minutes with occasional use 84.7 g of (cylohexy! Methyl) amine are added to the mixture.

6 0 98 13/10 40

and during this time the temperature rises to 70 C. The solution is cooled to room temperature and then evaporated under reduced pressure. This gives 61.55 g of colorless crystal ropes of melting point 113 to 115 ⁰ C. Recrystallization from absolute ethanol gives N- (cyclohexylmethyl) -o-hydroxyhydrocinnamide colorless in the form of crystals, melting at 113 to 115 ⁰ C.

Example 19 N- (Cyclohexy! Methyl) -ο- (2,3-epoxypropoxy) hydrocinnamic acid amide

A solution of 200 ml of epichlorohydrin in 120 ml of absolute ethanol is added over a period of 30 minutes with stirring with a solution of 52.27 g of N- (cyclohexylmethyl) -o-hydroxyhydrocinnamic acid amide and 20 ml of 10 η sodium hydroxide in 460 ml of absolute ethanol. The whole is left to stand for 4 days at room temperature, after which the reaction mixture is evaporated under reduced pressure. The residue obtained is suspended in chloroform, whereupon it is washed with dilute sodium hydroxide and then with water. The chloroform extract is dried over magnesium sulfate and filtered. Evaporation of this filtrate under reduced pressure gives 57.00 g of a mixture of colorless oil and crystals. This mixture is treated with hexane and filtered. This gives 54.35 g of colorless crystals of melting point 59-60 ⁰ C. Recrystallization from ethanol gives N- (cyclohexylmethyl) -O- (2,3-epoxypropoxy) hydrocinnamide colorless in the form of crystals, melting at 60 to 61 ⁰ C. . By reacting N- (cyclohexylmethyl) -2- (p-hydroxyphenyl) acetamide, which is prepared by reacting methyl 2- (p-hydroxyphenyl) acetate with (cyclohexylmethyl) amine, with epichlorohydrin according to the process described above one N- (cyclohexylmethyl) -2- / jp- (2,3-epoxypropoxy) phenyl / acetamide. In a similar way, one arrives at the implementation of

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N- (Cyclohexylmethyl) -p-hydroxyhydrocinnamic acid amide, the one through Reaction of methyl-p-hydroxyhydrocinnamic acid residues with (CyclohexylmethyDamin obtained, to N- (Cyclohexylmethl) -p- (2,3-epoxypropoxy) -hydrocinnamamide.

Example 20

N-Cyclohexylmethyl-o- (3-cyclohexylamino-2- hydroxypropoxy) hydrocinnamic acid amide

A solution of 6.34 g of N- (cyclohexylmethyl) -o- (2,3-epoxypropoxy) hydrocinnamic acid amide in 20 ml of cyclohexylamine is heated to reflux temperature for 2 hours and then evaporated under reduced pressure. As a residue is obtained 7.96 g of colorless crystals of melting point 127 to 129 ⁰ C. By twice ümkristallisation from ethyl acetate-methanol leads to N-cyclohexylmethyl-o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamide in the form of colorless crystals of melting point 129 to 13O, 5 ⁰ C. reaction of N- (cyclohexylmethyl) -2-Vp- (2,3-epoxypropoxy) phenyl / -acetamide (example 13) with cyclooctylamine obtained N- (cyclohexylmethyl) -2- / Jp - (3 -cy σ looctyl amino -2-hydroxypropoxy) phenyl / acetamide.

Example 21

4- (o-Hydroxyhydrocinnamoyl) -Ν, Ν-diethyl- 1-piperazynacetamide

A solution of 47.2 g NJN-diethyl-i-piperazineacetamide in 50 ml of ethanol is mixed with 35.0 g Hydro coumarin, causing by exothermic reaction in a temperature increase to 40 ⁰ C. The whole is left to stand at room temperature for 18 hours and the reaction mixture is evaporated under reduced pressure.

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This gives 4- (o-hydroxyhydrocinnamoyl) -N, N-diethyl-1-piperazine acetamide in the form of a dark amber syrup.

Example 22

4- / o- (2,3-epoxypropoxy) hydrocinnamoyl / -N, N- _ -diethyl-1-piperazine acetamide

The 4- (o-hydroxyhydrocinamoyl) -N, N-diethyl-1-piperazine acetamide produced from 35.0 g of dihydrocoumarin is converted into the sodium salt by dissolving it in 150 ml of 10N sodium hydroxide. The salt is extracted in 1 l of chloroform, and the extract is dried over molecular sieves (3A) and filtered. Evaporation of the filtrate under reduced pressure gives 83.4 g of the sodium salt of 4- (o-hydroxyhydrocinnamoyl) -N, N-diethyl-1-piperazine acetamide in the form of a dark amber-colored syrup. A solution of 77.6 g of this salt and 116 g of epichlorohydrin in 125 ml of ethanol is allowed to stand for 18 hours at room temperature. The reaction mixture is filtered off and extracted twice with 250 ml of ether each time and twice with 250 ml of chloroform each time. The combined extracts are dried over magnesium sulfate and the solution, after filtration, is evaporated under reduced pressure. 82.8 g of 4- £ o- (2,3-epoxypropoxy) hydrocinnamoyl / -Ν, Ν-diethylpiperazine acetamide are obtained in the form of a dark syrup. By reacting 4- / 2- (m-hydroxyphenyl) acety1 / -N, N-diethyl-1-piperazine acetamide, which is obtained by reacting methyl 2- (mhydroxyphenyl) acetate with Ν, Ν-diethyl-i-piperazine acetamide With epichlorohydrin by the process described above, 4-i-2- £ m- (2,3-epoxypropoxy) phenyl / acetyl? -N, N-diethyl-1-piperazine acetamide is obtained.

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Example 23

4- / ο- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamoyl / -N, N- diethyl-i-piperazine acetamide dihydrochloride * "

A solution of 17.3 g of 4- / o- (2,3-epoxypropoxy) hydrocinnamoyl / -Ν, Ν-diethyl-i-piperazine acetamide and 4.25 g of cyclohexylamine in 100 ml of isopropyl alcohol is heated to reflux temperature for 2 hours and then under evaporated under reduced pressure to a dark syrup. The syrup is dissolved in 15 ml of ethanol, whereupon 20 ml of 6.5 η hydrogen chloride in ethanol are added. By adding ether and filtering, 20.1 gummy material is obtained, which is recrystallized three times from methanol-ether. This gives 3.19 g of 4- / o- (3-cyclohexyl-2-hydroxypropoxy) hydrocinnamoyl / -N, N-diäthy1-1-piperazinacetamiddihydrochlorid colorless in the form of crystals, melting at 205 to 208 ⁰ C with decomposition. By reacting 4-4-2- / m- (2,3-epoxypropoxy) phenyl / acetyl? -N, N-diethy 1-1 -piperazine acetamide with 1-adamantylamine according to the process described above, 4 - <- 2- / m- (3-Adamantylamino-2-hydroxypropoxy) -phenyl / acetyl * -N, N-diethy1-1-piperazine acetamide.

Example 24

o- (3-Cycloheptylamineq _i r2-hydroxypropoxy) hydro cinnamic acid amide hemifumarate

A solution of 11.05 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 22.64 g of cycloheptylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for one hour and then evaporated under reduced pressure. 16.54 g of yellow oil are obtained as residue. This oil is dissolved in hot absolute ethanol together with 2.90 g of fumaric acid. Cooling and filtering the solution gives 13.52 g of colorless crystals with a melting point of 196 to 198 ^° C. Recrystallization from ethanol-methanol gives 10.49 g of o- (3-cycloheptylamino-2-hydroxypropoxy hydrocinnamic acid amide hemifumarate in the form colorless crystals, melting at 196-198 ⁰ C.

