DE2114420A1 - Substituted phenylalkanol derivatives and processes for their preparation - Google Patents

Description

Merck Patent Company,
with limited liability
Darmstadt

March 24, 1971

Substituted phenylalkanol derivatives and processes for their preparation

The invention relates to substituted phenylalkanol derivatives of the general formula I -

R ² O-CH 1 CH ₂ ^R

wherein R ¹

R-

R '

OH, alkoxy with up to 6 carbon atoms, cycloalkoxy with up to to 6 carbon atoms, aryloxy with '

6 - 12 carbon atoms, aralkoxy with

7-12 carbon atoms or acyloxy with up to 18, preferably up to 6 carbon atoms, H, alkyl with up to 6 carbon atoms, Cycloalkyl with up to 6 carbon atoms, aryl with 6-12 carbon atoms, aralkyl with 7-12 carbon atoms or acyl with up to 18, preferably up to 6 carbon atoms, H or

Cl, Br or CH ₃ and 2 or 3,

and their physiologically harmless acid addition salts and their quaternary ammonium salts. "

It has been found that compounds of the formula I, as well as their physiologically harmless salts with good tolerance

- 2 -

■ 209841/1157

'Have an excellent anti-inflammatory effect, accompanied by a good analgesic and antipyretic effect is. Bacteriostatic, bactericidal, antiprotozoal, diuretic, blood sugar lowering, choleretic, cholesterol-lowering and radiation protection effects. The compounds of the formula I. and their physiologically acceptable salts can therefore be used as drugs and also as Intermediate products used in the manufacture of other drugs

. will.

The invention thus relates to substituted phenyls alkanol derivatives of the formula I, and their acid addition salts and quaternary ammonium salts.

The invention also relates to the compounds of the following preferred formulas Ia to Iq and their acids addition salts and quaternary ammonium salts, which correspond to the formula I and in which the unspecified radicals the Have the meanings given above, but where in

Ia R ¹ = OH; ■

Ib R ¹ = OAcyl; '.

Ic R ¹ = OH, n = 3;

Id R = OAcyl, n = 3;

Ä ie R ² = OH; '■ "·

If R ² = OAcyl;

Ig R ² = OH, n = 3;

ρ
You R = OAcyl, n = 3;

Ii R ³ = CH ₃ ;
Ij R ⁴ = Cl;

Ik R ¹ = OH, R ³ = CH ^, n = 3;

II R ¹ = OH, R ^{2 = OH, R 3} = CH ₃ , R ^ = Cl;

Im R ¹ = OAcyl, R ² = OH, R ^ = CH ₃ , R- = C1;

In R ¹ = OAcyl, R ² = Oacyl, R 1 = CH ₃ , R ⁴ = C1;

Io R ¹ = OH, R ^{2 = OH, R 3} = CH ₃ , R ^ = Cl, n = 3; .

Ip R ¹ = OAcyl, R ² ^ = OH, R ^ = CH ₃ , R ^ = Cl, n = 3;

Iq R ¹ = OAcyl, R ² = Oacyl, R ⁵ = CH ₃ , R ⁴ = C1, n = 3;

2098A1 / 1157

211A A 2 Ο

where acyl is an acid residue which is up to 18, preferably Contains up to 6 carbon atoms.

The invention also relates to a method for production of substituted phenylalkanol derivatives of the general formula I

wherein R ¹

hr ³ -ch ₂ r ¹

R-

OH, alkoxy with up to 6 carbon atoms, cycloalkoxy with up to 6 carbon atoms, aryloxy with 6 - 1.2 carbon atoms, aralkoxy with 7-12 carbon atoms or acyloxy with up to 18, preferably up to 6 carbon atoms Atoms,
H, alkyl with up to 6 carbon atoms, cycloalkyl with up to 6 carbon atoms, aryl with 6-12 carbon atoms, aralkyl with 7-12 carbon atoms or acyl with up to 18, preferably up to 6 carbon atoms Atoms, H or CH ,,
Cl, Br or CH, and 2 or 3 mean

as well as their acid addition salts and their quaternary ammonium salts, characterized in that a compound of the general formula II

(CH ₉ )

Z'n

R ² O-CH

wherein

II

represents a radical which can be converted into the grouping of the formula -CHR ³ -CH ₂ R ¹ (= Z ¹ ),

with an agent which converts the group X into the

Grouping of the formula Z transferred

209841/1167

or that a compound of the formula III

wherein
e
formula

2
X one into the grouping of

X ² -CHR ³ -CH ₉ R ¹ ο

. R-O-CH

transferable remainder means

with an agent that converts the group X into a

Grouping of formula W transferred,

and / or that, if appropriate, a compound of the formula I obtained is converted into another compound of the formula I,
and / or that a compound of the formula I obtained is optionally converted into its physiologically acceptable acid addition salts or its quaternary ammonium compounds, or released from its acid addition salts, and that optionally obtained racemates or mixtures of racemates are separated into pure racemates and / or enantiomers.

The invention also relates to a process for the production of pharmaceutical preparations, characterized in that at least one compound of the general formula I, optionally together with at least one solid, liquid or semi-liquid auxiliary or carrier and
if necessary together with at least one other active ingredient in a suitable dosage form, ■ - -

and pharmaceutical preparations containing an effective dose of a compound of the formula I in addition to at least one
Solid, liquid or semi-liquid carrier or additive, in particular pharmaceutical preparations, containing 0.1 100 mg of a compound of the formula I in addition to at least one

• - 5 -

209841/1157

solid, liquid or semi-liquid carrier or additive, and a method for achieving an anti-inflammatory, analgesic and / or antipyretic effect in living beings, characterized in that an effective dose of a compound of the formula I is administered.

The invention also relates to the use of compounds of formula I for the production of medicaments.

1 Ix Λ Ρ

In the above formulas, R through R, n, X and X have given meanings.

In addition to a free one, R denotes an etherified or esterified OH group. If R is an etherified OH group, it is, for example, alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, Amyloxy, isoamyloxy, hexyloxy or isohexyloxy groups; Cycloalkoxy groups such as cyclobutyloxy, cyclopentyloxy or cyclohexyloxy; Heterocycloalkoxy groups such as tetrahydrofuran-2'-yloxy, tetrahydropyran-2'-yloxy, 4'-alkoxytetrahydropyran-4 ^f -yloxy; Aryloxy groups such as phenoxy, p-tolyloxy, xylyloxy or naphthyloxy; Aralkoxy groups, such as benzyloxy, 1-phenylethyloxy or 2-phenylethyloxy groups.

If r ″ denotes an esterified OH group, it is preferred with a saturated or unsaturated aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, substituted or unsubstituted carbon or Esterified sulfonic acid. Preferred carboxylic acids are fatty acids with 1 - 18, especially 1 - 6 carbon atoms, such as ants, vinegar, Propion, butter, isobutter, valerian, isovalerian, capron, isocapron, oenanth, capryl, caprine, lauric, myristic, Palmitic or stearic acid, but it can also be other carboxylic acids, such as pivalic acid, diethyl acetic acid, oxalic acid, Malonic acid, succinic acid, pimelic acid, acrylic acid, fumaric acid, maleic acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, Pheny! Propionic acid, gluconic acid, furan-2-carboxylic acid, Act nicotinic acid or isonicotinic acid.

- 6 -209841/1157

The OH group can also with sulfonic acids, such as Methanesulfonic acid, ethanedisulfonic acid, ß-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, naphthalene mono- and disulfonic acids or camphorsulfonic acid, but also with inorganic acids, preferably sulfuric acid, or Phosphoric acids such as orthophosphoric acid can be esterified

2
In addition to H, R denotes alkyl with up to 6 carbon atoms or acyl with up to 18, preferably up to 6 carbon atoms, for example. Methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl or isohexyl; as acyl residues both

for example, the acids specified above for R in question.

