DK141752B - Aalogy process for preparing piperidines or salts thereof. - Google Patents

Description

(11) FREDERAR TEACHING WRITING H1752 (W)

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DENMARK, B "lntcl · 'c 07" 401/04 f (21) Annotation No. 3114/75 (22) Inscribed on 9 · Jul · 1975 (23) Inadvertent 9 Jul. T9T5 (44) The note appeared and Q.

presentation & writing sacrificed on 9 · JUTi · 1 9oU

DIRECTORATE FOR Λ% __ __,. .

PATENT AND TRADE MARKETS i30) Priority committed to three '

Jul 31 1974, 10583/74, CH

Dec 16 1974, 533107, US

(71) CIBA-GEIGY AG, 4002 Basel, CH.

(72) Inventor: Kurt Eicheriberger, 36 Neubergweg, 4106 Therwil, CH: Christian Egli, Egg, 4465Tiagden, CH; Hans Kuehnis, Lange Gasse 26, 4052 Basel, "CH: Oswald Schier, Amselstr. 15, 404 Oberwil, CH: Lincoln Harvey Werner, 94 Lamed Hoad, Summit, N.J., US.

(74) Plenipotentiary under eager 'processing;

Dansk Patent Kontor ApS. (54) Analogous process for the preparation of piperidines or their salts.

The invention relates to an analogous process for the preparation of novel piperidines of the general formula I or salts thereof as claimed in the preamble of the claim. When n = 1, the compounds of formula v2 are E6 E5 E4 E5 f / s / 1 y- \> 3 C a

E -O-CH 2 -CH-CH 2 -N NCH-N

* * N_ / \ I - E "(Ia)

II

o and when n = 0, these are compounds of formula 14 R 2 R 5 R 5

R1-0-GHoGH-CHo-N / XGH-R / N / V

2 2 N._X \ Il - R '"\ Xy (II)

II

ISLAND

in which formulas R 1, R 2, R 2, R 1, R 2, R 2 and R 4 have the meanings specified in the claim.

An optionally substituted phenyl, indenyl or naphthyl group R · is e.g. a phenyl, indenyl or naphthyl group substituted by one or two substituents, such as an optionally substituted 2,3-dihydro-5- or -6-indenyl group, further e.g. an optionally substituted 516 5 7,8-tetrahydro-1- or -2-naphthyl group. Preferred is a once or twice-substituted phenyl group or naphthyl group and especially a once-substituted phenyl group.

However, particularly preferred substituents in the group R 1 are halogen atoms (which in the phenyl group are preferably in the o or p position) and hydroxyl groups (which in the phenyl group are preferably in the p position) and, in particular, C -C ^ alkyl groups and C --C C alkanoylamino groups (which in the phenyl group are preferably in the β position), and C C-C-alkyl groups, C,-C-alkenyl groups, C,-C ^ alkoxy groups , C - ^-G G-alkenyloxy groups (which in the phenyl group are preferably in the o-position).

2 R is as a G 1 -G 2 alkanoyloxy group e.g. an acetoxy, propionyloxy or butyryloxy group or preferably a pivaloyl oxy group.

C --C C alkyl groups are e.g. methyl, ethyl, n-propyl or isopropyl groups or straight or branched butyl groups which may be bonded at any position.

C ^-C ^ alkenyl groups are especially allyl or methallyl groups.

As a cycloalkyl group having 5 to 7 ring joints, above all, a cyclopentyl and also a cyclohexyl group are considered.

A halogen atom is, for example, a chlorine or bromine atom, but can also mean a fluorine or god atom.

Above all, hydroxy-C ^-C ^ alkyl groups are those in which the C

C C-CC alkoxycarbonylamino-G - ^-G ^ alkyl groups are understood e.g. such groups whose alkyl moieties are derived from the said C 1 -C 4 alkyl groups. Such groups are e.g. methoxycarbonylamino methyl, ethoxycarbonylaminomethyl, 4-methoxycarbonylamino-n-butyl, 2-ethoxycarbonylaminoethyl, 3-ethoxycarbonylamino-n-propyl and especially 2-methoxycarbonylaminoethyl and J-methoxycarbonylamino-n-propyl.

