DE2222471C3 - Process for the preparation of 1- (acylamino-aryloxy) -3-aminopropanol derivatives and their non-toxic acid addition salts - Google Patents

Description

as well as their non-toxic acid addition salts, in which means:

Ar is a substituted or unsubstituted benzene or naphthalene ring,

Ac is an organic acid residue,

Y is a hydrogen atom, a monovalent hydrocarbon radical with up to 12 carbon atoms or an organic acid residue or, together with the group Ac, a diacyl group,

Z is a hydrogen atom or an aliphatic ether bond to the oxygen atom bound protecting group and

R is an alkyl or aralkyl group,

characterized in that one Compound of the general formula

in

Ar is a substituted or unsubstituted benzene or naphthalene ring,

Ac is an organic acid residue

"^ Y is a hydrogen atom, a monovalent carbohydrate hydrogen radical with up to 12 carbon atoms or an organic acid radical or together mil the group Ac is a diacyl group,

Z is a hydrogen atom or one via an aliphatic atom Ether bond to the oxygen atom bonded protecting group and

R is an alkyl or aralkyl group

mean, which is characterized in that a compound of the general formula

Z -O-

NO

or a non-toxic acid addition salt. of that with a compound of the general formula

Ac N Ar Oll

I. I.

(IN THE)

at temperatures from IJO to 250 "C, optionally the protective group represented by Z. in the above-mentioned compound of formula 1 and, if desired, the obtained compound of formula Ib

OH

Ac N Ar O CII, CII CH, ONLY

I.
γ

(lh)

converted into a non-toxic acid addition salt.

The invention relates to a method of manufacture of I- (Acy lami no - a ryloxy) - 'i-aminopropunol derivatives the general formula

OZ

Ac N Ar O CM, (Il CII, NIIK

^Y
as well as their non-toxic Siurcadditionsal / s, wor-

ZO-,

NO

(H)

or a non-toxic acid addition salt thereof a compound of the general formula

Ac N
Y

Ar OH

(Hl)

at temperatures of 130 to 250 ° C, optionally the protective group represented by Z in the compound of the formula I given above and, if desired, the compound obtained of the formula Ib

OH

Ar O CH, CW CW, NHR

(lh)

converted into a non-toxic acid addition salt.
It is known that compounds of the general formula I given above have adrenergic blocking properties. In particular, has

1- (4'-Acetamidophenoxy) -3-isopropylamino-2-propanol the following formula

OH

O CII, CW CW, N

Il

CW, (Ie)

CII

CW,

NH COCH ₁

high organ selectivity, d. H. this connection acts selectively only on the heart muscle, and therefore this compound is considered excellent / i-adrenergic Blocking agent known that can be administered even to such patients, di; from heart failure Suffer.

The previously known processes / ur production of I - (acylamino-aryloxy) - i-substituted aminopropanol derivatives of the formula I or Ie given above, however, involve many complicated steps. That's why the reaction process is cumbersome and various difficulties arise in these known processes on. Since the dun h aid side reactions

Impurities only at the expense of the yield of the production of l- (4'-acetamidophenoxy) -3-isopropyl- The final product can be removed, it is very amino-2-propanol of the formula Ie given above

expensive, according to these known processes in the following reaction scheme A (see. Chemical

to produce the desired high-purity end product. Numerous cited for abstracts, 65, 7099 [1966])

Example must be carried out according to the usual procedure for 5 stages:

OH

Reaction scheme A

O-CH, -CH-CH ₂

NO, C] -CH ₁ CHCH, NO,

NH

\\ H ₂ CII- O N C. H ₂ C Ή Ul / C. _s O CH, -CH- -C CH (CHj) ₂ C ^- H ₂ C ₆ /
N C.
• NHCH H ₅ Y I. C. I. I. \ / CH., O C I. OH CH, C. H., // "- ■ OH H ₂ - CH j NO, / ι ι / ( n ' Y 1
I. cn., O C CH ₂ H, NH ₂ H ₂ C ₁₁ H ₅ CU, H, cn O ( H ₂ C H H, -CH

on

Nile (OCH,

CH

cn,

OH

NH (OCH,

CH.,

Another process is also already known, which is represented by reaction scheme B below can be [cf. Chemical Abstracts, 65, 7099 (1966)]:

Reaction scheme B

OO CH ₂ CH ClI,

Γ ι] (

NIl (OCH,

cn,

Nile, CII

In the process represented by the reaction scheme above, the isopropylamine must be used in large excess for the reaction of 1- (4'-acetamidophenoxy) -2, J-epoxypropane with an equiinolar amount of isopropylamine. Since the liasi / .itiil of isopropylumins is higher than that of an aromatic amine, the acetyl group is split off by the amnionolysis in the above process and therefore (4'-aminophenoxy) -2, I-epoxypropane or its isopropylamino-substituted product, which is obtained with the fnoxy ring white

O CH ₁ - CH CH ₂ NIlCH

// OH ClI,

NHCOCH,

reacted. As a result, the yield of the desired product (Ie) is lowered, and it can We do not avoid that the desired product contains by-products. These are serious ones Disadvantages of the known process illustrated by Reaction Scheme IJ above.

The object of the invention is therefore to create a process for the preparation of 1- (acylamino-aryloxy) -3-aminopropanol derivatives of the formula (I) given above and their non-toxic acid additive ! ion salts. this carried out in a single stage

can be obtained with high purity products obtained in high yield, and that of the above do not adhere to the disadvantages described. This object is achieved by the method of the invention.

A special feature of the process according to the invention is that the direct implementation of a Phenol or naphthol derivatives of the formula III with a substituted or unsubstituted acylamino group with a 3-azetidinol derivative of the formula II. which contains a tertiary nitrogen atom, to one Ring opening of the 3-azetidinol derivative of the formula H leads, so that the desired end product according to the Formula I can be formed in one step without the acylamino group of the phenol or naphthol derivative is attacked during implementation and can therefore be kept unchanged, whereby the The inventive method brings unexpected great advantages.

The invention is explained in detail below.

Tertiary azetidinol derivative
of the general formula II

In the tertiary azetidinol derivative of the general formula II given above, the group R is preferably an alkyl group with up to 12 carbon atoms, in particular with up to 5 carbon atoms, or an aralkyl group with 7 to 9 carbon atoms. The alkyl group can be either a straight chain alkyl group or a branched chain alkyl group however, a branched chain alkyl group is preferred.

It is particularly preferred that Z is a hydrogen atom (H) or a protecting group (Za) and R cinn branched-chain alkyl group with up to 5 carbon atoms, for example an isopropyl, tert-butyl, Means isobutyl and sec-bulyl group. The case in where R is an isopropyl group is particularly advantageous. If Z is a protecting group, can it is any of the known Schulz groups for the hydroxyl group. Preferred Examples of the protective group Za are those of the general formula

CH

.J '

oxymethyl, ethoxymethyl and benzyloxymethyl groups.

Among the tertiary azetidineGl derivatives of the general formula II given above, preference is given to Compounds of the following formula Ha are used

in the R 'any group having such properties means that the group

Z O

(Ha)

NO'

in which R 'is a straight or branched chain alkyl group having 1 to 5 carbon atoms and Z is a Hydrogen atom (H) or a protective group (Za) mean, which via an aliphatic ether bond to

ι s the oxygen atom is bound.

From the standpoint of pharmaceutical activity, among the compounds of the above formula Ha, the compounds having an isopropyl, sec-butyl, isobutyl or tert-butyl group as the group R and a hydrogen group as the group Z are particularly preferred.

Process for the preparation of tert-azetidinol
_{2 <} . Derivative of the formula II

The 1-substituted 3-azetidinols of the general formula II given above and the hydroxy-protected derivatives thereof, which are used as starting materials in the process according to the invention, y> are new compounds with a few exceptions. These compounds can be prepared, for example, by a process which consists in using a compound of the general formula

Z; i O

(H, X

(Ή, Χ

(IVl

in which X denotes a halogen atom or a reactive ester radical and Za as above with reference on the protecting group Z is defined with a primary amine of the following general formula

H, N R

(Vl

in which R is as defined above, reacts to form a 1-substituted azetidinol derivative of the following the general formula given, its 3-position is protected

can be split off as a whole under reducing conditions, in particular R 'preferably denotes a hydrogen atom, an alkoxy group having up to 3 carbon atoms, such as. B. a methoxy, ethoxy and propoxy group, an alkyl group containing up to 3 carbon atoms, e.g. B. a methyl, ethyl, n-propyl and isopropyl group, a halogen atom such as. B. a Chlorine and bromine atom, a halogenated alkyl group such as e.g. B. a Trifkiormethylgruppc, an amino group. a group which can be converted into an amino group, such as e.g. B. a nitro group, or another electron donor group and π denotes an integer from 1 to 3, preferably 1, it being particularly preferred that the substitution - (K ') ,, i; i 4-position of the benzene ring stands, and Alkoxyalkylschuizgruppen such. Ii. Meth-Zn O

(lib)

- NO

and, if desired, of the azctindinol derivative thus formed of the general formula Hb given above by a method known per se, for example by hydrogen reduction, the protective group Za is split off, thereby converting it into an azctidinol derivative general formula to convert

HO

Ml.