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Example 25 o- (3-Cyclooctylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifuinarate

A solution of 11.05 g of o- (2,3-epoxypropoxyhydrocinnamic acid amide and 12.72 g of cyclooctylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for one hour and then evaporated under reduced pressure. 16.85 g of a colorless oil are obtained as residue Oil is dissolved together with 2.90 g of fumaric acid in hot absolute ethanol. By cooling and filtering the solution, 9.54 g of o- (3-cyclooctylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate are obtained in the form of colorless crystals, which at 194, 5 melt to 195.5 ⁰ C.

Example 26
o- (3-Cyclononylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate

A solution of 2.21 g of o- (2,3-epoxypropoxy) hydroxycinnamic acid amide and 1.41 g of cyclononylamine in 10 ml of isopropyl alcohol is heated to reflux temperature for 4 hours and then evaporated under reduced pressure. 3.79 g of a colorless oil are obtained. This oil is dissolved with an equivalent amount of fumaric acid in absolute ethanol, and by cooling and filtering the resulting solution , colorless crystals with a melting point of 166 to 168 ^° C. are obtained. Recrystallization from absolute ethanol-methanol-ether leads to o- (3- Cyclononylamino-2-hydroxypropoxy) hydrocinnamide hemifumarate as colorless crystals, melting at 175-176 ⁰ C.

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Example 27 ο- (3-Cyclodecylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate

A solution of 4.42 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 3.00 g of cyclodecylamine in 20 ml of isopropyl alcohol is heated to reflux temperature for 6 hours. A solution of 1.12 g of fumaric acid in 15 ml of hot absolute ethanol is added to the solution obtained. The resulting solution is left to stand at room temperature for 18 hours, after which it is filtered. Evaporation of the filtrate under reduced pressure gives 11.7 g of a colorless syrup. The syrup is treated with acetone and crystallized from ethanol. This gives 4.00 g of O- (3-Cyclodecylamino-2-hydroxypropoxy) hydrocinnamide hemifumarate colorless in the form of needles, melting at 165-166 ⁰ C.

Example 28

o- (3-Cycloundecylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate sesquihydrate

A solution of 11.05 g of o- (2,3-epoxypropoxy) hydroxyζimtsäureamid and 8.45 g of cycloundecylamine in 50 ml of isopropyl alcohol is heated to reflux for 3 hours and then evaporated under reduced pressure. 20.0 g of colorless oil are obtained. A solution of 9.80 g of this oil in 100 ml of hot absolute ethanol is mixed with 1.45 g of fumaric acid. The solution obtained is then evaporated to a colorless oil under reduced pressure. The oil is crystallized from acetone. 1.65 g of colorless crystals with a melting point of 170 to 178 ° C. are obtained. Recrystallization from ethanol-methanol leads to 0.85 g of o- (3-cycloundecylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemifumarate sesguihydrate in the form of colorless crystals 189 to 190 ⁰ C melt.

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Example 29

ο- / 2 -hydroxy- 3 - (exo- 2 -norbo r ny 1 amino) propoxy_ / hydrozimamic acid amide hemifumarate

A solution of 11.05 g of ο- (2,3-epoxypropoxy) hydrocinnamon sureamide and 11.11 g of exo-2-norbornylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for 2 hours and then evaporated under reduced pressure. 16.14 g of a slightly straw-colored glass-like mass are obtained. This glass-like mass is dissolved together with 2.82 g of fumaric acid in hot absolute ethanol. After cooling and filtering this solution, 12.17 g of colorless crystals with a melting point of 183 to 185 ^° C. are obtained. Recrystallization from methanol gives 6.37 g of o- / 2-hydroxy-3- (exo-2-norbornylamino) propoxy / hydroz imtsäureamid-Hemifumarat in the form of colorless crystals, which melt at 185 to 186 ° C.

Example 3O

O- / 3- (1-Adamantylamino) ^ -hydroxypropoxyyhydrocinnamic acid amide hemifumarate hydrate (4: 1) and hydrochloride hemihydrate

A solution of 11.05 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 7.57 g of 1-adamantylamine in 50 ml of isopropyl alcohol is heated to reflux temperature for one hour and then filtered. 2.90 g of fumaric acid are added to the hot filtrate. The resulting solution is cooled and the colorless crystals which have accumulated are filtered off. Recrystallization from methanol leads to 16,15 g of o / 3- (1-Adamantylamino) -2-hydroxypropoxy_ / hydrocinnamide hemifumarate hydrate (4: 1) in the form of colorless crystals of melting point 240-241 ⁰ C. 10, 00 g of this material is dissolved in dilute hydrochloric acid. The solution is then made basic with sodium hydroxide. Then extract with chloroform and dry the extract over magnesium

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sulfate. The solution is then filtered and evaporated under reduced pressure. 4.43 g of colorless oil are obtained. This oil is dissolved in 25 ml of absolute ethanol, and the solution is treated with 2 ml of 6.5 η ethanolic hydrogen chloride. Then 200 ml of ether are added, whereupon the supernatant liquid is decanted. The colorless, gummy mass that remains is treated with ether, resulting in a semicrystalline mass. Recrystallization of this material from isopropyl alcohol-ether leads to 0.83 g of O- / 3- (1 -Adamantylamino) -2-hydroxypropoxy_ / hydrozimtsMureamidhydrochlorid hemihydrate colorless in the form of needles, melting at 131 to 134 ⁰ C.

Example 31 O- / 2-Hydroxy-3- (1 -indanylamino) propoxy / hydrocinnamic acid amide

A solution of 5.53 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 3.33 g of 1-indanylamine in 25 ml of isopropyl alcohol is heated to reflux temperature for 6 hours and then evaporated under reduced pressure. This gives 10.09 g of a colorless crystalline residue of melting point 89 to 136 ⁰ C. Recrystallization of this residue from ethyl acetate-heptane and then from ethyl acetate leads to 1.80 g of o / 2-hydroxy-3- (1-indanylamino ) propoxv / hydrocinnamic acid amide with a melting point of 146 to 148 ⁰ C.

Example 32 ο- Σ3 - / (cyclohexylmethyl) amino / -2-hydroxypropoxy | -hydrocinnamic acid amide

A solution of 5.53 g of o- (2,3-epoxypropoxy) hydrocinnamic acid amide and 2.83 g (CyclohexylmethyDamin in 25 ml isopropyl alcohol 6 hours heated to reflux temperature and then under

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evaporated under reduced pressure. 8.84 g of a colorless residue from oil and crystals are obtained. Recrystallization from ethyl acetate leads to 3.15 g of o-i3 - / (cyclohexylmethyl) amino / -2-hydrocinnamide hydroxypropoxy4 colorless in the form of crystals, melting at 116 to 118 ⁰ C.

Example 33 N-Cyclohexyl-o-hydroxyhydrocinnamic acid amide

A solution of 100.0 g of hydrocoumarin in 150 ml of ethanol is added with stirring over a period of 10 minutes with 74.4 g of cyclohexylamine, whereupon the resulting mixture is ^{cooled to 0 °} C. and filtered. In this way one arrives at 105.0 g of colorless crystals of melting point 155-156 C. Recrystallization from ethanol gives N-cyclohexyl-o-hydrocinnamide in the form of colorless prisms, melting point 155-156 ⁰ C.