C1-G2) - Alkoxy groups are especially such, groups derived from the said C1 -C4 alkyl groups. Examples of such low alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

C ^-G ^ -Alkenyloxy groups are e.g. allyloxy or methallyl oxy groups.

As C 1 -C 4 alkanoyl groups are to be mentioned above all pivaloyl, propionyl or butyryl groups, but above all an acetyl group; alkanoylamino groups are e.g. those in which the alkanoyl moiety has the above meaning.

The compounds of the present invention have valuable pharmacological properties. Thus, they show a blood pressure lowering effect that can be detected by animal testing, e.g. by i.v. administration in doses of approx. 0.01 to 1 mg / kg for narcotic cats as indicated in the following test report.

A. Compounds tested: In 2- [1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride, - {1- [3- (o-allyloxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone, III 2- {1- [3- (o-cyanophenoxy) -2 -hydroxy-1-propyl] -piperidyl- (4) j - 3,4-dihydro-1 (2H) -isoquinolinone, IV 1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4- (1-oxoisoindolino) -piperidine hydrochloride, V 1- [3- (o-cyanophenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, VI 1- {1- [3- (o-me tho xyphenoxy) -2-hydroxy-1-propyl] -piperidyl- (4)} -imidazolidinone- (2), VII-1- [3- (p-acetamido-phenoxy) -2-hydroxy-1-propyl] -piperidyl- (4)} - imidazolidinone- (2), VIII 1- [3- (p- (2-methoxyethyl) phenoxy) -2-hydroxypropyl] -4- (2-oxo-hexahydro-1-pyrimidinyl) -piperidine, IX 1-1 [3- (m-methoxyphenoxy) -2-hydroxy-1-propyl] -piperidyl- (4) -imidazolidinone.

Compounds I-V are prepared according to the process of the invention, while Compounds VI-IX are described in Danish Patent Application No. 4650 / 73- B.

The blood pressure lowering effect was determined on adult male and female cats (weight 2.2-4.0 kg) who had been anesthetized with 'VAllo-barbital' (Dial®) by administration of an intraperitoneal dose. Blood pressure before and after intravenous administration of the test substance was recorded on a printer associated with the pressure gauge and the blood pressure change was expressed as a percentage and lasted for at least 20 minutes.

C. Results

Test Dose in mg / kg i.v. Percentage of blood pressure (may last for at least 20 minutes) I 0.01 -15 II 0.1 -18 III 0.01 -20 IV 0.03 - 7 V 0.01 - 6 141752 5

Table continued: VI 1 - 8 VII 3 - 7 VIII 10 - 2 IX 3 -11 D. Conclusion

The results above show that the compounds I-V prepared according to the invention according to the invention are already at a dose of 0.01-0.1 mg / kg i.v. causes a significant decrease in blood pressure, whereas the known compounds VI-IX first produce a substantial or even only low blood pressure lowering.

Furthermore, the compounds of the invention cause a tachycardia inhibition, which can also be shown in animal experiments, e.g. by in vitro experiments at concentrations of 0.3 to 3 µg / ml in isolated guinea pig hearts according to Langendorff (cessation of tachycardia induced by isoproterenol (3 x 10- ^ // ml) or histamine (3 x 10 ml)). Furthermore, the compounds of this invention cause a vasodilatation which can be detected in animals, e.g. narcotic dogs, by measuring hemodynamics by intraduodenal administration at a dose of approx.

10 mg / kg.

Furthermore, the compounds of this invention have a noradrenolytic effect that can be detected in vitro, e.g. in experiments with isolated perfused mesenteric arteries from rats at concentrations of 0.001 to 0.01 // ml.

Furthermore, the compounds of the present invention show an antiarrhythmic and positive tinotropic effect.

Accordingly, the compounds of the present invention may find use particularly as antihypertensive agents and as vasodilative agents. Furthermore, the compounds of the invention may serve as starting or intermediate products for the preparation of other, in particular, therapeutically effective compounds.