NO

in the row as above delimerl isi.

For example, the 1-isopropyl-azetidinol can following formula

CH.,

HO

N Cl

that for making the connection of the above given formula Ie, d. H. according to the invention Process preparable, most preferred compound, used as the starting compound is, easily prepared by a process which consists in a compound of the following formula

CH ₁ CI

'f / ^ W ₁ O - CH

CIl ₂ Cl
with a compound of the following formula

CH.,
NH, -CH

Vn.,

and the resulting compound of the following formula

ί N-CH

Vh.,

in the presence of a known reduction catalyst, for example a Raney nickel catalyst, with Hydrogen reduced.

Although the above reaction between the compound of the formula IV and the amine of the formula V can be carried out in the absence of a solvent in order to avoid the formation of diamines or polymers as by-products and to obtain an azetidinol derivative of the above formula Mb in high yield , the reaction is preferably carried out in the presence of a suitable inert liquid medium. As the inert liquid medium benzyl alcohol is most convenient, however, it may also contain other organic solvents, for. B. high-boiling organic solvents such as xylene, mesitylene and decalin can be used.

The primary amine of the above formula V can be added to the reaction system in the form of an aqueous solution, and it is possible to carry out the reaction while maintaining such a state that the compound of the above formula IV is dispersed in the aqueous solution of the primary amine of the formula V is. In general, the primary amine is preferably used in an amount which exceeds the stoichiometric amount, for example in an amount from 2 to 5 mol per mol of the compound of the formula IV. Even when the primary amine is used in such a molar excess, the formation of diamines as a by-product is hardly observed. The reaction may be at a temperature of 10O ⁰ C or performed later. In order to shorten the reaction time, it is convenient to carry out the reaction at 120 to 160 ⁰ C. In this case, the reaction is usually carried out for 10 to 50 hours.

The hydrogen reduction of the compound of the above formula Mb can be carried out at a temperature within the Range from room temperature to 100 ° C under a hydrogen pressure of 1 to 100 atmospheres

ίο Use of a metal catalyst, such as / .. B. Raney nickel, Raney cobalt, Urushibara nickel, palladium and platinum.

Phenol or naphthol derivative of formula III

Any arbitrary representative is used according to the invention of the acylaminophenols and acylaminonaphthols the following general formula is used

Ac-N Ar Oll

(III)

in which Ac, Ar and Y are as defined above.

In the compounds of the above general formula 2s III, the groups

Ac- Ν -

and -OH attached to the phenylene group -Ar- in any of the ortho, meta and para positions but they are preferably bound in the para position. In case the group does

; t <; —Ar— is a naphthylene group, the two can the above groups in the 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7- and 1,8-positions be bonded to the naphthylene group, however, they are preferably attached in the 1,4-, 1,5- or 1,8-position.

As indicated above, the group -Ac in the above general formula III means one organic acid residue. Examples of such organic acid residues are

4s acyl groups, such as formyl, acetyl,

Propionyl, benzoyl, ethoxycarbonyl,
Methoxycarbonyl, benzyloxycarbonyl,
p-methoxybenzyloxycarbonyl and
tert-butyloxycarbonyl groups;
organic sulfonyl groups, such as mesyl,

Benzylsulfonyl and tosyl groups;
organic sulfinyl groups such as
Benzenesulfinyl and toluenesulfinyl groups;
organic sulfenyl groups, such as
o-nitrophenylsulfenyl and

p-nitrophenylsulfenyl groups; and
organic phosphonyl groups such as benzene phosphonyl and methane phosphonyl groups. 60

Also, as an exception, a triphenylmethyl group is used as equivalent to the above-mentioned organic acid residues. This triphenylmethyl exceptional group therefore belongs in the present application to the group of organic acidic ste. Among these organic acid residues, the mono- or dicarboxylic acid residues having 1 to 8 carbon atoms are preferred.