Example 34 N-Cyclohexyl-o- (2,3-epoxypropoxy) hydrocinnamic acid amide

A solution of 250 ml of epichlorohydrin in 150 ml of ethanol is added with stirring over a period of 30 minutes with a solution of 61.83 g of N-cyclohexyl-o-hydroxyhydrocinnamic acid amide and 25 ml of 10 η sodium hydroxide in 575 ml of absolute ethanol. The whole is left to stand for 4 days at room temperature. The suspension obtained is then evaporated under reduced pressure, whereby a colorless mixture of crystals and oil is obtained. This mixture is suspended in methylene chloride, the suspension is washed with water and the organic layer is dried over magnesium sulfate. After filtering and evaporating the solution under reduced pressure, 76.48 g of whitish crystals with a melting point of 75 to 80 ^° C. are obtained.

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Recrystallization of this material from ethyl acetate-hexane gives 19.00 g of N-cyclohexyl-o- (2,3-epoxypropoxy) hydrocinnamide colorless in the form of crystals of melting point 82 to 85 ⁰ C. By reaction of N-cyclohexyl-m-hydroxyhydrocinnamide, obtained by reacting methyl-m-hydroxyhydrocinnamic acid residues with cyclohexylamine, with epichlorohydrin according to the procedure described above, N-cyclohexyl-m- (2,3-epoxypropoxy) hydrocinnamic acid amide is obtained.

Example 35
N-Cyclohexyl-o- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamic acid amide

A solution of 7.59 g of N-cyclohexyl-o- (2,3-epoxypropoxy) hydrocinnamic acid amide in 25 ml of isopropylamine and 25 ml of isopropyl alcohol is heated to reflux temperature for two hours and then evaporated under reduced pressure. 9.97 g of colorless crystals with a melting point of 150 to 152 ° C. are obtained. By recrystallizing twice from ethyl acetate, 5.44 g of N-cyclohexyl-o- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamic acid amide are obtained in the form of colorless crystals 150 to 152 ⁰ C melt. The reaction of N-cyclohexyl-m- (2,3-epoxypropoxy) hydrocinnamic acid amide with isopropylamine leads to N-cyclohexyl-m- (3-isopropyl amino-2-hydroxypropoxy) hy dr oz imt acid amide.

Example 36

N-Cyclohexylmethyl-o- (3-isopropylamino-2-hydroxypropoxyhydro- ζ imt acid amide

A solution of 6.34 g of N-cyclohexylmethyl-o- (2,3-epoxypropoxy) hydrocinnamic acid amide in 20 ml of isopropylamine is heated to reflux temperature for 2 hours and then evaporated under reduced pressure. 7.21 g of colorless crystals with a melting point of 135 to 137 ^° C. are obtained. By recrystallizing twice

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Ethyl acetate leads to N-cyclohexylmethyl-o- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamic acid amide in the form of colorless crystals that melt at 138 to 139 ° C. By implementing N- (Cyclohexylmethyl) -p- (2,3-epoxypropoxy) hydrocinnamic acid amide (Example 13) with isopropylamine, N-cyclohexylmethylp- (3-isopropylamino-2-hydroxypropoxy) hydrocinnamic acid amide is obtained.

Example 37 m-Hydroxyzimtsäureamid

A solution of 24.4 g of m-hydroxybenzaldehyde, 41.2 g of malonic acid amide and 10 ml of piperidine in 600 ml of pyridine is ^{heated to 95 °} C. for 2 hours. Evaporation of the resulting solution under reduced pressure gives a brown oily residue. The residue is mixed with dilute hydrochloric acid and the crystal sludge obtained is filtered off. This gives 29.85 g of tan crystals melting at 187-189 ⁰ C. By recrystallization from ethanol-water leads to 24.00 g m-Hydroxyzimtsäureamid / J. Biol. Chem. 216, 507 (1955) in the form of tan crystals, melting at 193 to 195 ⁰ C.

Example 38 m-Hydroxyhydrozamic acid amide

A solution of 16 _r, 32 g of m-Hydroxyzimtsäureamid in 375 ml of methanol is hydrogenated at a pressure of 2.11 kg / cm and room temperature over a period of 45 minutes 1.0 g of platinum oxide. The filtrate obtained after filtering off the catalyst is evaporated under reduced pressure. 16.86 g of amber-colored crystals with a melting point of 126 ° to 129 ° C. are obtained. Recrystallization of this material from ethanol-methanol gives 11.22 g of m-Hydroxyhydroz imtsäureamid in the form of tan crystals melting at 127 to 129 ⁰ C.

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254D552

Example 39 m- (2,3-Epoxypropoxy) hydrocinnamic acid amide

A solution of 50 ml of epichlorohydrin in 30 ml of absolute ethanol is added with stirring over a period of 30 minutes with a solution of 8.26 g of m-hydroxyhydrocinnamic acid amide and 5 ml of 10 η sodium hydroxide in 115 ml of absolute ethanol. The suspension obtained is evaporated under reduced pressure, whereby a colorless mixture of oil and crystals is obtained. A suspension of this mixture in chloroform is washed with water and dried over magnesium sulfate. Filtration of the resulting solution and evaporation under reduced pressure gives 9.77 g of colorless, waxy crystalline precipitate. A sample of this material was recrystallized from ethyl acetate-hexane, is obtained to give m- (2,3-epoxypropoxy) hydrocinnamide colorless in the form of crystals, melting at 58 to 60 ⁰ C.

Example 40 m- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide

A solution of 3.00 g of m- (2,3-epoxypropoxy) hydrocinnamic acid amide in 15 ml of cyclohexylamine is heated to reflux temperature for 6 hours and then evaporated under reduced pressure. This gives 3.46 g of colorless crystals of melting point 123 to 126 ⁰ C. By recrystallization from ethyl acetate-methanol leads to m- (3-cyclohexyl-2-hydroxypropoxy) hydrocinnamide colorless in the form of crystals, melting at 123 to 126 ⁰ C. . One arrives in a similar way

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using cycloheptylamine to m- (3-cycloheptylamino-2-hydroxypropoxy) hydrocinnamic acid amide and using 1-indanylamine to m- / 3- (1-indanylamino) -2-hydroxypropoxy) hydrocinnamic acid amide.

Example 41 p ~ Hydrozimtsäureamid

A solution of 24.4 g of p-hydroxybenzaldehyde, 41.2 g of malonic acid amide and 10 ml of piperidine in 600 ml of pyridine is ^{heated to 95 °} C. for 2 hours and then evaporated under reduced pressure. The remaining brown oil is treated with 100 ml of water and acidified with hydrochloric acid. The resulting crystalline sludge is filtered off, whereby 27.0 g of tan-colored crystals with a melting point of 185 to 187 ^° C. are obtained. Recrystallization of this material from water gives 23.7 g of p-hydrocinnamic acid amide / ber. 50, 619 (1917) _ / in the form of pink crystals that melt ^{at 192 to 194 ° C.}

Example 42 p- (2,3-epoxypropoxy) 2-amide hydrate (8: 1)

A solution of 50 ml of epichlorohydrin in 30 ml of ethanol is stirred with a solution of 5.00 g of p-hydroxycinnamic acid amide and 3.1 ml of 10 η sodium hydroxide in 100 ml of absolute ethanol are added. The whole is left at room temperature for 20 hours stand, whereupon it is evaporated under reduced pressure. The remaining colorless crystals will be

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washed with water and air dried. 6.40 g of p- (2,3-epoxypropoxy) cinnamic acid amide hydrate (8: 1) are obtained in the form of pale tan crystals with a melting point of 163 to 167 ^° C. In a similar way, m-hydroxycinnamic acid amide is obtained by reacting with epichlorohydrin m- (2,3-epoxypropoxy) cinnamic acid amide.