Particular mention should be made of the compounds of formula Ia.

6 14ί752

Of the compounds of formula Ia, in particular, mention is made of 2- [1- (3- (o-allyloxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone, 2-11- [3 - (o-chlorophenoxy) -2-hydroxypropyl] -4-piperidyl-1,4-dihydro-1 (2H) -isoquinolinone, 2- | 1- [3- (o-Methoxyphenoxy) -2-pivaloyloxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone, 2- | 1- [3- (o-tolyloxy) -2-hydroxyprine opyl] -4-piperidinyl-3,4-dihydro-1- (2H) -isoquinolinone, and in particular 2- [1- (3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4 -dihydro-1- (2H) -isoquinolinone, 1- [3- (o-methoxyplienoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine and 1- [3- (o-cyanophenoxy) -2 -hydroxypropyl] -4- (1-oxo-iso-indolino) -piperidine and their therapeutically useful acid addition salts, which compounds, e.g. in anesthetized cats, a clear antihypertensive effect is induced by intravenous administration of a dose of 0.01 mg / kg.

the process according to the invention is characterized by the characterizing part of the claim.

According to variant a), e.g. thus proceed to translate a compound of the formula

X

R1 - 0 - CH2 - OH - CH2 - Z (IIa) having a compound of formula R1 R2 R3 4 -. H + - C-j.

'CH - ϊΚ (Illa) N- / I - R' '

II

o 3 4 5 6 wherein n, R, R, R, R and R "1 have the above meanings and together form an epoxy group.

2

is a reactively esterified hydroxyl group, or X and Z

3 2 4

either X is the group R, where R has the given meanings, and Z

141752 7

In particular, a reactive esterified hydroxyl group is a hydroxyl group which is esterified with a strong, inorganic or organic acid, especially a hydrogen halide such as hydrogen chloride, bromide or iodide, in addition sulfuric acid or an organic sulfonic acid, e.g. . benzenesulfonic acid, p-bromobenzene sulfonic acid or p-toluenesulfonic acid. Thus, Z stands especially for chlorine, bromine or iodine.

This turnover is carried out in the usual manner. Using a reactive ester as starting material is preferably worked in the presence of a basic condensing agent and / or with an excess of the compound of formula IIla.

Furthermore, the subject compounds can be obtained by the process variant b).

According to variant b), the reduction can be carried out in the usual manner, preferably by catalytic hydrogenation, such as with hydrogen in the presence of a hydrogenation catalyst, e.g. heavy metals such as palladium, platinum or Raney nickel, or with nascent hydrogen such as sodium and alcohol such as a low alkanol, e.g. ethanol.

During the reduction, care must be taken that other reducible groups are not attacked.

Furthermore, the compounds of the present invention can be obtained by the process variant c)

According to variant c), a reactive esterified hydroxyl group is in particular one of the above.

The cyclization (the intramolecular condensation) may take place in the usual manner, preferably in the presence of a solvent such as an inert polar solvent such as an alcohol, e.g. ethanol or isopropanol, or dimethylformamide, and advantageously in the presence of a condensing agent, especially a basic condensing agent. Preferably, one is employed in the presence of an alkali or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate or potassium hydrogen carbonate, or an alkali metal acetate such as sodium acetate, Q U1752

ISLAND

or an alkali metal alcoholate such as sodium methylate or organic tertiary nitrogen bases such as trialkylamines, e.g. trimethylamine or triethylamine, or pyridine.

7. 5

The present compounds in which R and R together are another bond when n = 1 can also be obtained by the process variant d).

According to variant d), the reaction can take place in a manner known per se.

Advantageously, it is employed in the presence of an organic base such as a tertiary amine, above all pyridine, whereby this base can also serve as a solvent. However, one can also work in the presence of other solvents.

Furthermore, the compounds of the present invention can be obtained by the process according to the variant e).