When the group Y represents a hydrocarbon group, preferred examples of the group Y are Alkyl groups with up to 3 carbon atoms, such as methyl and ethyl groups. The groups Ac and Y may be linked together to form a diacyl group, such as e.g. B. ethylene dicarbonyl, maleyl, Phthalyl and naphthalyl groups. When Ac is a dicarboxylic acid residue, the groups Ac and Y are in the Formula III linked to each other and to the nitrogen atom. The phenylene or naphthylene group - Ar— in the above formula IM can have 1 to 3 substituents (Ri, R ;? or Ri). These substituents Ri, R2 and Rj can be the same or different and for an alkyl or alkenyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 Carbon atoms, a hydroxy group or an amino group. R | and R ^ can be with each other be linked to form an alkylene or ketoalkylene group or to form a 5- or O-membered heterocyclic ring by a heteroatom. The group - Y in the above general Formula III means a hydrogen atom, a monovalent one Hydrocarbon group with up to 12 carbon atoms or an organic acid residue and in addition, the groups Ac- and Y - can be linked to one another to form a Diacyl group, as mentioned above by way of examples. Among the phenols and naphthols the Formula III above are those of the formula

CH ₁ CO-NH-Ar 'OH

la)

in which Ar 'is a phenyl or naphthyl group, preferably a phenyl group, is advantageous in view of the pharmaceutical effects, and therefore they are most preferred.

Reaction conditions

According to the invention, 1- (Acy! Amino-uryloxy) -3-substituted Amino-2-propanol derivatives (the desired compounds) of the following general ones formula

OZ

Ac N-Ar- O -CH ₁ -CH-CFI, -NFIR

(I)

in which Ac, Ar, Y, Z and R are as defined above, formed by reaction of a tertiary azetidinol derivative of the above formula Ii with a phenol or naphthol of the above formula III, in particular with a phenol or naphthol substituted by a substituted or unsubstituted acylamino group, in the presence or absence of an inert organic solvent.

The reaction can be carried out in the absence or in the presence of an inert solvent, preferably a non-polar organic solvent, such as. B. benzene, xylene, ether, benzyl alcohol, decalin and dioxane can be carried out. In general, the reaction according to the invention is allowed to proceed at elevated temperatures within the range from 130 to 250 ^° C., preferably from 150 to 180 ^° C., but the temperature range is not particularly critical for the present invention. The reaction can be carried out under atmospheric pressure or under increased pressure. The reaction according to the invention runs smoothly even in the absence of a catalyst, but if desired it is also possible to use a basic catalyst, such as. B. solid potassium hydroxide, sodium hydroxide or triethylamine, or an acidic catalyst such as ? .. B. trifluoroacetic acid, or a strongly acidic cation exchange resin to be used.

According to a preferred embodiment of the invention, a tertiary azetidinol derivative of the above formula II with a phenol or naphthol derivative of the above formula III in the molten state or in the presence of an inert organic solvent, such as. B. benzyl alcohol and xylene, reacted in the presence of a solid alkali hydroxide in an amount of 1/100 to 1/10 mole per mole of phenol or naphthol. In this embodiment it is advantageous to use the phenol or naphthol in a slight excess over the tertiary azetidinol derivative, for example in an amount of at least 1.1 mol, preferably of at least about 1.2 mol per mol of the tertiary azetidinol derivative, to use. In this reaction, products of the general formula 1 given above are formed. Accordingly, an azetidinol derivative according to the invention upon reaction of the above formula Ha with a phenol or naphthol of the above formula IIIa under the above reaction conditions, a l- (acylamino-aryloxy) -3-substituie ^r th amino-2-propanol derivative formed by the following general formula

OZ

CFI ₁ CO NFI-Ar'-O-CHj-CFJ CH ₃ -NHR '(Ic)

in which Ar ', Z and R' are as defined above.

When Z in the above formula Ic represents a protecting group (Za), the compound obtained becomes the known hydrogenation reaction, for example in Ge

_{in the} presence of one of the above-mentioned reduction catalysts, thereby to split off the protective group (Za) and form an 1- (acylaminoaryloxy) -3-substituted amino-2-propanol derivative represented by the following general formula

4s OFI

CH ₁ CO-NH-Ar ^- -O-CH ₁ -CH-CH ₂ -NHR '(Id)

in which Ar 'and R' are as defined above.