Example 43 p- (S-Cyclopentylamino ^ -hydroxypropoxy) cinnamic acid amide

A suspension of 2.19 g of p- (2,3-epoxypropoxy) cinnamic acid amide in 0.90 g of cyclopentylamine and 25 ml of absolute methanol is left to stand for 2 hours at ambient temperature. Then 9 ml of cyclopentylamine are added and the suspension is heated to reflux temperature for 2.5 hours. Evaporation of the resulting solution under reduced pressure gives 2.96 g of cream-colored crystals with a melting point of 143 to 146 ^° C. The crystals are recrystallized from absolute ethanol, whereby 2.31 g of p- (3-cyclopentylamino-2-hydroxypropoxy) are obtained. cinnamic acid amide is obtained in the form of colorless crystals which melt ^{at 143 to 146 ° C.} Reacting m- (2,3-epoxypropoxy) cinnamic acid amide (Example 42) with cyclopropylamine gives m- (3-cyclopropylamino-2-hydroxypropoxy) cinnamic acid amide, and a corresponding reaction with cycloundecylamine gives m- (3-cycloundecylamino) -2-hydroxypropoxy) cinnamic acid amide.

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- 59 - ■

Example 44

p- (3-Cyclopent, ylamino-2-hydroxypropoxy) hydrocinnamic acid amide-hydro-

chloride

A solution of 5.00 g of p- (3-Cyclopentylamino-2-hydroxypropoxy) cinnamic acid amide in 150 ml of absolute ethanol with a water

2
material pressure of 2.81 kg / cm 4 hours in the presence of 0.50O g 10% palladium-on-carbon reduced. The catalyst is then filtered off, whereupon the colorless filtrate is concentrated under reduced pressure to a volume of 5 ml. To this end, 3.5 ml of 5.3 η ethanolic hydrochloric acid are first added, after which ether is added to precipitate the crude product. The precipitate obtained is filtered off and crystallized from ethanol. Leads to 2.1 g of p- (3-cyclopentylamino-2-hydroxypropoxy) hydroz imtsäureamid hydrochloride in the form of colorless crystals, melting at 155 to 157 ⁰ C.

Example 45 p- (3-Cyclohexylamino-2-hydroxypropoxy) cinnamic acid amide

A solution of 21.9 g of p- (2,3-epoxypropoxy) cinnamic acid amide and 25 ml of cyclohexylamine in 500 ml of isorpopyl alcohol is heated to reflux temperature for 4 hours. The reaction mixture is filtered off and the filtrate is evaporated under reduced pressure to a colorless solid residue. By crystallization of the residue from ethyl acetate and recrystallization from ethanol to 13.5 g p- obtained (3-cyclohexylamino-2-hydroxypropoxy) cinnamamide cream in the form of crystals, melting at 159-160 ⁰ C.

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Example 46

ρ- (3-Cyclohexylamine) - ^ - hydroxypropoxy) hydroz imtsäureamid-hydro-

chloride

A solution of 5.00 g of p- (3-Cyclohexylamino-2-hydroxypropoxy) cinnamic acid amide in 100 ml of ethanol is at a hydrogen pressure

2
of 2.81 kg / cm 4 hours in the presence of 0.500 g 10%

Palladium-on-carbon reduced. After the catalyst has been filtered off, the filtrate is treated with 3.5 ml of 5.3 η ethanolic hydrochloric acid. The colorless solution obtained is evaporated to a colorless residue under reduced pressure. The residue is crystallized from ethanol and then recrystallized from ethanol, so as to obtain 1.26 g of p- (3-cyclohexylamino-2-hydrcxypropoxy) hydrocinnamide hydrochloride in the form of colorless crystals, melting at 166 to 168.5 ⁰ C.

Example 47 p-Hydroxyhydroxy acid amide

A solution of 16.32 g of p-hydroxycinnamic acid amide in 250 ml of ethanol is hydrogenated over 2.0 g of platinum oxide at atmospheric pressure and room temperature for 6 hours. The filtrate obtained after filtering off the catalyst is evaporated under reduced pressure. One arrives at 15.97 g colorless crystals of melting point 105 to 112 ⁰ C. Recrystallization from chloroform-ethyl acetate yields 9.22 g of p-hydroxyhydrocinnamide / Annalen 102, 145 (1852 / colorless in the form of crystals, melting at 127 to 131 ⁰ Melt C.

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Example 48 ρ- (2,3-Epoxypropoxy) hydrocinnamic acid amide hydrate (8: 1)

A solution of 50 ml of epichlorohydrin in 30 ml of absolute ethanol is mixed with a solution of 8.26 g of p-hydroxyhydrocinnamic acid amide and 5 ml of 10 η sodium hydroxide in 115 ml of absolute ethanol while stirring. The whole is left to stand for 6 days at room temperature. The mixture is then evaporated under reduced pressure to a colorless crystalline residue. Recrystallization of the residue from ethyl acetate-chloroform, 7.31 g p- receives (2,3-epoxypropoxy) hydrocinnamide hydrate (8: 1) in the form of colorless crystals, melting at 127 to 129 ⁰ C.

Example 49 p- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide hemihydrate

A solution of 2.00 g of p- (2,3-epoxypropoxy) hydrocinnamide hydrate (8: 1) in 10 ml cyclohexylamine is heated for 5 hours at 95 ⁰ C and then evaporated under reduced pressure. 2.63 g of waxy crystals are obtained as residue. Recrystallization from ethyl acetate-methanol resulting in 2.00 g of p- (3-cyclohexylamino-2-hydroxypropoxy) hydroz imtsäureamidhemihydrat in the form of colorless crystals of melting point 118 to 121 ⁰ C. Similarly, leads using Cyclononylamin to p- ( 3-Cyclononylamino-2-hydroxypropoxy) hydrocinnamic acid amide and using exo-2-norbornylamine to p- / 2-hydroxy-3- (exo-2-norbornylamino) propoxy_ / hydrozimic acid amide.

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Example 50 1- / ο- (3-aminopropyl) phenoxy _ / - 3-cyclohexylamino-2-propanol

A solution of 20.0 g of o- (3-cyclohexylamino-2-hydroxypropoxy) -hydrocinnamic acid amide hydrate (4: 1) in 700 ml of dry tetrahydrofuran is added under an argon atmosphere for a period of

10.0 g of lithium aluminum oxide are added in portions for 1 hour. The reaction mixture is refluxed for 20 hours heated. After the mixture has cooled, 25 ml of absolute ethanol are slowly added, whereupon one after the other 100 ml of 20 percent aqueous tetrahydrofuran and then 50 ml

2 added sodium hydroxide. The filter cake obtained after filtering the mixture is washed with tetrahydrofuran. The combined filtrates are evaporated under reduced pressure. The liquid remaining as a residue is again treated with 5.00 g of lithium aluminum hydride in refluxing dry tetrahydrofuran. The resulting syrupy product is distilled under reduced pressure. 12.0 g of 1- / o- (3-aminopropyl) phenoxy / -3-cyclohexylamino-2-propanol are obtained in the form of a colorless liquid which ^{boils at 185 to 190 °} C. at a pressure of 0.1 torr and increases colorless crystals with a melting point of 65.5 to 67 ^° C. crystallized. In a similar way, from o- (3-cyclononylamino-2-hydroxypropoxy) hydrocinnamic acid amide (Example 20) to 1- / o- (3-aminopropyl) phenoxy _ / - 3-cyclononylamino-2-propanol, from 2- / m- (3-cyclobutylamino-2-hydroxypropoxy) phenyl / acetamide (Example 4) to 1- / m- (2-aminoethyl) phenoxy _ / - 3-cyclobutylamino-2-propanol and from 2- / p- (3-cyclopentylamino- 2-hydroxypropoxy) phenyl / acetamide (Example 6) to 1 - / p- (2-aminoethyl) phenoxy / - 3-cyclopentylamino-2-propanol.