1 1

X is a radical which can be converted into a grouping of the formula Z can be convicted. In particular, it concerns groups of Formula -CHR-A, where A represents a radical which is ■

by reaction with a reducing agent into a residue can be convicted. The radical A is therefore, for example, an aldehyde group, which is also present in a functionally modified form can, for example, as an acetal group such as a dialkyl acetal group, preferably a dimethyl or diethyl acetal group or as an alkylene acetal group, preferably an ethylene acetal or 1,2-propylene acetal group; or'an if applicable ^ functionally modified carboxyl group, preferably a ™ "alkoxycarbonyl group with up to 7 carbon atoms, in particular one. Methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl group or an aralkoxycarbonyl group with up to 9 carbon atoms, in particular a benzyloxycarbonyl group; but it can also be a carboxylic acid halide, preferably a -chloride- or -bromide- • group; a carboxylic anhydride group with up to 16 carbon atoms, preferably an acetoxycarbonyl group; a carboxylic acid azide or amide group; or a nitrile group.

1 2 4

For example, X can also be one of the following groups Z to Z:

-C (= CH ₉ ) -CH ₉ R ¹ (= Z ² ), -C (-CH ₇ J = CHR ¹ (= Z ³ -), -CH = CHR ¹ (. = Z ⁴ ) ..

- 7 -

209841/1157

2114A20

1 3

X can also be a group of the formula -CHR-CH ₂ Y, in which Y is Cl, Br, J or a reactively modified QH group, for example an alkylsulfonyloxy group with up to 4 carbon atoms, preferably a methanesulfonyloxy or ethanesulfonyloxy group, or a Arylsulfonyloxy group with up to 10 carbon atoms, preferably a p-tolylsulfonyloxy or a p-bromosulfonyloxy group, but also a tetrahydropyranyloxy group.

1
Finally, X can also be an oxiran-2-yl or 2-methyl-oxirane

2-yl group mean.

2 1

X is a residue that is converted into a grouping of the formula ¥ can be. This is preferably one of the following groups ¥ to ¥:

worxn

U-NH

(CH ₂ ) -N-

2 '

R ^ O-CH-

U Y- (CH ₂ ) _n -CH (OR ⁱⁱ ) -CH ₂ -, Y-CH ₂ -CH (OR ² ) - (CH ₂ ) _n -, CH ₂ -CH- (CH ₂ ) _Λ - or

Cf

(CH ₂ ) _n -CH-CH ₂ - means 0

wherein

Y ^{1 is} Cl or Br,

H = CH- (CH ₉ ) ^ - N-

2'm

R ² OCH-

wherein

m (n-2) is

209841/115

21-Η420

wherein · "R ⁵ (H, Y), (H, OM) or 0 and M is an equivalent of a metal.

atoms, preferably Na or K . is.

In the following, a "common solvent" is used for the reaction in question understood a suitable, inert solvent, in particular water; a hydrocarbon like heptane, Cyclohexane, benzene or toluene; a halogenated hydrocarbon such as chloroform, ethylene chloride, hexachlorobutadiene or chlorobenzene; an alcohol such as methanol, ethanol, ethylene glycol monoethyl ether or tert-butanol; an ether like diethyl ether, Ethylene glycol dimethyl ether, tetrahydrofuran or dioxane; a. Ketone such as acetone, butanone or acetophenone; an ester such as ethyl acetate; an aprotic dipolar solvent such as dimethylformamide, acetonitrile, diethyl sulfoxide, tetramethylurea, Tetrahydrothiophene-1,1-dioxide, propylene carbonate or hexamethylphosphoric triamide; or a mixture of these Solvent.

In the case of the starting compounds of the formula II (X = -CHR-A; A = optionally functionally modified carboxyl) is preferably substituted 3-chloro-4- (3-hydroxypyrrolidino) - or -piperidino) ~ phenylacetic acids, or substituted 2- / 3-chloro-4- (3-hydroxypyrrolidino) -phenyl / - or -hydroxypiperidino) -phenyl7-propionic acids or their esters, preferably 'their alkyl, in particular their methyl or Ethyl esters, their acid halides, preferably their chlorides or bromides, their anhydrides, optionally mixed thereof Anhydrides with other acids, their acid azides, amides or nitriles. But it can also be the corresponding in the 3-position of the phenyl ring by Br or CHj. (.instead of Cl) substituted acids or their functional derivatives listed above. . ■ -

- 9 -'2 09841/1157

" ⁹ ""21H420

The starting compounds of the formula II (X = -CHR-A; A = optionally functionally modified carboxyl) are known or can be prepared by known methods described in the literature getting produced.

For example, the amides of the formula II (X = -CHR-CONHp) are obtained by pouring in the corresponding carboxylic acid chlorides or bromides (these in turn are obtained by treating the free acids with an inorganic acid chloride or bromide, such as SOCl ₂ , SO ₂ Cl ₂ , PCl ₃ , PCl ₅ , POCl ₃ , PBr ₃ , POBr ₃ ) in an excess aqueous ammonia solution. If a mono- or dialkylamine is used instead of ammonia, the corresponding mono- or dialkylamides are obtained. The acid azides of the formula II (X ¹ = -CHR CON ₃ ) are obtained according to known methods, for example by reacting the acid halides with

The anhydrides of the formula II (X ¹ = -CHR ³ -COOCOR ⁶ ; R ⁶ = any organic radical, but preferably CH ^ - or

(CH ₂ ) - N - - P V - CHR - is obtained by known methods, 2 \ IR ² +, for example by reacting R O - CH CH ₂ alkali metal salts of the acids

Formula II (X = -CHR-COOH) with an equimolecular amount of an acid halide, or by heating the acid of the formula II (X ¹ = -CHR ^ -COOH) with acetic anhydride; In order to obtain the mixed anhydrides with acetic acid, the acids of the formula II (X = -CHR -COOH) can also be reacted with ketene.

The nitriles of the formula II (X ¹ = -CHR ^ -CN) are obtained, for example, in a known manner from compounds of the formula IV

R ² O-CH-

IV

by reaction with an inorganic cyanide, preferably. NaCN or KCN.

- 10 2098A 1/1157

- 10 - ■. .

■■■■■. ■ 21U420

In some cases it is also ^{possible to produce a nitrile of the formula II:} (X = —CHR — CN) by splitting off water from an amide of the formula II (X ¹ = —CHR ³ —C0NH ₂ ).

Aldehydes of the formula II (X ¹ = -CHR ^ -CHO) are obtained, for example, by reacting an acetophenone of the formula V (R ⁷ = H)

(CH _Q ) -N (TV-CO-CHoR ⁷

■ 2'n

R ² O-CH

with methoxymethyltriphenylphosphonium chloride and subsequent acid hydrolysis.

The allyl alcohols substituted in the 2-position or their

12 "

functional derivatives of the formula II (X = Z) are obtained, for example, by reacting an a-alkoxy-acetophenone of the formula V (R ⁷ = OR ⁸ ; R ⁸ = alkoxy with up to 6 carbon atoms, cycloalkoxy with up to 6 carbon atoms) Atoms, aryloxy with 6-12 carbon atoms, aralkoxy with 7-12 carbon atoms or acyloxy with up to 18, preferably up to 6 carbon atoms) by reaction with triphenylmethylphosphonium bromide and phenyllithium. ■

The vinyl ethers or vinyl esters of the formula II (X = lic or lld) is obtained, for example, from aldehydes of the formula II (X = -CHR-CHO) by heating in a mixture of an acid anhydride and an alkali salt of the same acid. Preference is given to using the enol acetates, which are obtained from the aldehydes of the formula II obtained by heating with acetic anhydride / sodium acetate.