Among the products obtained by the process according to the invention are from the point of view of pharmaceutical effect preferred the products in which Z in the above general formula I a Hydrogen atom means, namely the products in which the protective group (Za) is split off Products of the formula I or Ic given above, in particular the products in which the protective group (Za) is split off (e.g. the products of the formula Id) can be obtained in the form of the free bases. It it is also possible to convert the free bases into their acid addition salts. Examples of such acid addition salts are the salts of non-toxic inorganic or organic acids, such as. B. the hydrochloride, Hydrobromides, sulfates, succinates, tartrates and salicylates. The non-toxic acid addition salts of the compounds of the general formula I given above can also be prepared directly by reaction of an addition salt of a tertiary azetidinol

Derivative of the above formula 11 with one of the above-mentioned non-toxic acids, with a Phenol or naphthol of the above general formula I. Accordingly, by reacting the non-toxic Acid addition salts of the compounds of the formula Ha with compounds of the formula IHa directly non-toxic acid addition salts of the! - (acylaminoaryloxy) -3-substituted Amino-2-propanol derivatives are produced.

For the conversion to the direct production of the non-toxic acid addition salts of the compounds of the formulas I, Ic and Id can have the same reaction conditions as described above with respect to the synthesis of the free bases are given. In the event that the above Reaction is carried out in the presence of a solvent, organic solvents are preferred used, which are able to the acid addition salts of the compounds of formula II or to solve Ha at least partially. Polar solvents can advantageously be used as such solvents can be used, such as B. benzyl alcohol, phenethyl alcohol and dioxane. These have polar solvents preferably a basicity which is not higher than that of aniline and the use of Non-basic polar solvents are particularly preferred and advantageous.

Di ^p products of the formula I, in which Z is a hydrogen atom, which represent representatives of the compounds given above, have excellent / 3-adrenergic blocking properties and are very effective in curing and preventing coronary disorders such as e.g. B. Heart attacks and arrhythmias.

Among the products of the formula I or Ic prepared by the process according to the invention are those Products with a protecting group (Za) are new compounds and they are not only useful as intermediates for the synthesis of the products free of the protective group (Za), namely the products in which Z is a Hydrogen atom means, but also as a remedy for gastric and duodenal ulcers as they have an activity to control gastric secretion.

The invention is explained in more detail below with the aid of examples.

example 1

In a nitrogen atom, 11.6 parts of p-acetamidophenol and 8.1 parts of 1-isopropyl-3-azetidinol were dissolved in 50 parts of benzyl alcohol, and in this state, 0.3 part of potassium hydroxide was added to the solution. ^{The solution was heated to 140 °} C. for 6 hours with stirring. After the mixture was cooled, it was extracted with 2N hydrochloric acid and the extract was made alkaline to obtain an oily substance, which was then extracted with chloroform. The extract was concentrated to dryness and the residue was recrystallized from n-butyl acetate, giving 13.3 parts of 1- (4'-acetamidophenoxy) -3-isopropylamino-2-propanol in a yield of 69%, mp 133 up to 134 ° C. The hydrochloride of 1- (4'-acetamidophenoxy) -3-isopropylamino-2-propanol had a melting point of 139 to142 ° C.

Example 2

A mixture of 16.6 parts of p-acetamidophenol and 20.5 parts of l- (isopropyl) -3-benzyloxy-azetidine was

^{S de heated to 170 °} C. for 8 hours with stirring in a stream of nitrogen gas. The reaction mixture was then cooled and dissolved in 100 parts of ether. The solution was washed with 50 parts of water and dried over anhydrous sodium sulfate. The ether

It was distilled off and the residue was distilled, giving 20.5 parts of 1- (p-acetamidophenoxy) -2-benzyloxy-3- (isopropyl-amino) propane, bp. 193 to 196 ^ι Ο0.5ηΐΓη Hg.

'■ ^s ' example 3

To 3.6 parts of 1- (p-acetamidophenoxy) -2-benzyloxy-3- (isopropylamino) propane 10 parts of ethanol were added. Then became the mixture in one

»O Autoclave 4 parts of Raney nickel-containing ethanol were added and the mixture was ^{hydrogenated at 40 °} C. for 5 hours while the hydrogen pressure in the autoclave was kept at 40 kg cm ² . The reaction mixture was cooled and the catalyst was removed by filtration. After concentrating the filtrate, 2.4 parts of 1- (p-acetamidophenoxy) -3- (isopropylamino) -2-propanol with a melting point of 132 to 134 ° C. were obtained.