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2540557

Example 51 1 -Cyclohexylamines - ^ - / ο- (3-morpholinopropyl) phenoxy _ / - 2-propanol

1.00 g of 1- £ o- (3-aminopropyl) phenoxy / 3-cyclohexylamino-2-propanol and 0.350 g of sodium bicarbonate in toluene are treated with 0.25 ml of 2,2'-dichloroethyl ether, whereupon the mixture is made up for 20 hours Heated to reflux temperature. Evaporation of the mixture under reduced pressure gives a yellow syrup and precipitate. The residue is mixed with 10 ml of water and then extracted twice with 25 ml of chloroform each time. The chloroform extract is dried over magnesium sulphate, the whole is filtered and evaporated under reduced pressure. 1.78 g of a pale yellow syrup are obtained. The syrup is chromatographed over 25 g of silica gel using methanol for development. After evaporation, 0.680 g of crystals are obtained from the first 200 ml of eluate. By ümkristallisation of this material from 10 ml heptane leads / to 0.530 g of 1-cyclohexylamino-3 / o- (3-morpholinopropyl) ph enoxy _ - 2-propanol, which melt in the form of yellow granular-like crystals at 72 to 74 ⁰ C. In a similar way, 1-cyclononylamino-3- / o- (3-morpholinopropyl) phenoxy-2-propanol is obtained from 1- / o- (3-aminopropyl) -phenoxy-3-cyclononylamino-2-propanol 1- / m- (2-J ^ minoäthyl) phenoxy _ / - 3-cyclobutylamino-2-propanol to 1 -Cyclobutylamino-S-Zm- (2-morpholinoäthyl) phenoxy _ / - 2-propanol, and from 1- ^ p- (2-Aminoethyl) phenoxy _ / -3-cyclopentylamino-2-propanol to 1-cyclopentylamino-3- / p- (2-morpholinoethyl) -phenoxy _ / -2-propanol.

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B e i s ρ i e 1 52

o - ^ - Acetoxy-S-cyclohexylaminopropoxy) hydrocinnamic acid amide

hydrochloride

A solution of 9 _f 00 g of o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide hydrate (4: 1) in 25 ml of 6.5 η ethanolic hydrogen chloride is evaporated under reduced pressure to give a yellow syrup. The syrup is heated to reflux temperature with 25 ml of acetyl chloride for 2 hours, after which the reaction mixture is evaporated under reduced pressure. O- (2-Acetoxy-3-cyclohexylaminopropoxy) hydrocinnamic acid amide hydrochloride is obtained in the form of a colorless crystalline residue.

Example 53

o- (2-Acetoxy-3-cyclohexylaminopropoxy) hydrocinnamonitrile

hydrochloride

o- (2-Acetoxy-3-cyclohexylaminopropoxy) hydrocinnamonitrile hydrochloride, made from 9.00 g o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide quartohydrate, is heated to reflux temperature for 2 hours with 10 ml of phosphorus oxychloride in 50 ml of dry benzene. The reaction mixture is evaporated under reduced pressure. O- (2-Acetoxy-3-cyclohexylaminopropoxy) hydrocinnamonitrile hydrochloride is obtained in the form of a dark amber syrup.

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Example 54

o ~ (S-Cyclohexylamino - ^ - hydroxyporpoxy) hydrocinnamonitrile

hydrochloride

o - ^ - Acetoxy-S-cyclohexylaminopropoxy) hydrocinnamonitrile hydrochloride, prepared from 9.00 g of o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid amide hydrate (4: 1), is dissolved in 20O ml of methanol which is saturated with ammonia . After 18 hours, the solution is evaporated under reduced pressure to give an amber syrup which also contains some precipitate. This material is suspended in water, whereupon the suspension is extracted twice with 100 ml of chloroform each time. The combined extracts are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure. 12.8 g of a dark amber-colored syrup are obtained. The syrup is dissolved in 10 ml of 6.5 η ethanolic hydrochloric acid and then ether is added. Filtration gives 4.44 g of tan crystals with a melting point of 161 to 165 ^° C. Recrystallization from 50 ml of ethanol leads to 3.72 g of o- (3-cyclohexylamino-2-hydroxypropoxy) -hydrocinnamonitrile hydrochloride in the form of colorless granular Crystals with a melting point of 165.5 to 166.5 ⁰ C.

Example 55 o-Acetoxyhydrozamide

o-Hydroxyhydrocinnamic acid amide, made from 60.0 g of hydrocoumarin, is dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, causing an exotherm Reaction comes. The whole is left at room temperature for 18 hours stand and then evaporate the reaction mixture to a syrup. The syrup is made with equal amounts of chloroform

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and water mixed, followed by stirring for 2 hours. The layers are separated and the aqueous layer is extracted with an equal volume of chloroform. The combined chloroform extracts are dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives a syrup which is recrystallized from a mixture of benzene and petroleum ether. Leads to 68.3 g o-Acetoxyhydrozimtsäureamid colorless in the form of granular-like crystals of melting point 68 to 70 ⁰ C.

Example 56 o-Acetoxyhydrocinnamonitrile

A solution of 31.6 g of o-acetoxyhydrocinnamic acid amide in 250 ml of benzene is mixed with 25 ml of phosphorus oxychloride. The resulting solution is refluxed for 2.5 hours and then evaporated under reduced pressure to a dark yellow syrup. This syrup is shaken vigorously with a mixture of 100 ml of water and 100 ml of benzene. The liquid phase is extracted with 100 ml of benzene, and the combined benzene extracts are dried over magnesium sulfate and treated with activated charcoal. The solution obtained after filtration is evaporated under reduced pressure. Leads to 28.4 g of colorless crystalline residue which is recrystallized from ethanol-ether, In this case, one g of o-Acetoxyhydrozimtsäurenitril colorless in the form of needles, melting at 57.5 to 59 ⁰ C is 16.0.