The styrene oxides II (X ¹ = oxiran-2-yl or 2-methyl-oxiran-2-yl group) are obtained from the. corresponding styrenes by known methods, for example by treatment with trifluoroperacetic acid or perbenzpeic acid. "..

'. - 11 2098A1 / 115 7

OO

Compounds of the formula III (X = W) can be prepared by processes known per se by reacting compounds of the formula VE

Y- (CH ₂ ) _n -CH (OR ² ) -CH ₂ -Y

VI

or of compounds of the formulas Vila or VIIb

H- (CH ₂ ) _n -Y

Vila VIIb

with a compound of the formula VIII (R = R)

YOUR ³ CH ₂ R ¹

VIII ■

getting produced. ~

The diazonium salts of the formula III (X = W) are obtained, for example, by methods known per se, for example by reacting a compound of formula IX

Br- / ^

IX

with a 3-hydroxypiperidine or 3-hydroxypyrrolidine or their 0-alkyl or O-acyl derivatives, reduction of the nitro group, preferably with a base metal in a mineral acid solution,

- 12 2 0 9 8 U 1/1 1 "57

: ~ 12-21UA20

eg with Fe in dilute HCl., or by catalytic hydrogenation; but also in an alkaline environment, for example with Zn dust in aqueous NaOH; and subsequent diazotization at temperatures between -20 ° and + 5 °, preferably at 0 ° · in hydrochloric acid. ": or hydrobromic acid aqueous solution, by adding the calculated amount of an inorganic nitrite, preferably NaNOp or KNOp the usual: _-; work organic solvent and the diazotization by ^ adding an organic nitrite such as n-butyl nitrite, n-amyl;:... or nitrite, isoamyl nitrite vorzugsweise.in reach the presence of HCl, HBr qThe '* ■ - .

The compounds of the formula III (X = W) are obtained, for example from the 2- (4-aminophenyl) ethanols or propanols of Formula VIII (R = H) by reacting with compounds of the formula VI, VIIa or VIIb.

The compounds of the formula III (X = W ^) are obtained, for example, in an known manner from compounds of the formula X.

CH = CH- (CH ₂ ) -N-

by bromination, preferably with a bromimide such as ri-bromosuccinimide, in one of the usual solvents at temperatures between 20 and 120, preferably at the boiling temperature of the solvent, optionally with simultaneous irradiation of preferably short-wave light, and subsequent solvolysis . Depending on the solvolysing agent used, either alcohols of the formula III (X ¹ = W ⁵ ; R ² = H) or esters of the formula III (X ² = W ⁵ ; R ² = acyl) are obtained.

2 0 9 8 Λ 1/1157 - 13

21U420

Starting compounds "of the formula III (X = lilf; R = 0) can be prepared, for example, from compounds of the formula IX by reaction with 3-piperidone or 3-pyrrolidone ethylene ketal, subsequent reduction of the nitro group, diazotization and replacement of the diazonium group with chlorine or bromine If R ^{5 is,} for example, (H, Br), the corresponding compounds of the formula III are obtained by bromination of compounds of the formula X and subsequent hydrogenation.

According to the invention, the compounds of the formula I are easily obtained from the compounds of the formula II (X = -CHR-A) by treatment with a reducing, preferably hydrogen-donating agent, in particular with a complex metal hydride.

As a reducing agent, one can also use catalytically excited hydrogen, hydrogen in the statu nascendi or chemical reducing agent- use.

For catalytic hydrogenations, for example, are catalysts Noble metal, nickel and cobalt catalysts, for the reduction of carboxylic acid derivatives also mixed catalysts suitable as copper chromium oxide. The precious metal catalysts can be used on carriers (e.g. platinum on carbon, palladium on calcium carbonate or strontium carbonate) as oxide catalysts (e.g. platinum oxide) or as finely divided metal catalysts. Nickel and cobalt catalysts are conveniently used as Raney metals, nickel also on kieselguhr or pumice stone Carrier used. The hydrogenation can be carried out at room temperature and Normal pressure or also at elevated temperature and / or elevated pressure can be carried out. It is preferable to work in printing between 1 and 100 at, occasionally, as in the hydrogenation of Esters with e.g. Co acetate, even at higher pressures, and at temperatures between -80 ° and 200 °, especially between room temperature and H-100 °. The implementation is expedient in counter

_ 14 - 209841/1 15.7

was carried out using one of the usual solvents. The free compounds or the corresponding can be used for the hydrogenation Salts, for example the hydrochlorides or sodium salts, can be used.

The hydrogenation of multiple bonds is preferred at normal pressure in such a way that the hydrogenation is terminated after the calculated amount of hydrogen has been taken up. One can basically work in acidic, neutral or basic areas.

Implementation is also generally applicable as a reduction method with nascent hydrogen. You can do this, for example by treating metals with acids or bases. For example, a mixture of zinc with acid or Use alkali, iron with hydrochloric acid or acetic acid, or tin with hydrochloric acid. Use is also suitable of sodium or another alkali metal in an alcohol such as ethanol, isopropanol, butanol, Amy 1 or isoallyl alcohol or phenol, with reductions of carboxylic acid derivatives according to Bouveault-Blanc, preferably at the boiling point of the used Alcohols works. An aluminum-nickel alloy can also be used Use in alkaline-aqueous solution, if necessary with the addition of ethanol. Also sodium or Aluminum amalgams in aqueous-alcoholic or aqueous solution are suitable for generating the nascent hydrogen. The implementation can also be carried out in a heterogeneous phase be, whereby one expediently an aqueous and a .Benzene or toluene phase used. The reaction temperatures used are between room temperature and the boiling point the solvent used. ■

If a complex metal hydride is used as the reducing agent, such as above all LiAlH _{Z (} , NaAiH ₂ (OCH ₂ CH ₂ OCEU) ₂ or NaBH ^, possibly with the addition of catalysts such as BF ^, AlCl ^ "or *" LiBr, this works one of the usual solvents, preferably in an ether such as diethyl ether, is expedient in the opposite direction,

20984 17 1 1 57 '

Tetrahydrofuran or dioxane. The reactions are advantageously carried out between -80 ° and the boiling point of the solvent. The metal complexes formed can be decomposed in the usual way, for example with moist ether or an aqueous ammonium chloride solution. A particularly preferred • reducing agent is NaAlH ₂ (OCH ₂ CH ₂ OCHv) ₂ J. It can be used to reduce aldehydes, carboxylic acids, carboxylic acid esters, anhydrides and halides of the formula II (X = -CHR-A) to give compounds of the formula I use. - - - -

Aldehydes of the formula II (X ¹ = -CHR ^ -CHO) can also be reduced according to Meerwein-Ponndorf, using aluminum alcoholates, preferably isopropylate or ethylate, in, for example, benzene or toluene at temperatures between room temperature and the boiling point of the solvent .

Nitriles of the formula II (X ¹ = -CHR ^ -CN) can, for example, by treatment with hydrogen in the presence of Raney nickel and a cation exchanger. be converted into the alcohols of the formula I in an aqueous medium. Amides of the formula II (X = -CHR -CÖNHp) can also be split reductively to give the alcohols of the formula I by electrolysis in aqueous methanolic solution in the presence of tetramethylammonium chloride.