Example 4

A mixture of 16.6 parts of p-acetamidophenol and 11.5 parts of 1- (isopropyl) -3-azetidinol in decalin was stirred for 5 hours in one

vs nitrogen stream at 150 ⁰ C heated. The reaction mixture was cooled and dissolved in ether. The solution was washed with water and dried over anhydrous sodium sulfate. The ether was distilled off and the residue obtained was 18.9 parts of 1- (p-acetamidophenoxy) -3- (isopropylamino) -2-propanol, mp 133-135 ° C.

Example 5

In 50 parts of benzyl alcohol were 19.7 parts of 4-acetamido-2,3-xylenol and 12.9 parts dissolved l-tert-butyl-3-azetidinol, and to the solution was added under heating them in a nitrogen stream at 100 ⁰ C 0 , 5 parts of potassium hydroxide were added. The mixture was then heated ^{to 140 °} C. for 8 hours with stirring. The reaction mixture was cooled and 100 parts of 2N hydrochloric acid was added. The acidic aqueous solution obtained was washed twice with 50 parts of ethyl acetate. The water layer was made alkaline by adding 8 parts of 4N NaOH and extracted three times with 50 parts of ethyl acetate. The ethyl acetate layer was washed with 50 parts of water, dried over anhydrous sodium sulfate and then concentrated. When the concentrate was allowed to stand in the dark, crystals precipitated. After recrystallization from ethyl acetate, 12.4 parts of 1- (4'-acetamido-2 ', 3'-xyloxy) -3-tert-butylamino-2-propano! in a yield of 52%, m.p. 107 to 108 ^° C.

The 4-acetamido-2,3-xylenoI was prepared as follows:

In a stream of nitrogen, 5.3 parts of finely ground 4-amino-2,3-xylenol hydrochloride were mixed with 3

22 22 13th Example 6 CH, > 471 14th I. CH, CH, CH, Divide finely ground anhydrous sodium acetate 20.6 parts of 4-methanesulfonamidophenol, 11.5 parts OCH ₂ CH (OH) CH ₂ NHCh 175-177 C NHCO-Y OCH ₁ CH (OH) CH ₁ NHCiI S9 90 C
j \ well mixed. To this mixture became a mixture 1-isopropyl-3-azetidinol and 0.5 part of potassium hydroxide (Ik'HiimJil ¹ Su uklui Nt / hiiK'l / punkι OCH ₁ CH (OHiCH ₂ NHCH 177 IHO C OCH, CH (OH) CH, NHCH 126 127 c
ι of 3 parts of anhydrous acetic acid and 6 parts were dissolved in 50 parts of benzyl alcohol and the Cu j '■' <■ CW NHSO ₂ -Y ■ -CH, Glacial acetic acid was added and the resulting mixture was 3 Solution was heated to 130 ° C. for 20 hours with stirring Y IO ι ■ CH,
OCH _: CH (OH) CH ₂ NHCH 97 9S C Heated to reflux for hours. The reaction mi heated. The reaction mixture was cooled and NHCOCH, / IJ Γ ij Y ' The mixture was cooled and the solid obtained treated in the same manner as in Example 4. the OCh ₂ CH (OH) CH ₁ NHC (CH,), 120 122 C ν H, Y / NHCOCH CHC H, Y '■ · was dissolved in 50 parts of hot water. At the
When the solution was cooled, crystals precipitated. After ethyl acetate solution obtained was dried over anhydrous / \ A. ΟίΉ, ΓΗίΟΗίΠΙ, ΝΙΚ Η 17! 17.1 C ι "
ι,. -. Recrystallization from water gave 4.5 parts Sodium sulfate dried and concentrated and after I Jl 1 IS (' I ι NHCO V '-Cl N
/ \ 4-Acetamido-2,3-xylenol in a yield of 83%, F. Adding petroleum ether to the concentrate formed VV ^ I 1, CH., SO ₂ CH, 180 to 181 ° C. crystals. After recrystallization from ethyl acetate T Production of acetidines or acetidinols did and petroleum ether gave 14.4 parts of l- (4'-methane NHCOCH, Example a sulfonamido-phenoxy) -3-isopropylamino-2-propanol in 21.9 parts of 2-benzyloxy-1,3-dichloropropane, 59.1 parts a yield of 48%, mp 125-127 ° C. 20th Isopropylamine and 59.1 parts of water were in one Example 7 Autoclave and the mixture was 48 hours According to the previous examples heated for a long time with stirring. The reaction mixture procedures described were the following conn was cooled and in the same manner as in Example applications made: 1 treated, then was under reduced (iK-niisclii "Sliuklut melting point 2S Distilled pressure. In this way 17.4 parts were obtained /H, OCH ₁ CH (OH) Ch ₁ NHCH 9S 101 C ¹ Ox
NHCOCH, 10 OCH ₂ CH (OH) CH ₁ NHC (Ch,), 123 125 C ό NHCOCH, 35 40 45 5 ° 55 do fts