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Example 57

o-Hydroxyhydrocinnamonitrile

Anhydrous ammonia is passed through a solution of 14.0 g of o-acetoxyhydrocinnamonitrile in 200 ml of methanol for 10 minutes. It leaves the whole 18 hours at 5 ⁰ C, followed by evaporating the solution under reduced pressure. 11.2 g of pale yellow oil are obtained. The oil is mixed with 50 ml of chloroform, 50 ml of water and 10 ml of 10N sodium hydroxide, and the aqueous phase is washed with 25 ml of chloroform. The aqueous phase is acidified by adding 25 ml of 5 η hydrochloric acid and then extracted twice with 25 ml of chloroform each time. The combined extracts are dried over magnesium sulfate and evaporated in vacuo. 11.2 g of a pale yellow oil are obtained. Distillation of this oil gives 8.53 g of o-hydroxyhydrocinnamonitrile in the form of a colorless liquid which boils ^{at 124 to 126 ° C. at a pressure of 0.2 torr.}

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ο- (2,3-epoxypropoxy) hydrocinnamonitrile

A solution of 6.00 g of o-hydroxyhydrocinnamic acid nitrile and 5 ml of 10 η sodium hydroxide in 50 ml of ethanol is mixed with a solution of 23.1 g of epichlorohydrin in 50 ml of ethanol. The whole is left to stand for 18 hours at room temperature, whereupon the reaction mixture is filtered and the precipitate is washed with ethanol. The combined filtrates and wash liquors are evaporated under reduced pressure to give 9.38 g of a pink liquid. This liquid is suspended in 100 ml of water and the suspension is extracted twice with 100 ml of ether each time. The combined extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. 8.83 g of a colorless liquid are obtained. By distillation of this fluid leads to 6.34 g of o- (2,3-epoxypropoxy) hydrozimtsäurenitril in the form of a colorless liquid, boiling at a pressure of 0.5 torr at 137 to 139 ⁰ C. In a similar way, the p- (2,3-epoxypropoxy) hydrocinnamonitrile is obtained using p-hydroxyhydrocinnamonitrile and the 2- / m- (2,3-epoxypropoxy) pheny is obtained using 2- (m-hydroxyphenyl) acetonitrile! / acetonitrile.

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Example 59 ο- (B-Cyclohexylamino - ^ - hydroxypropoxy) hydrocinnamonitrile

o- (2,3-Epoxypropoxy) hydrocinnamonitrile is in refluxing Isopropyl alcohol reacted with cyclohexylamine, whereby one o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamonitrile receives. Using cyclopropylamine, o- (3-cyclopropylamino-2-hydroxypropoxy) hydrocinnamonitrile is obtained in a similar manner, and using cyclononylamine to give o- (3-cyclononylamino-2-hydroxypropoxy) hydrocinnamonitrile.

By reacting p- (2,3-epoxypropoxy) hydrocinnamonitrile (Example 47) with cyclobutylamine, p- (3-cyclobutylamino-2-hydroxypropoxy) hydrocinnamonitrile is obtained, and using 1-adamantylamine one arrives at p- / 3- (1-Adamantylamino) -2-hydroxypropoxy ^ / hydrocinnamonitrile. By reaction of 2- / m- (2,3-epoxypropoxy) phenylacetonitrile with cycloheptylamine, 2- / m- (3-cycloheptylamino-2-hydroxypropoxy) phenylacetonitrile is obtained.

Example 60 4-Ethyl-o-hydroxyhydrocinnamic acid ester

A solution of 14.8 g of hydrocoumarin in 75 ml of absolute ethanol is with 15.5 ml 6.48 η ethanolic hydrochloric acid offset. The whole thing is left at room temperature for 18 hours, whereupon the colorless solution is evaporated to a syrup. The syrup obtained is dissolved in 250 ml of ether, and the The solution is extracted twice with 25 ml of water each time. The ether layer is dried with magnesium sulfate and becomes a

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evaporated crystallizing syrup. Recrystallization from ether-hexane gives 10.3 g of ethyl-o-hydroxyhydrozimtsäureester as colorless granular-like crystals of melting point 35-36 ⁰ C. In Ber. 38, 2067 (1905) a melting point of 34 ^° C. is given for this.

Example 61 Ethyl o- (2,3-epoxypropoxy) hydrocinnamic acid ester

57 ml of 10 η sodium hydroxide are added to a solution of 109.6 g of ethyl o-hydroxyhydrocinnamate in 1 l of absolute ethanol. This solution is then added in portions over a period of 30 minutes to a solution of 250 ml of epichlorohydrin in 150 ml of absolute ethanol. The whole is left to stand at room temperature for 18 hours. The reaction mixture is then filtered and the filtrate is evaporated under reduced pressure. A pale yellow oil is obtained. A solution of this oil in 500 ml of ether is extracted with 100 ml of water. The water layer is washed with 200 ml of ether and the combined ether layers are dried over magnesium sulfate, filtered and evaporated. A yellowish oil is obtained. The oil is distilled under reduced pressure, thus obtaining 92.9 g Äthylo- (2,3-epoxypropoxy) hydrocinnamate used in the form of a colorless liquid, boiling at a pressure of 0.2 torr at 143 to 146 ⁰ C.

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Example 62 Ethyl p- (2,3-epoxypropoxy) hydrocinnamic acid ester

A solution of 332 g of ethyl p-hydroxyhydrocinnamic acid ester / Ber. 50, 611 (1917) / and 220 ml of 10 η sodium hydroxide in one liter of ethanol are mixed with 8OO ml of epichlorohydrin. The whole is left to stand for 18 hours at room temperature, whereupon the reaction mixture is filtered and the filter cake is washed with ethanol. The combined filtrates and wash liquors are evaporated under reduced pressure to a white gelatinous residue. The residue is washed in 1 liter of water and then dissolved in 1 liter of chloroform. The solution is dried over magnesium sulphate , filtered and then evaporated under reduced pressure to give 379 g of oil. Distilling this oil gives 272 g of a colorless liquid which boils ^{at 162 to 165 ° C. at a pressure of 0.05 torr.} The redistillation of this fraction leads to ethyl p- (2,3-epoxypropoxy) hydrocinnamate in the form of a colorless liquid, boiling at a pressure of 0.04 Torr at 152 to 154 ⁰ C. Methyl 2- (m-hydroxyphenyl) acetate is obtained in a similar manner to methyl 2- / m- (2,3-epoxypropoxy) phenyl acetate.

Example 63 Ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrochloric acid ester

A solution of 116 g of ethyl p- (2,3-epoxypropoxy) hydrocinnamic acid ester in 250 ml of isopropyl alcohol is mixed with a solution of 50.0 g of cyclohexylamine in 15Ο ml of isopropyl alcohol. The reaction mixture is heated to reflux temperature for 2 hours and then under reduced pressure to a crystalline

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evaporating syrup. The crude product is recrystallized from ethyl acetate to give 82.7 g of ethyl-p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate obtained in the form of colorless needles melting at 65 to 68 ⁰ C. Recrystallization of 5 g of these needles from ethyl acetate leads to 4.50 g of colorless needles melting at 69-70 ⁰ C. Similarly, using cyclopropylamine leads to ethyl p- (3-cyclopropylamino-2-hydroxypropoxy) hydrocinnamate and using cyclononylamine to give ethyl p- (3-cyclononylamino-2-hydroxypropoxy) hydrocinnamic acid ester.

By reacting methyl 2- / yne (2,3-epoxypropoxy) phenyl / acetate with cyclopentylamine, methyl 2- / m- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetate is obtained.

Example 64 Ethyl o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid ester

A solution of 203.5 g of ethyl o- (2,3-epoxypropoxy) hydrocinnamate and 89.10 g of cyclohexylamine in 1000 ml of isopropyl alcohol is heated to reflux temperature for 2 hours and then evaporated to a crystalline residue under reduced pressure. By recrystallizing this residue from ether-hexane, 177.0 g of colorless crystals are obtained. 10.0 g of these crystals are recrystallized from ether, whereby 8.60 g of ethyl-O- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamate obtained in the form of colorless crystals, melting at 83 to ⁰ C.