According to variant e), an oxo group-containing functionally converted carb-oxyl group is e.g. an esterified carboxyl group such as, in particular, a lower alkanol or aralkanol such as methanol, phenol, p-nitrophenol or benzyl alcohol esterified carboxyl group or an activated esterified carboxyl group such as a cyano-methanol esterified carboxyl group, or an acid halide, such as especially chloride grouping, or an acid azide, acid amide or anhydride grouping. Especially considered as anhydride grouping are those of mixed anhydrides, especially of mixed anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl or isobutyl esters.

The turnover can be done in the usual way. Preferably one works at elevated temperature. Advantageously, the reaction is carried out in a solvent such as an inert solvent, e.g. a hydrocarbon such as benzene or toluene, or in high boiling inert solvent such as diphenyl ether.

Said reactions may be carried out in the usual manner in the presence or absence of solvents or diluents, acidic or basic condensing agents and / or catalysts at lowered, ordinary or elevated temperature, optionally in a closed container under elevated pressure and / or under an elevated pressure. atmosphere of an inert gas.

Depending on the process conditions and the starting materials, the final products are obtained in free form or in the form of their acid addition salts, also included in the invention. Thus, e.g. available basic, neutral or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof. The acid addition salts of the compounds of the invention can be transferred in a manner known per se to the free compounds, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the obtained free bases can form salts with organic or inorganic acids. In particular, for the preparation of acid addition salts, such acids are used which are suitable for forming therapeutically useful salts. As such acids, e.g. are mentioned: Hydrogen halides, 'e.g. hydrogen chloride, sulfuric acids, f.eJcs. sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocydic carboxylic or sulfonic acids such as formic, acetic, propionic, amber, glycol, lactic, apple, wine, lemon, ascorbic, maleic, hydroxymaleic or pyruvic, fumaric, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfone, ethanesulfone, hydroxyethanesulfone, ethylenesulfonic acid; halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulphanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the subject compounds, such as picraterrie, can also serve to purify the obtained free bases by transferring the free bases to salts, separating them from and releasing the salts again. Due to the close connection between the compounds in question in free form and in the form of their salts, the previous and subsequent free compounds may also have to be understood as corresponding salts.

The compounds of the invention may, depending on the choice of starting materials and working methods, be available as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, also as racemate mixtures and / or as pure geometric isomers or as mixtures thereof (isomer mixtures).

t4tm 10

The obtained isomer mixtures can be divided into the two pure geometrical isomers, e.g. by chromatography on a suitable stationary phase, such as with a complex heavy metal compound, e.g. with a silver compound, pretreated silica gel or alumina, or by forming a heavy metal addition compound, e.g. the silver nitrate complex, separation thereof in the addition junctions of the pure isomers, e.g. by fractional crystallization and subsequent release of the pure isomers.

Obtained pure isomers, e.g. trans isomers, can be converted to the opposite configured isomers, e.g. to the cis isomers, in the usual manner, e.g. photochemical, e.g. by irradiation with light of suitable wavelength, advantageously in a suitable solvent such as an aliphatic ear hydride, or in the presence of a suitable catalyst.

Racemate mixtures can be divided into the two stereoisomeric (diastereomeric) pure racemates on the basis of the physico-chemical differences between the constituents in a known manner. by chromatography and / or fractional crystallization.

Obtained racemates can according to known methods, e.g. by recrystallization from an optically active solvent, by microorganisms or by reaction with an optically active acid which forms salts with the racemic compound, and separation of the salts thus obtained, e.g. on the basis of their various solubilities, are cleaved into the diastereomers from which the antipodes can be released by the action of suitable agents. Particularly useful optically active acids are e.g. The D and 1 forms of tartaric acid, di-o-toluene tartaric acid, malic acid, almond acid, camphor sulfonic acid or quinic acid. It is advantageous to isolate the most effective L-antipode.

Conveniently, in order to carry out the reactions of the invention, such starting materials are used which lead to the previously mentioned groups of end products and in particular to the specially described or highlighted end products.

The starting materials are known or, if they are novel, can be obtained by methods known per se.

141752 11

The compounds of formula c R5 R4, R6 used as preferred starting materials. In I / R 5 C - (cf.