A compound of the formula II (X ¹ = Z ² , Ί? Or Z) can also be converted into a compound of the formula I by treatment with reducing agents, preferably hydrogen-donating agents, for example with sodium amalgan or catalytically excited hydrogen. ·. ·

If one starts from an epoxide of the formula II. (X = oxiran-2-yl or 2-methyl-oxiran-2-yl), the compounds of the formula I are obtained, for example, by treatment with LiAlfL. in the presence of AlCl ^ or with BH-Z-BF ₇ , preferably in tetrahydrofuran at 0 °. ,

- 16 1/1157

The compounds of the formula are also obtained. I by adding a halogen compound or a sulfonic acid ester of the. . Formula II (X = -CHR-CH ₂ Y) with. a solyolysing agent, such as an alcohol, an acid or HpO, preferably in the presence of an acidic or basic catalyst, or with. a metal salt or metal alcoholate. For example, alcohols of the formula I are obtained by adding a halogen compound of the formula II (X ¹ = -CHR ⁵ -CH ₂ -Hal; Hal = Cl, "Br, J) in aqueous or aqueous-alcoholic solution or suspension, possibly with the addition of a solubilizer such as an alcohol, glycol or polyglycol ether, saponified.

The saponification agents used are generally bases or basic salts, preferably alkalis such as NaOH or KOH; but you can also use slurries of Ca (OH) ₂ , Pb (OH) ₂ or AgOH _: . The saponification is usually carried out at a higher temperature, for example at the boiling point of the solution.

1 ^ 5 by means of. A halide of the formula II (X = -CHR-CH) can also be reacted in a non-aqueous medium by stirring its solution in a conventional solvent with exclusion of water with suspended AgOH or Pb (OH) ₂ at the boiling point.

Ί Λ O? "*

One arrives at ethers of formula 1. (R = "QR; R = H), if compounds of formula II (X ¹ = -CHR ³ -CH ₂ OM; M = one equivalent of a metal atom, preferably Na or K) according to the Methods of Williams on. Synthesis with a compound of the formula XI

. in which,

YR ¹⁰ R ¹⁰ alkyl with up to 6 carbon atoms,

Cycloalkyl with up to 6 ΟΧΙ atoms, aryl with 6 - 12 C- '

; . ■. . Atoms or aralkyl with 7-12

C atoms means

implements. To get to, uniform products, one becomes protect the OH group in the "heterocycle in general beforehand and remove the protective group again after the reaction

209841/115

columns. It is advantageous to put the sodium alcoholate through A solution of the alcohol of the formula I (R = OH) in a customary solvent is added dropwise to a finely divided suspension the calculated amount of Na in an inert solvent, preferably Toluene or xylene. If the less reactive chlorides or bromides of the formula XI (Y = Cl or Br) used, you can add a little KJ. The reaction mixture is then boiled until it becomes neutral. Phenyl ether are obtained by adding one equivalent of the phenol in question to the alcoholic alkali metal alcoholate solution and otherwise continues to work as described for the alkyl ethers. In the representation of the phenyl ethers water or aqueous alcohols can also be used as solvents. But you can also alkali or

10
-Phenolate of the formula R OM with halogen compounds of the formula II (X ¹ = -CHR ^ -CH ₂ -HaI). If one works in suspension, then in this case in particular inert solvents such as ether, tetrahydrofuran, acetone or benzene are used. Of course, the dieters of the formula I (R ¹ = -OR ¹⁰ , R ² = R ¹⁰ ) can also be prepared by this method if starting compounds of the formula II (X = -CHR-CHpOM;

2 Ί Ο
R = R) with the compounds of the formula XI. j

Λ Ι

In an analogous manner, esters of the formula I (R = OAcyl, R = H) are obtained by mixing the substances of the formula II (X = -CHR-CHp-Y) in aqueous, aqueous-alcoholic or alcoholic solution with the alkali salts of carboxylic acids to be esterified boils. An addition of triethylamine accelerates. the implementation. If you want to obtain acetates of the formula I (R ¹ = OCOCH ,; R = H), a preferred procedure is that the halides or sulfonic acid esters of the formula II (X · = -CHR-CH ₀ -Y) with solutions of boiling anhydrous sodium acetate in glacial acetic acid. For the preparation of esters of the formula I (R =

OAcyl, R = H) is also possible. To implement halogen compounds of the formula II (X ¹ = -CHR ^ -CH ₂ -HaI) in one of the customary inert solvents with silver salts of the corresponding acids. In all of these implementations, in order to

- 18 209841/1157

'21U420

union products to get the OH group in the heterocycle in generally protect beforehand and the protective group after the implementation split off again.

Compounds of the formula I obtained can also be converted into other compounds of the formula I: For example, the alcohols of the formula I (R ¹ - OH, R = H) can be converted directly with excess acid, optionally in the presence of one of the customary ones. Solvent, preferably a hydrocarbon such as benzene

Λ P

or toluene to the diesters of the formula I (R · ■ '= OAcyl, R = acyl) to esterify. For example, you can also get one

1 2
Diesters of the formula I (R = OAcyl, R = acyl) with excess acid, if appropriate in the presence of one of the customary solutions. agent and / or a sulfonic acid such as p-toluenesulfonic acid to convert into another diester of the formula I.

Compounds ^ of the formula I can be obtained from starting materials of the '

1
Formula II, where X is an oxiran-2-yl or 2-methyl-oxiran-2-yl radical, by treatment with hydrogen _{donating agents, preferably hydrides such as B 2} Hg or LiAlH ^ in the presence of a Lewis acid such as BF-, or 'Prepare AlCl ₃ . The reaction is carried out in one of the customary solvents, preferably an ether such as diethyl ether or tetrahydrofuran, at temperatures between -20 ° and + 30 °, preferably between -5 ° and + 5 °.

2 2

Starting from a compound of the formula III (X = W), the compounds of the formula I are obtained by known processes by reaction with a cyclizing agent, preferably by heating in aqueous solution or suspension, optionally in the presence of an acidic or basic catalyst, or in one of the customary organic solvents, but preferably in an organic acid such as formic acid, acetic acid or propionic acid, especially in the presence of an acidic one Catalyst, such as HCl.

. '"- 19 209 84 17 1157

~ 19 .- ■

21U42Q

line particularly preferred and advantageous procedure is not to isolate the compounds of the formula III (X ² = W ² ), but to prepare them in statu nascendi with or without the presence of one of the customary solvents, optionally with the addition of a suitable catalyst, and to prepare them directly To cyclize compounds of the formula I. Depending on which starting materials are used, the process is carried out at low temperatures, for example room temperature, or at higher temperatures, preferably at the boiling point of the solvent used. In individual cases it may be necessary to carry out the reaction under pressure (up to 200 at) or at increased pressure. Temperature (up to 300 °). The use of a catalyst, e.g. a base such as NaOH, KOH, sodium or. Potassium carbonate is possible, but not essential. ^

The compounds of the formula I are also obtained if the diazonium grouping in the diazonium compounds of the formula III (X = W) is exchanged for Cl or Br by methods described in the literature. The exchange for chlorine is preferably carried out in an aqueous solution in the presence of CUpCl ₂ according to the Sandmeyer method. The exchange for bromine can, for example, take place in an aqueous solution in.Gegenwart von CupBr ^ according to Sandmeyer or by reaction with bromine in the diazonium perbromide and subsequent boiling in a suitable solvent, for example water or a lower alcohol. However, it is also possible to convert the diazonium bromides with HgBrp into the diazonium mercury bromides and to decompose them thermally to give the desired bromine compounds.

The radical R can in compounds of the formula III (X = W) according to methods described in the literature, through direct substitution, are preferably introduced by treatment with chlorinating or brominating agents.