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Example 65

1 -Cyclohexylamino-S-Zp- (3-hydroxypropoxy) phenoxy _ / - 2-propanol-

hemifumarate

A solution of 6.00 g of ethyl-o- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid ester in 50 ml of dry tetrahydrofuran is added over a period of 30 minutes to refluxing dry tetrahydrofuran which contains 1.30 g of lithium aluminum hydride. The resulting mixture is heated to reflux temperature for 2 hours, then cooled and treated with 2 ml of absolute ethanol and then in succession over a period of 1 hour with 10 ml of 20 percent aqueous tetrahydrofuran and 6 ml of 2.5 η sodium hydroxide. The mixture is stirred at room temperature for 18 hours and then filtered. The filter cake is washed with tetrahydrofuran. The combined filtrates and wash liquors are evaporated to an oily residue under reduced pressure. The oil is dissolved in 10 ml of absolute ethanol, and 1.00 g of fumaric acid in 15 ml of absolute ethanol is added to the solution. After 3 hours of standing was filtered off, yielding 5.24 g of 1-cyclohexylamino-S-ZP (3-hydroxypropyl) phenoxy _ / - 2-propanol hemifumarate obtained in the form of colorless crystals, melting at 168-169 ⁰ C.

Example 66

1 -Cyclohexylamino-S-Zp- (3-hydroxypropyl) phenoxy _ / - 2-propanol-

hemifumarate

A solution of 6.00 g of ethyl p- (3-cyclohexyl-2-hydroxypropoxy) -hydrocinnamic acid ester in 100 ml of dry tetrahydrofuran is over a period of 30 minutes in portions with 1.3 g of lithium aluminum hydride added and then heated to reflux temperature for 2.5 hours. The mixture is cooled and stirred

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2 ml of absolute ethanol are added, whereupon 10 ml of 20 percent strength aqueous tetrahydrofuran and then 6 ml of 2.5 η sodium hydroxide are added one after the other. The batch is stirred for 18 hours at room temperature and then filtered. The filter cake is washed with tetrahydrofuran. The combined filtrates are evaporated to an oily residue under reduced pressure. Recrystallization from ethyl acetate-hexane and then from ether leads to 4.56 g of colorless crystals of melting point 41 to 45 ⁰ C. A solution of these crystals in 10 ml of absolute ethanol is treated with 0.870 g of fumaric acid in 10 ml of absolute ethanol and then filtered . 2.00 g of colorless crystals with a melting point of 161 to 168 ^° C. are obtained. Two recrystallization from ethanol yields 1.13 g of 1-cyclohexylamino-3- / p- (α-hydroxypropyl) phenoxy / 2-propanol hemifumarate in the form of colorless crystals of melting point 166 to 169 ⁰ C. Similarly, leads using ethyl p- (3-cyclopropylamino-2-hydroxypropoxy) hydrocinnamate (example 52) i-cyclopropylamino-S- ^ p- (3-hydroxypropyl) -phenoxy-2-propanol, using ethyl-p- (3-cyclononylamino-2-hydroxypropoxy) hydrocinnamic acid ester (Example 52) to give T-cyclononylamino-3- / p- (3-hydroxypropyl) phenoxy-2-propanol and using methyl 2- / m- (3-cyclopentylamino-2-hydroxypropoxy) phenyl / acetate (Example 52) to 1-cyclopentylamino-3- / m- (2-hydroxyethyl) phenoxy-2-propanol.

Example 67 o- (3 -Cyclohexylamino-2-hydroxypropoxy) hydrozim acid hydrochloride

A solution of 5.00 g of ethyl o- (2-hydroxy-3-cyclohexylaminopropoxy) hydrocinnamic acid ester and 15 ml of 10 η sodium hydroxide in 100 ml of absolute ethanol is refluxed for 20 hours

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heated and then evaporated under reduced pressure to a pasty residue. The residue is dissolved in water, whereupon the aqueous solution is extracted twice with 100 ml of benzene each time and then three times with 75 ml of chloroform each time. The chloroform extracts are combined, dried (molecular sieve 3A) and evaporated under reduced pressure. 5.50 g of a foam are obtained. The foam is treated with 20 ml of 5 η hydrochloric acid and the suspension obtained is then evaporated under reduced pressure to give a mixture of oil and crystals. This mixture is extracted with 50 ml of acetone, whereupon it is filtered and the filtrate is treated with 25 ml of ether. By filtration of the extract leads to 3.33 g of o- (S-cyclohexylamino - ^ - hydroxypropoxy) -hydrozimtsäure hydrochloride as pale pink colored crystals, melting at 127-128 ⁰ C.

Example 68 p- (3-Cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid hydrate (4: 1)

A solution of 5.00 g of ethyl p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid ester and 15 ml of 10 η sodium hydroxide in 100 ml of ethanol is heated to reflux temperature for 8 hours. The whole is allowed to stand at room temperature for 18 hours, after which the solution is evaporated under reduced pressure to a white foam. The foam is dissolved in water and when the pH is adjusted to 6-7 with hydrochloric acid, a pink solid results. The solid is filtered off and crystallized from N, N-dimethylformamide, yielding 2.62 g of p- (3-cyclohexylamino-2-hydroxypropoxy) hydrocinnamic acid hydrate (4: 1) is obtained in the form of colorless crystals, melting at 118-120 ⁰ Melt C.

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Example 69 2- (o-Hydroxyphenyl) -N, N-dimethylacetamide

A solution of 25 g _r O 2-coumaranone in 100 ml of ethanol is mixed with 21.0 g of dimethylamine hydrochloride and 30 ml 10η sodium hydroxide. The whole is left to stand for 1 hour at room temperature, after which the solution is evaporated under reduced pressure to give a tan residue. The residue is suspended in 100 ml of 5 η hydrochloric acid and the suspension is extracted three times with chloroform. The combined extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. 23.5 g of pink crystals with a melting point of 80 to 84 ^° C. are obtained. 8.5 g of this material are recrystallized from ethanol-ether, resulting in 4.3 g of 2- (o-hydroxyphenyl) -N, N-dimethylacetamide in form reaches colorless granular-like crystals, melting at 91 to 92.5 ⁰ C.

Example 70 2- / o- (2,3-Epoxypropoxy) phenyl / -N, N-dimethylacetamide hydrate (4: 1)

A solution of 100 g of epichlorohydrin in 250 ml of ethanol is stirred with a solution of 40.0 g of 2- (o-hydroxyphenyl) -N ^ N-dimethylacetamide and 25 ml of 10 η sodium hydroxide are added. The whole is left to stand for 18 hours at room temperature, whereupon the suspension obtained is evaporated under reduced pressure. The resulting pale yellow paste is with

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100 ml of 5 percent sodium bicarbonate are mixed, whereupon it is extracted three times with 100 ml of chloroform each time. The combined extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellowish oil. By treating this oil with ethyl acetate and filtration to obtain 39.5 g of pink crystals, melting at 85 to 87 ⁰ C. Recrystallization of 10.0 g of these crystals from ethyl acetate leads to 6.30 g of 2- / o- (2,3-epoxypropoxy) phenyl / -N, N-dimethylacetamide hydrate (4: 1) in the form of pink crystals with a melting point 87 - 88.5 ⁰ C.