• "CZz ™ \ Tj ~ e" "cma)« o one can, e.g. few know that translating a compound of formula

R11 - r '* ^ CH - KEL

Wherein R11 is an α-aralkyl group, such as a benzyl group, having a compound of formula R6 β5 \ I 3 χ · - in R5 £ £ 0- 3456 wherein n, R, R, R, R and R "'has the meanings given and X' and have the meanings given by Formula VI and IX respectively, and in the obtained compound of Formula 6 R5 R4 3 R6. II / R3> - (C) n

R11 _ SCH - N VS

Substitutes the α-aralkyl group R R with hydrogen, e.g. by catalytic hydration as described above.

The compounds of this invention can be used as drugs, e.g. in the form of pharmaceutical preparations.

12 utm

The following Examples further illustrate the process of the invention

Example 1.

A mixture of 30.2 g of 1- (o-methoxyphenoxy) -2,3-epoxypropane and 3 $, 7 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in 50 ml of absolute Ethanol is refluxed for 6 hours and then vacuumed. The residue is acidified with ethanolic hydrochloric acid; after addition of ether, 2- [1- (o-methoxyphenoxy) -2-hydroxy-propyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride is precipitated after recrystallization from ether. ethanol / ether melts at 174-176 ° C.

The 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone used as starting material is prepared as follows:

To a mixture of 53 g of potassium hydroxide and 30 g of 4-amino-1-benzyl-piperidine in 600 ml of acetone, drop at room temperature a solution of 40 g of 2- (2-chloroethyl) benzoyl chloride in 100 ml of acetone. After the addition is complete, the reaction mixture is heated to reflux for four hours and then evaporated to dryness. The residue is taken up in water and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated. The oily residue is taken up in a little ethanol and acidified with ethanolic hydrochloric acid. The hydrochloride of 2- (1-benzyl-4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone is obtained crystalline and melts at 276-27 ° C (dec.).

13.6 g of 2- (1-benzyl-4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride are hydrogenated together with 1.5 g of 10 $ palladium carbon at room temperature and atmospheric pressure. The reaction mixture is filtered from the catalyst and the residue is washed well with water. The filtrate is evaporated to dryness, the residue is dissolved in as little ethanol as possible and the hydrochloride of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone is precipitated with ether. It melts after recrystallization of ethanol at 31 # -320 ° C (dec.).

The base is released with 10 N sodium hydroxide solution and extracted with methylene chloride. Drying and evaporation of the solvent gives the base as a crystalline substance with m.p. 220-222 ° C.

141752 13

Example 2.

A solution of 9.9 g (0.06 mole) of 1- (o-tolyloxy) -2,3-epoxypropane, 15.9 g (0.06 mole) of 2- (4-piperidyl) -3,4-dihydro -1 (2H) -isoquinolinone hydrochloride and 24 ml of triethylamine in 240 ml of isopropanol are heated at reflux for 6 hours and then evaporated in vacuo. The residue is crystallized by ethanol / water. After recrystallization from ethanol / water, 2-yl- [3- (o-tolyloxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone melts at 104-105 ° C.

The maleic acid salt of this compound melts after recrystallization of ethanol / ether at 165-166 ° C (dec.).

Example 3

A solution of 8.1 g of 2-jl- [3- (o-methoxyphenoxy) -2-hydroxy-1-propylpiperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone hydrochloride and 5 g of pivaloyl chloride in 50 ml of pyridine are heated for 1 1/2 hours to 100 ° C and then evaporated in vacuo. The residue is acidified with alcoholic hydrochloric acid and evaporated again. After recrystallization from isopropanol, 2-jl- [3- (o-methoxyphenoxy) -2-pivaloyloxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone hydrochloride is obtained. mp. 232-234 ° C.

Example 4

A mixture of 5.5 g of 1- (o-chlorophenoxy) -2,3-epoxypropane and 7 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in 100 ml of isopropanol is boiled for 5 minutes. hours at reflux and then evaporated in vacuo. The oily residue is dissolved in absolute ethanol and an equivalent amount of maleic acid is added. After addition of ether, 2- [1- (3- (o-chlorophenoxy) -2-hydroxy-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone maleate) precipitated after recrystallization of ethanol / ether melts at 139-140 ° C.