- 20 -

20934 1/11 57

Chlorination takes place, for example, by direct reaction with elemental chlorine in an inert solvent such as water, CCl ^, acetic acid, without or with the addition of specific catalysts such as FeCl ,, AlCl ,, "SbCl, or" SnCl ^, preferably between -10 ° and 100; or by reaction in a strong hydrochloric acid solution with H ₂ O ₂ or with NaClO, the chlorination being brought about by the chlorine that is formed in statu nascendi; or by reaction with SO ₂ Cl ₂ in an inert solvent, such as Chlorobenzene, in the presence of catalysts which form free radicals, for example peroxides, preferably at 80 ° -180 °; or by _; Reaction with NO ₂ Cl or NOCl in CS ₂ or hexane. line bromination is particularly easy, for example, by direct reaction of P with elemental bromine in an inert solvent, such as CS ₂ , acetic acid or CCl ^, in particular with the addition of specific catalysts that act as bromine carriers, such as iron filings, AlCl ,, AlBr, , FeCl ,, iodine or pyridine, preferably between -30 ° and 90 °; or · by reaction with sub-bromine. Acid, acyl hypobromites, N-bromo-imides, such as N-bromosuccinimide, N-bromophthalimide ο the other bromine-releasing agents, such as 1,3 ~ · dibromo-SjS-dimethyl-hydantoin, in inert solvents, such as nitrobenzene or CS ₂ , preferably at -10 ° to 150 °; or by reaction with NOBr or NO ₂ Br in CS ₂ or cyclohexane. .

The compounds of the formula I are obtained from the compounds

OK

fc of the formula III (X = Vr) by treatment with reducing, preferably hydrogen-donating agents. So can a hydrogenation the double bond in the heterocycle can be carried out by one of the methods explained above. .

The ethers of the formula I (R ¹ = OH; R ² = R ¹⁰ ) are obtained. when compounds of the formula III (X ² = W; R ⁵ = / H, OM7) are reacted with a compound of the formula XI by the methods of Williamson synthesis. One works, for example, with the .Reaktionsbedingungen .. described above. ...

The esters of the formula I. (R = OH; R = acyl) can also be used using the methods already described.

- 21 -:

■ 20984 171157

The compounds of the formula I can also be ^{prepared from compounds of the formula III (X 2} = W ⁶ ; R ⁵ = βi, tj) by treatment with solvolyzing agents such as alcohols, acids or HnO, preferably in the presence of an acidic or basic catalyst known methods or by reaction with a metal salt or metal alcoholate.

An oxo compound of the formula III (X = W; R = 0) can by Treat with reducing, preferably hydrogen-releasing Agents, especially complex metal hydrides, reduced to the corresponding hydroxy compounds by known methods will. The reaction conditions must be chosen in such a way, for example by using NaBH ^ in methanol, optionally in the presence of aluminum chloride or lithium bromide that the phenyl ring is not reduced. Man works appropriately in the presence of one of the usual solvents, preferably in a lower alcohol, ether, tetrahydrofuran or ethylene glycol dimethyl ether; The implementation will advantageously by boiling the reaction mixture to the end. The decomposition of the formed metal complexes can occur

usual way, e.g. with an aqueous ammonium chloride solution take place.

A variant of the methods described above consists in ^{starting from a compound X 2} -X ¹ (X ¹ = -CHR ³ -A, Z ² , Ί? Or Z ^; X = w or W with R = 0) and this with one of the. implement the reducing agent described above. Intermediate compounds of the formula II (X = -CHR-A, Z, 2? Or Z ⁴ ) or III (X ² = W ⁵ or W ⁶ with R ⁵ = 0) are formed, which can be isolated without them - Further to the compounds of formula I converts. »

2 11 It is also possible to use a compound of the formula X-X (X =

-CHR 1 -CH ₂ Y; X ² = W ⁶ with R ⁵ = / Ti ₇ Yj) to react with one of the solvolyzing agents described above, the resulting compounds of the formula II (X ¹ = -CHR ^ -CH ₀ Y) or ^{III (X 2} = W ⁶ With R = / S, Y /) not to isolate, but immediately with over-

- 22 209 84 1 / -11 57

Schüssigem solvent further to compounds of formula I umzu- ~ set. However, these starting compounds of the formula X-X can also be mixed with 2 equivalents of a metal salt or metal alcoholate convert to compounds of the formula I to obtain. It is particularly advantageous to obtain a connection of the -

1 2 '

Formula I (R = OH, R = H) according to one of the methods described in more detail above by alkylation or acylation in a diether of the formula I (R ¹ = OR ¹⁰ , R ² = R ¹⁰ ) or a diester of the formula (R j = OAcyl, R = acyl). This mostly forms. . intermediate the corresponding monoethers or monoesters, which are immediately further alkylated or acylated.

A compound of the formula I can with an acid in the associated Acid addition salts are transferred. For this reaction, those acids come into question that are physiologically harmless Deliver salts. Organic and inorganic acids such as aliphatic, alicyclic, araliphatic aromatic or heterocyclic mono- or polybasic carbon or Sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, Pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, pheny! Propionic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methanesulphonic acid, ethane disulphonic acid, ß-hydroxyethanesulphonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, Sulfuric acid, nitric acid, hydrohalic acids, such as · ■■ _ ■ Hydrochloric acid or hydrobromic acid, or phosphoric acids, such as orthophosphoric acid ,, can be used.

Conversely, compounds of the formula I can be derived from their acid.addi- _:

ionic salts by treatment with strong bases such as sodium; or potassium hydroxide, sodium or potassium carbonate, or from their metal and ammonium salts by treatment with acids, mainly mineral acids such as hydrochloric or sulfuric acid, in free, be set. ·

-23 20984 1/1157

- 23 -.

If the compounds of the formula I contain an asymmetry center, they are usually in racemic form. Point If they have two centers of asymmetry, then they fall during synthesis in general as mixtures of two racemates, from which the individual racemates, for example can isolate and recover in pure form by repeated recrystallization from suitable solvents.

The racemates can be converted into their optical antipodes by a large number of known methods, as indicated in the literature be separated. So you can get some racemic mixtures precipitate as eutectics instead of in the form of mixed crystals and separate in this way, whereby in these cases also a selective one Precipitation may be possible. However, the chemical separation method is preferable. Then the racemic Mixture formed by reaction with an optically active auxiliary diastereomers. So, if necessary, you can use a react optically active acid with the amino group of a compound of formula I. For example, one can use diastereomeric salts of the compounds of the formula I with optically active acids, such as (+) - and (-) - tartaric acid, dibenzoyl - (+) ~ and (-) - tartaric acid, Diacetyl - (+) - and - (-) - tartaric acid, camphoric acid, ß-camphorsulphonic acid, (+) - and (-) - mandelic acid, (+) - and (-) - malic acid, (+) - and (-) - 2-pheny! butyric acid, (+) - and (-) - dinitrodiphenic acid or (+) - and (-) - form lactic acid. The desired enantiomer of the formula I is then obtained by separating off the optically active auxiliary according to known methods.

The hydroxy compounds of the formula I (R = OH and / or R = H) can also be esterified with one of the above optically active acids converted into suitable diastereomeric esters which can be separated due to their different properties. The optically active compounds of Formula I are obtained in each case by saponifying the pure diastereomer. But you can also start with phthalic acid.

- 24 -

209841/1157

21UA20

or succinic anhydride, the acidic phthalic or succinic esters represent and the dibasic ones obtained in this way Acids with, for example, one of the following, optically active Convert bases into the diastereomeric salts and from these win the pure enantiomers: quinine, quinchonidine, brucine, Cinchonine, Hydrbxyhydrindamin, Morphine, 1-Phenyläthylamin,. 1-naphthylethylamine, phenyloxynaphthylmethylamine, quinidine or strychnine.