3-Benzyloxy-1- (isopropyl) -azetidine in one yield of 85%, b.p. 105 to 107 ° C / 2 mm Hg.

Example b

21.9 parts of 2-BCnZyIoXy-MdIChIOrPrOPaH, 713 parts tert-Butylamine and 50 parts of water were placed in an autoclave and the mixture was kept for 48 hours heated to 90 ° C. for a long time with stirring. The reaction mixture was cooled and processed in the same manner as treated in Example 1, then under reduced Distilled under pressure In this way, 17.5 parts of 3-benzyloxy-1- (tert-butyl) azetidine were obtained in one yield from 80%, bp 94 to 96 ° C / 2 mm Hg.

Example c ' ⁵

A solution of 4.1 parts of 3-benzyloxy-1- (isopropyl) azetidine in 30 parts of ethanol was together with 2 parts of Raney nickel as a catalyst in an autoclave and under a hydrogen gas pressure of 100 atmospheres, the mixture was carried out the reduction stirred for 15 hours at 40 ° C. Der The catalyst was removed by filtration and the remaining ethanol solution became dry concentrated. The oily substance obtained was distilled under reduced pressure or dissolved in η-hexane and cooled. In this way, 1.9 parts of 1 - (isopropyl-3-azetidinol were obtained in the form of white crystals The yield was 82%, the product had a melting point of 56 to 57 ° C. and a boiling point from 75 to 76 ° C at 3 mm Hg.

Example d

A solution of 4.4 parts of 3-benzyloxy-1-tert-butyl) azetidine in 30 parts of ethanol was placed in an autoclave together with 2 parts of Raney nickel as a catalyst. The mixture was stirred to carry out the reduction for 15 hours at 4O ⁰ C under a hydrogen gas pressure of 100 atmospheres. The catalyst was separated off by filtration and the remaining ethanol solution was concentrated to dryness. The oily substance obtained was dissolved in η-hexane and cooled. In this way, 2.0 parts of 1- (tert-butyl) -3-azetidinol were obtained in a yield of 76%, m.p. 42 to 43 ° C.

Example 8

In a nitrogen stream, there were 11.6 parts of p-acetamidophenol and 16.0 parts of 1-isopropyl-3-azetidinol hydrochloride dissolved in 50 parts of benzyl alcohol 'and the solution was stirred for 6 hours at 140 ° C After the reaction mixture had been evaporated, the residue was recrystallized from methanol / ethyl acetate and 14.2 parts of 1 - (4'-acetamidophenoxy) -3-isopropylamino-2-propanol hydrochloride were obtained, F 140 to 142 ° C.

Example 9

In a stream of nitrogen, 19.7 parts of 4-acetamido-2,3-xylenoI and 17.1 parts of 1-tert-butyl-azetidinol hydrochloride added to 50 parts of benzyl alcohol, and the mixture was heated at 150 ° C for 6 hours with stirring. After evaporating the mixture the residue was recrystallized from methanol / ethyl acetate, and 13 parts of 1- (4'-acetamido-2 ', 3'-xyloxy) -3-isopropylamino-2-propanol hydrochloride were obtained, 129-131 ° C.

Example 10

In a stream of nitrogen, there was 11.6 parts of p-acetamidophenol and 15.3 parts of 1-isopropyl-3-azetidinol hydrochloride mixed together and the mixture was heated at 145 ° C for 5 hours The reaction mixture was recrystallized from methanol / ethyl acetate and 11.7 parts of 1- (4'-acetamidophenoxy-3-isopropylamino-2-propanol hydrochloride, 139-141 ° C.

709 685/234

Claims (1)

Claim: Process for the preparation of 1- (acylaminoaryloxy) -3-aminopropanol derivatives the general formula OZ Ac -N-Ar-O-CH ₁ -CH CM, -NHR (I)