Example 71

2- / o- (3-cyclopropylamino-2-hydroxypropoxy) phenyl / -N, N-dimethyl-

acetamide hydrochloride

A solution of 15.0 g of 2- / p- (2,3-epoxypropoxy) phenyl / -N, N-dimethylacetamide hydrate (4: 1) and 5.74 g of cyclopropylamine in 250 ml of isopropyl alcohol is refluxed for 3 hours and then evaporated under reduced pressure. The pink oil obtained is extracted with 1 liter of hot ether. The ether extract is filtered and treated with 12 ml of 5.3 η ethanolic hydrogen chloride. The whole is left to stand for 1 hour at room temperature, after which the resulting colorless, gummy residue is separated off by decanting. The recrystallization of this material leads to 6.12 g of 2- / o- (3-cyclopropylamino-2-hydroxypropoxy) phenyl / -N, N-dimethylacetamide hydrochloride in the form of colorless granular crystals which melt ^{at 164.5 to 166 ° C} .

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Claims (6)

FRG - 78 -. Patent claims ( 1. 1-Aryloxy-3-amino-2-propanols of the formula OH I OCH ₂ CHCH ₂ NH-R, AY
wherein R for cycloalkyl with 3 to 11 carbon atoms, 1-indanyl, 1-adamantyl or exo-2-norbornyl, A denotes vinylene or alkylene having 1 to 3 carbon atoms and Y amino, alkoxycarbonyl, cyano, hydroxy, carbamoyl, N-cyclohexylmethylcarbamoyl, Ν, Ν-dimethylcarbamoyl, morpholine or a residue of the formula S x ^C 2 ^H 5 and the hydrates as well as the non-toxic acid addition salts thereof. 609813/1040 Germany - 79 - 2. Process for the preparation of 1-aryloxy-3-amino-2-propanols the formula OCH ₂ CHCH ₂ NH-R, OH A-Y wherein R for cycloalkyl with 3 to 11 carbon atoms, cyclohexylmethyl, Exo-2-norbornyl, 1-adamantyl or 1-indanyl stands, A denotes alkylene having 1 to 3 carbon atoms or vinylene and Y carbamoyl, cyclohexylcarbamoyl, N, N-dimethylcarbamoyl, Cyclohexylmethylcarbamoyl, hydroxy, amino, cyano, carboxy, alkoxycarbony1, morpholino or a radical of the formula O / ^N If, C ₂ H ₅ -CN N-CHo-CN is,
characterized in that a compound of the formula 609813/1040 Germany - 80 - OCHo-X A-Y wherein A and Y have the meanings given above, with the proviso that the amino group by a hydrogenolytic removable group is protected and the carboxyl group in the form of a lower carbalkoxy group is present, and X is a remainder of the formulas OH or -CH-CH ₂ Z is, in which Z is halogen, alkylsulphonate or arylsulphonate, with an amine of the formula R-NH ₂ , in which R has the above meaning, and, if necessary, the amino protective group is hydrogenolytically split off from the compounds obtained or the lower carbalkoxy group is hydrolyzed. 3. Process for the preparation of 1-aryloxy-3-amino-2-propanoien the formula CH ₂ CHCH ₂ NH-R OH A-Y for cycloalkyl with 3 to 11 carbon atoms, cyclohexylmethyl, Exo-2-norbornyl, 1-adamantyl or 1-indanyl ^{stands /} 609813/1040 Germany - 81 - A denotes alkylene having 1 to 3 carbon atoms or vinylene and Y carbamoyl, cyclohexylcarbamoyl 1, Ν, Ν-diriethylcarbamoyl, Cyclohexylmethylcarbamoyl, hydroxy, amino, cyano, carboxy, Alkoxycarbonyl, morpholino or a radical of the formula O / \? / C ₂ H ₅ CN 9 ~ ^CH 2 " ^C " ^N n ^U ^ ^yl · ■ ^N C ₂ H ₅ is, characterized in that a compound of the formula OH A-Y wherein A and Y have the meanings given above, with the proviso that the amino group with a hydrogenolytic Removable group is protected and the carboxy group is in the form of a lower carbalkoxy group exists, with a combination of the formulas OH / 0 Z-CH ₂ CHCH ₂ NH-R or CH ₂ where Z represents halogen, alkyl sulfonate or aryl sulfonate and R has the meaning given above, reacts, and, if necessary, splitting off the amino protective group hydrogenolytically from the compounds obtained in this way or the lower carbalkoxy group is hydrolyzed. 609813/1040 Germany - 82 - 4. Process for the preparation of i-aryloxy-3-amino-2-propanols the formula OCH ₂ CHCH ₂ NH-R, OH A-Y R for cycloalkyl with 3 to 11 carbon atoms, exo-2-norbornyl or 1-indanyl, A denotes alkylene having 1 to 3 carbon atoms or vinylene and Y carbamoyl, cyclohexylcarbamoyl, N, N-dimethylcarbamoyl, Cyclohexylmethylcarbamoyl, hydroxy, amino, cyano, carboxy, alkoxycarbonyl, morpholino or a radical of the formula μ / ^λ Ι ' -C-N N 'C ₂ H ₅ is,
characterized in that a compound of the formula 609813/1040 och ₂ chch ₂ nh ₂ Ah A-Y wherein A and Y have the meanings given above, with the proviso that the amino group by a hydrogenolytitisch or hydrolytically cleavable group is protected with 1-indanone, 2-norbornanone or a cycloalkanone with 3 to 11 carbon atoms in the presence of an alkali borohydride converts and, if necessary, the amino protective group from the compounds obtained split off hydrogenolytically and hydrolytically. 5. Process for the preparation of 1-aryloxy-3-amino-2-propanols the formula OCH ₂ CHCH ₂ NH-R, OH A-Y wherein R for cycloalkyl with 3 to 11 carbon atoms, cyclohexylmethyl, Εχσ-2-norbornyl, 1-adamantyl or 1-indariyl stands, 609813/1040 Germany - 84 - A denotes alkylene having 1 to 3 carbon atoms or vinylene and Y carbamoyl, cyclohexylcarbamoyl, Ν, Ν-dimethylcarbamoyl, Cyclohexylmethylcarbamoyl, hydroxy, amino, cyano, carboxy, alkoxycarbonyl, morpholino or a radical of the formula / \ I / C ₂ H is,
characterized in that there is a compound of the formulas OCH ₂ TCH-CH ₂ YA * 'O NR or OCH ₀ -CH-CH ₀ ² II ² ° v ~ ^R Il wherein R, A and Y have the meanings given above, cleaves hydrolytically. 6 09813/1040 Germany - 85 - 6. Process for the preparation of i-aryloxy-3-amino-2-propanols the formula OCH ₂ CHCH ₂ OH A-Y NH-R wherein R for cycloalkyl with 3 to 11 carbon atoms, cyclohexylmethyl, Exo-2-norbornyl, 1-adamantyl or 1-indanyl stands, A denotes alkylene having 1 to 3 carbon atoms or vinylene and Y carbamoyl, cyclohexy1carbamoyl, N, N-dimethyl- carbamoyl, cyclohexylmethylcarbamoy1, hydroxy, amino, Cyano, carboxy, alkoxycarbonyl, morpholino or a residue the formula «/ - \ ο OX 1 "C * H -Ö-N N-CH ₂ -CN ^ ² " is,
characterized in that a compound of the formula 609813/1040 OCH ₀ CCH ₉ NHR, wherein A, Y and R have the meanings given above, with an alkali borohydride such as sodium borohydride. 6098 13/1040