The separation of the racemates or racemate mixtures is particularly "advantageous with the help of chromatographic methods. You can either optically active carrier materials, such as z * B. Wine-, acid, starch, cane sugar, cellulose or acetylated cellulose and optically inactive and / or optically active mobile solvents for Use separation into the pure enantiomers or an optically inactive carrier material such as silica gel or aluminum oxide in combination with an optically active running agent. The optical Antipodes can also be used biochemically using selective, enzymatic reactions are separated. For example, the use of a hydrolase is on an ester of the racemic mixture possible for the preferred formation of an optically active form which selectively saponifies one enantiomer and that leaves others unchanged.

It is of course also possible to use optically active compounds to be obtained according to the methods described by starting materials that are already optically active.

The new compounds can be mixed with solid, liquid and / or semi-liquid drug carriers as drugs in used in human or veterinary medicine. As carrier substances such organic or inorganic substances come into question, which for the parenteral, enteral or topical Application are suitable and do not react with the new compounds, such as water, vegetable Oils, benzyl alcohol, polyethylene glycols, gelatine,

- 25 ■ 20 9 841/1157

- ²⁵ -, 2 I H420

Lactose, starch, magnesium stearate, talc, petrolatum, cholesterol. Solutions, preferably oily or aqueous solutions, and suspensions, are used in particular for parenteral administration. Emulsions or implants. Suitable for enteral application. Tablets, coated tablets, syrups, juices or suppositories, for topical application of ointments, creams or powders. The specified preparations can optionally be sterilized or with auxiliaries such as lubricants, preservatives, stabilizers or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, taste and / or flavorings are added.

The substances are preferably administered in a dosage of 0.1 to 2000 mg per dosage unit.

example 1

a) 3.6 g of 2- / 3-chloro-4- (3-hydroxypiperidino) phenyl7-allyl alcohol (can be prepared from 2- (S-nitro ^ -chlorophenyl ^ allyl alcohol and 3-hydroxypiperidine, catalytic ^ reduction for Amino compound, Diazotieruhg and exchange of the diazonium group for chlorine) are in a mixture of methanol and ethyl acetate is hydrogenated with hydrogen at room temperature in the presence of 0.6 g of a Pd-C catalyst (5% by weight of Pd). After the uptake of hydrogen has ended, the mixture is filtered, the filtrate is evaporated and the residue is fractionated. Man receives 2- / 3-chloro-4- (3-hydroxypiperidino) -phenyl / -propanol- (1) as a mixture of two racemates, bp = 180 ° / 0.05 mm, f = 75-82 °.

Analogously one obtains from: '

2_ ^ 3_Chlor-4- (J-hydroxypyrrolidino) -phenylZ-allyl alcohol 2- / 5-Bromo-4- (3-hydroxypyrrolidino) phenylj-allyl alcohol 2- £ 3-methyl-4- (3-hydroxypyrrolidino) phenyl / allyl alcohol 2- ^ 3-bromine-4- (3-hydroxypiperidino) phenyl7-allyl alcohol 2- / 3-methyl-4- (3-hydroxypiperidino) -phenylj-allyl alcohol

- 26 209841/1157

- 26 by hydrogenation in the presence of Pd-C 2 1 1 4 4 Z U-

2- / 3-chloro-4- (3-hydroxypyrrolidino) phenyl7-1-propanoI

Kp. = 186-192 ° / 0.1 mm

2- / 3-bromo-4- (3-hydroxypyrrolidino) -phenyl7 ~ 1-propanol 2- / 3-methyl-4- (3-hydroxypyrrolidino) -phenylJ-1-propanol 2- / 3-brom-4- (3-hydr oxypip er idino) -phenylj-1-propanol 2- / 3 ^; -Methyl-4- (3-hydr oxypip eridino) -phenylj-1-propanol.

b) 5.4 g of 2- / 3-chloro-4- (3-hydroxy ~ piperidino) phenyl7-1-propanol (F = 75-82 °) are dissolved in 60 ml of dimethylformamide, 1 g NaH, stir for a further 2 hours at 40 °, then slowly add dropwise 6.2 g of methyl iodide, dissolved in 10 ml of dimethylformamide, stir at 50-60 °, after 5 hours add another 3.1 g of methyl iodide in 10 ml. Dimethylformamide is added and the mixture is stirred for a further 13 hours at 50-60. The reaction solution is poured into water, extracted with ether, the ether phase washed with HpO _5, dried over Ha2SO ^, the ether is distilled off and the residue is obtained after chromatographic purification (silica gel / benzene ) 2- / 3-Clilor-4- (3-methoxypiperidino) -phenyl7-1-methoxy-propane, Ep = 143-146 ° / 0.1 mm. .

Analogously, by reacting 2- / 3-chloro-4- {3-hydroxypiperidino) -pheny Ij- 1-propanol with NaH and ethyl, n-propyl, isopropyl, n-butyl, isobutyl or see .-Butyl iodide: ·. - - "

2- / 3-chloro-4- (3-ethoxypiperidino) -phenyl / -1-ethoxy-propane 2- / 3-chloro-4- (3-n-propoxypip eridino) -phenyl / -1-n-propoxy-

propane 2- / 3-chloro-4- (3-isopropoxypiperidIno) -phenyl7 ~ 1 -isopropoxy-

- propane

2- / 3-chloro-4- (3-n-butoxypiperidino) -phenyl7-1-n-butoxy-propane 2- / 3-chloro-4- (3-isobutoxypiperidlno) -phenyl7-1 -isobutoxy-

■ propane

2- / 3-chloro-4- (3-sec. -Butoxypip eridino) -phenyl7-1 -see. " ^: .. - - propane"

- 27 -

209841/1157

- "27 -.

At. Instead of the above-mentioned alkyl iodides, the corresponding Bromides or sulfates are used.

c) 5.4 g of 2- / 3-C3alor-4- (3-hydroxypiperidino) phenyl7-propanol (melting point 75-82 °) are dissolved in 25 ml of pyridine, 25 ml of acetic anhydride are added, and the mixture is left at room temperature for 24 hours stand, pour into H ₂ O, extracted with ether, washed with NaHCO ^ solution and water, dried over NapSO », the solvent is distilled off and the residue is fractionated. 2- £ 3-chloro-4- (3-aceto3 {ypiperidino) -phenyl7-1-propyl acetate, as a mixture of two racemates, b.p. 175-178%), 05 mm is obtained.

Analogously, one obtains from the higher melting racemate des 2- / 3-chloro-4- (3-hydroxypiperidino) -phenyl7-1-propanols (F = 83-85 °) a diacetate with bp = 175-177%), 05 mm and off the lower-melting racemate (F = 70-72 °) is a diacetate with-Kp = 175-180 ° / 0.05 'mm.

Example 2

A solution of 5.3 g of 2- / 3-C3alor-4- (3-hydroxypiperidino ^ -propanal (prepared from 2- £ 3-chloro-4- (3-hydroxypiperidino) phenyl7-propionitrile by hydrogenation in a pyridine HpO-acetic acid mixture in the presence of Raney nickel and sodium hypophosphite) in 20 ml of ether is added dropwise to a suspension of 1.0 g of LiAlil. In 50 ml of ether. The reaction mixture is boiled for 2 hours, 2 ml of ethyl acetate and then 20 ml of an aqueous solution are added iffi ^ Cl solution to, separates off the ether phase, washes it with HpO, dries over Na ₂ SO ^, the solvent is distilled off and receives 2- / 3-chloro-4- (3-hydroxypiperidino) -phenyl / -1- ^ propanol as a mixture of two racemates; F. = 75 - 82 ° (from ethyl acetate / hexane). "-

- 28 20 9 841/115 7

Example 3 ■ ■

a) 6.2 g of 2- / 3-chloro-4- (3-hydroxyp.iperidino) -phenyl-7-propionic acid e-ethyl ester (mixture of two racemates, F. = 160 - 165) are in 300 ml dry tetrahydrofuran with 1.0 g LiAlH ^ cooked .. After cooling down, the excess is decomposed LiAlEL with moist tetrahydrofuran, 6 ml of aqueous drip In NaOH to, filtered:,:, the solvent, distilled off, takes the. Residue in ether, wash with water, dry over NaoSör, the solvent is distilled off and receives: 2 - ^ - Ghlor-4 ~ (3-hydroxypiperidino) ~ phenyl7--1-propane0: 1 as. (Mixture of two racemates), from F. = 75 - 8: 2 °. -

The same. Product can be obtained analogously from other esters, of 2- / 3-chloro-4- (3-hydroxypilperidina) - phenyl7-propionic acid or the free acid itself. © *; *

b) Dissolve 5 ^ 4 g of 2- £ 2-chloro-4- (3-hydrQxypiperidina) -phenyl7-propanol in 25 ml of pyridine. added dropwise while cooling with ice: 5.6 g of hexanoyl chloride, allowed to stand for 18 hours at room temperature, then poured into water, extracted with ether and washed the ether phase with aqueous NaHCO ^ solution and H ₂ O. After drying over la- SO ^ the ether is distilled off, and after chromactographic purification (silica gel /

• Benzene ·) 2T- / 3-chloro ~ 4-C3-hexaniöylQxypiperidino) -phenyl / -1 propyl-hexanoat, Kp = 210-215 ° / 0.05 mm.

Analogously, one obtains by converting with

Acetyl chloride ". · ■

Propionyl chloride

Butyryl chloride

Pentanoyl chloride or

Benzoyl chloride

- 29 9841/1157

• 2- / 3-chloro-4- (3-acetoxypiperidino) -phenyl7-1-propyl ~ acetate,

Kp = 175-178 ° / 0.05 mm, 2- / 3-chloro-4- (3-propionyloxypiperidino) -phenyl / -1-propyl-

propionate, bp = 195-200 ° / 0.1 mm 2- / 3-chloro-4- (3-butyryloxypiperidino) ~ phenyl7-1-propyl-

"butyrate, '

2- / 3-chloro-4- (3-pentanoyloxypiperidino) -phenyl7 ~ 1-propyl-

pentanoate,
2- / 3-chloro-4- (3- "benzoyloxypiperidino) -phenyl7 ~ 1-propyl-

benzoate.

Example 4

a) Analogously to Example 3, the low-melting racemate is obtained of 2- / 3-chloro-4- (3-hydroxypiperidino) phenyl7 ~ propionic acid (F = 140-143 °), or the corresponding esters, by reduction with LiAIHa, the low-melting point of 2- / 3-chloro-4- (3-hydroxypiperidino) -phehyl7-1-propanol, F = 70-72 °.

b) Analogously to Example 3, 2- / 5-chloro-4- (3-hydroxypiperidino) -phenylj-propionic acid is obtained from the high-melting racemate (F = 179-181 °), or the corresponding esters, by reduction with LiAlH ^ the high-melting racemate of 2-, / 3-chloro-4- (3-hydroxypiperidino) -phenyl7-1-propanol, F = 83-85 °,

Example 5

Example 3 is obtained from

3-chloro-4- (3-hydroxypyrrolidino ^ phenylacetic acid, 3-bromo-4- (3-hydroxypyrrolidino) phenylacetic acid, 3-methyl-4- (3-hydroxypyrrolidino! -Phenylacetic acid,

- 30 209841/1157

3-chloro-4- (3-hydroxypiperidino ^ phenylacetic acid, 3-bromo-4- (3 ~ hydroxypiperidino ^ phenylacetic acid, 3-methyl-4- (3-hydroxypiperidino) phenylacetic acid, 2- / 3-chloro-4- (3-hydroxypyrrolidino) -phenyl / -propionic acid, 2- / 3-BrOm-4 - "(3 * -hydroxypyrrolidino.) - pheny! / - propionic acid, 2- / 3-methyl-4- (3-hydroxypyrrolidino) phenyl / propionic acid 2- / 3-bromo-4- (3-hydroxypiperidino) phenyl / propionic acid, 2- / 3-methyl-4- (3-thiydr oxypip eridirio) -phenyl / -propionic acid,

t> betw. the esters of these acids, by reduction with LiAlIL-

2- / 3-ChIo r-4- (3-hydroxypyrrolidino) -phenyl / ~ ethanol, " 2- / 3-bromo-4- (3-hydroxypyrrolidino) -phenylZ-ethanol, 2- / 3-methyl-4- (3-hydroxypyrrolidino) -phenylZ-ethanol, 2 "/ 3-chloro-4- (3-hydroxypiperidino) phenyl / ethanol, F = ^ 98-100

. · -. . Kp = 18Ö-182 ° / 0.1 mm, 2- / 3-bromo-4- _(3-r hydrox3 rpiperidino) -phenylZ-ethanol, 2- / 3-methyl-4- (3-hydroxypiperidino} -phenyl / -ethanol, 2- / 3-chloro-4- {3-hydroxypyrrolidino) -phenyl / -1-propanol,

Kp = 186-192 ° / 0.1 mm- ,.

2- / 3 ~ bromo-4- (3-hydroxypyrrolidine ©) -phenyl / -1-propanol -, - 2- / 3-Me thyl-4- (3-hydroxypyrrolidino) -phenyl / -1-propanol, 2- / 3-Bromo-4- (3-hydroxypiperidino) -phenyl / -1-propanol s 2- / 3-methyl-4- (3-hydroxypiperidino) -phenyl / -1-propanol.

Example 6

4.7 g 1-bromo-2- / 3-chlQr-4 ~ (3-hydroxypiperidino) -phenyl / -propane (made from 4 ~ broin-3-nitr ο acetophenone by reacting with 3-hydroxypiperidino, - Catalytic hydrogenation of the 4- (3-hydroxypiperidino) -3-nitro-acetophenone obtained, diazotization * and Sandmeyer-Re alction to 3-chloro ~ 4- (3-hydroxyp xp eridino) - ac e to phenone / bp 19O-195 ° / 0s.2 mm], reaction with methylmagnesium iodide to form 2- / 3-chloro-4- (3-hydroxypiperidino) -phenyl / -2 ~ propanol (F = 110-112 °), dehydrate by boiling with p —Toluenesulionic acid in toluene, Formation with M-Broiisuccinimid in boiling

- 31 209841/1157

f and subsequent catalytic hydrogenation) are boiled for 4 hours in a mixture of 40 ml of H ₂ O and 30 ml of ethanol with 2 g of KOH. 50 ml of the solvent are then distilled off, diluted with 20 ml of HpO, extracted with ether, the organic phase is washed with water and dried over Na ₂ SO ₁ . , Distilled off the ether and receives 2- £ 3-chloro-4- (3-hydroxypiperidino) phenyl / -propanol- (. 1) as a mixture of two racemates, Kp = 180 ^o / 0P5mn, mp = 75-82 ° .

Example 7 - "

10 g of 2- (4-amino-3-chlorophenyl} -1-propanol (obtainable from 2- (4-amino-3-chlorophenyl) propionic acid (mp 114-115) by reduction with LiAlH ₄ ) are boiled with 28 g 1,4-dibromobutan-2-ol (bp = 70-75 ° / 0.4 mm; obtainable from 1,2,4-trihydroxybutane and HBr) for 7 hours in 70 ml of 50% aqueous ethanol and leaves at the same time Add dropwise 14.4 g of NaOH in 50 ml of HpO .. Then the mixture is boiled in ... in which 2- / 3-chloro-4- (4-bromo-3-hydroxy-1-butylamino) -phenyl7-1-propanol and 2- / 3-chloro-4- (4-bromo-2-hydroxy-1-butylamino) ~ phenylj-i-propanol are formed as an intermediate, another 3 hours, 80 ml of the solvent is distilled off, diluted with 30 ml of HpO, extracted with ether, the organic phase washes with HpO, dried over Na ₂ SO ₄ , the ether is distilled off and obtained 2- £ 3-chloro-4- (3-hydroxypyrrolidino) -phenyl7-1-propanol as a mixture of two racemates, bp = 186 - 192 ° / 0.1 mm.

Example 8.

19 g of 2- / 3-amino-4- (3-hyärox ¥ pIperidino) -pheny 3-7-1-propanol (obtainable from 2- / 5-amino-4- (3-hydroxypiperidino) -phenylj-propionic acid are dissolved by reduction, with LiAlH.) in 75 ml of H ₂ O and 26 ml of concentrated HCl, 5.5 g of NaNO ₂ , dissolved in 25 ml of H ₂ O, are added at 0-5 ° and the resulting mixture is poured in a thin stream to a low-boiling solution of 9 g of Cu ₂ Cl ₂ in 40 ml of concentrated HCl. It is left for a further 30 minutes

- 32 20934 1/1157

90 - 95 °, cool, saturated with H ₂ S, filtered, stirred in until an alkaline reaction, extracted with ether, washed the ether phase with HpO, dried over Na ₂ SO ^, filtered, distilled off the ether and obtained 2- /3-Chlor-4-(3~hydroxypiperidino)-phenyl7.-propanol-(l) as a mixture of two racemates ^ Kp = 18OfVo ^ OS mm | F. = 75-82 °.

Example 9. · ■■ ·

Inalog: Example 3 is obtained from 2- £ 3r-chloro-4- (3-oxopiperidLEn \ a;) - phenylJ-1-propanol (obtainable by reaction wn 2- (3-Mi.tra-4-bromophenylJ - ^ - propaneQl with ^ -piperidon-äthylenketaCL, reduction, of the obtained 2- / 3-nitro-4- (3,3-ethylenedioxy-piperidino) -phenyl / -1-propanol to the amino compound, diazotization with simultaneous ketal hydrolysis and Sandmeyer reaction) 2 - / 3-Chloro-4- (3-hydroxypiperidino) -phenyl7-propanol - ('i) as a mixture of two racemates, bp = 180 ° / 0.05 mm, m.p. = 75-82 °.

Example 10

8.0 g 2- / 5-chloro-4- (3-bromopiperidino) phenyl7-1-propanol (can be prepared from 2- (3-nitro-4-bromophenyl) -1-propanol by reaction with 3j4-pehydropiperidine _i reduction of the 2- ^ 3-nitro-4- (3,4-dehydropiperidino) -phenyl7 ~ 1-propanol, Sandmeyer reaction, bromination of the 2- / 3-chloro-4- ( , 3, 4-dehydropiperidino) - obtained phenyl / -1-propanol with N-bromosuccinimide and subsequent catalytic hydrogenation) are _{boiled for 6 hours in a mixture of 80 ml of H 2} O and 40 ml of ethanol with 4 g of KOH. After cooling, 80 ml of concentrated aqueous NaCl solution are added, the mixture is extracted with ether, the ether phase is washed with HpO, _{dried over Na 2} SO ^ and the solvent is distilled off. 2- / 3-chloro-4- (3-hydr.oxypiperidino) - "phenyl7-propanol- (1) is obtained as a mixture of two racemates, bp = 180 ° / 0.05 mm, m.p. = 75-82 °.

- 33 '■ "■■ 209841/1157

Example 11

4.6g 1-propionyloxy ^ - ^ - chloro ^ - (5-propionyloxy ~ 3,4-dehydropiperidino) -phenyl7-propane (available from 2- / 3-chloro-4- (5-bromo-3,4-dehydropiperidino) -phenyl7-1-propanol by reaction with sodium propionate and propionic acid in the presence of a little propionic anhydride) are in a mixture of 40 ml Dissolved methanol and 20 ml of ethyl acetate and at room temperature in the presence of 1 g of a Pd-C catalyst (5% by weight of Pd) hydrogenated. After the hydrogen uptake has ended, it is filtered, the filtrate evaporated and the residue fractionated. 2- / 5-chloro-4- (3-propionyloxypiperidino) -phenyl7-1-propionyloxypropane is obtained as a mixture of two racemates, b.p. 195-200 / 0.1 mm.

~ 34 -0 9 8 4 1/115 7

Claims (1)

Claims Compounds of Formula I. at what R OH, alkoxy with up to 6 carbon atoms or acyloxy with up to 8 carbon atoms (CH ₂ ) _n —N— / 3 "CHR ³ -CH ₂ R ¹ / atoms,
'-I- - _; I ^ 4 · ■ · "■ - - R ² (H, R ⁵ ) or = 0,
R = *. CH _{2 R} 3 .η - or CH ₅ , R ⁴ .Cl, "Br- or CH ₃ , R OH, alkoxy with up to 6 carbon atoms or acyloxy with up to 8 C- Atoms and
η 2 or 3 mean, as well as their physiologically harmless acid addition salts and their quaternary ammonium compounds. 2. Compounds of the formula Ia "to Iq. 3. 2- / B ~ chloro-4- (3-hydroxypiperidino) -phen3? -L7 ~ i-propanol * 4. '1-Acetoxy-2- / 5-chloro-4- (3-acetoxypiperidino) -phenyl7-propane. 5. Process for the preparation of compounds of the formula I where '■ ..' * R OH, alkoxy with up to 6 C atoms (g _H ) - N ~ - / ~ VcHR ³ -CHoR ¹ or -acyloxy with up to 8 C- '2' ■ ■ I MT - -.'-. _o atoms,
R = 1__ £ η ₂ ^Κ _r 2 _(HR 5 _} bP H or ^ ₈ R ^ Gl, Br or ₃ 841 / 11S7 R OH, alkoxy with up to 6 carbon atoms or acyloxy with up to 8 carbon atoms and η 2 or 3 mean, as well as their physiologically harmless acid addition salts and their quaternary ammonium compounds, characterized in that a compound of the formula II wherein _χ 1 _a Jj _{1 the} grouping of the Formula -CHR ³ -CH ₂ R ¹ (= Z ¹ ) represents a transferable radical, 1
with an agent that converts the group X into a Grouping of the formula z ¹ transferred, or that a compound of the formula III wherein 2
. X one in the grouping of X -CHR -CH ₂ R formula III (? ^H 2> n- ~ f R ² Y __J ff represents transferable remainder, with an agent that converts the group X into a Grouping of the formula ¥ transferred, and / or that, if appropriate, a compound of the formula I obtained is converted into another compound of the formula I, - 36 209841/1157 and / or that optionally a compound obtained of the formula I in-their physiologically acceptable acid addition salts or their quaternary ammonium compounds converted or set free from their acid addition salts and that one optionally obtained racemates or Mixtures of racemates in pure racemates and / or enantiomers separates, - - Process for the production of pharmaceutical preparations, characterized in that at least one compound of the general formula I, optionally together with at least one solid, liquid or semi-liquid auxiliary or carrier and optionally together with at least one other active ingredient in a suitable dosage form brings. Pharmaceutical preparation containing an effective dose a compound of the formula I in addition to at least one solid, liquid or semi-liquid carrier or additive. 8. Pharmaceutical preparation containing 0.1 to 100 mg a compound of the formula I in addition to at least one solid, liquid or semi-liquid carrier or additive .. 9. Procedure for P * tables and / ptfer ani; ipyretis
by gek ^ nnzeicl'in # t,
Connection of the ForkeJ? ¹ ***! expire-h't *. an anti-inflammatory, analgesic effectno ^ fn Living beings, that same dose of one a W, Use of compounds of the formula I for the production of medicaments. " 209841/1157