ψ

Example 5

A solution of 6.2 g of 1- [p- (2-methoxyethyl) phenoxy] -2,3-epoxy-propane and 7.0 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in isopropanol (SO) is heated for 5 hours to reflux. The reaction mixture is evaporated to dryness, whereby 2- [1- [3- (2-methoxyethyl) phenoxy] -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) - isoquinolinone precipitates. After recrystallization from an ethanol / ether mixture, the product melts at 116-117 ° G. The maleic acid salt crystallizes from a mixture of ethanol / ether and melts at 13S-139 ° C.

Example 6

6.1 g of 1- (o-allyloxyphenoxy) -2,3-epoxypropane and 7.0 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinoline are dissolved in 100 ml of isopropanol. The solution is heated to reflux for 5 hours and then evaporated in vacuo. The oily residue is transferred with 3.1 g of fumaric acid to the crystalline 2- [1- (3- (o-allyloxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone fumarate . After recrystallization from ethanol / ether, the salt melts at 145-146 ° C with decomposition.

Example 7

A mixture of 3.6 g of 1- (o-methoxyphenoxy) -2,3-epoxypropane and 4.32 g of 4- (1-oxo-isoindolino) -piperidine in 35 ml of isopropanol is heated for 4 hours with stirring to reflux. After cooling to room temperature, acid is acidified with ethyl acetate saturated with hydrochloric acid gas to obtain a pH of 1 and then cooled using an ice bath. After filtration, the residue is washed with an ice-cooled isopropanol / diethyl ether mixture and recrystallized from 100 ml of isopropanol. There is obtained 1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4- (1- ° x ° -isoindolino) -piperidine hydrochloride, melting at 172-174 ° C.

The starting material is prepared as follows:

A mixture of 150.0 g of 2-formyl-benzoic acid and S5.2 g of 4-aminopyridine in 2, δ liters of toluene is heated using a water separator for 2.5 hours with still stirring under reflux. Stirring is continued for approx. 16 hours at room temperature. After filtration, the residue is washed with toluene to give 1- (4-pynidylamino) -3-oxo-phthalane, m.p. 215-220 ° G.

141752 15

To a slurry of 27 # g of the product obtained above in 4> 7 liters of absolute ethanol, 96.0 g of sodium borohydride are added in portions for a period of 105 minutes with stirring at a temperature of 1 ° C. Stirring is continued at room temperature for approx. 16 hours and then the mixture is filtered. The filtrate is evaporated to a volume of 1.2 liters, cooled, and the precipitate formed is collected. 2- (4-pyridylamino-methyl) -benzoic acid is obtained which melts above 250 ° C.

ISO, 6 g of 2- (4-pynidylaminomethyl) benzoic acid are added to 1.4 liters of concentrated sulfuric acid over 40 minutes with stirring. Thus, the temperature must rise to approx. 67 ° C. The reaction mixture is stirred for one hour at a temperature of approx. 95 ° C, cool to 25 ° C and slowly pour on 4.0 kg of ice. The reaction mixture is neutralized approximately.

4.5 liters of aqueous ammonia solution, the precipitate formed is filtered off and taken up in a mixture of 2.3 liters of isopropanol and 600 ml of chloroform. The mixture is heated to reflux for 30 minutes, filtered warm, the filtrate is cooled and the precipitate formed is collected.

4- (1-oxo-isoindolino) -pyridine is obtained.

30 g of the obtained 4- (1-oxo-isoindolino) pyridine is hydrogenated in 400 ml of glacial acetic acid in the presence of 30 g of 10 $ palladium-on-charcoal catalyst at a temperature of 65 ° C and a pressure of 3 atm. , until absorption of the theoretical amount of hydrogen. After cooling to room temperature, filter and evaporate in vacuo. The residue is taken up in 6N sodium hydroxide solution, the reaction mixture is extracted with chloroform and the extract is washed with a saturated aqueous sodium chloride solution, dried and then evaporated in vacuo. 4- (1-oxo-iso-indolino) -piperidine with a m.p. at 144-146 ° C.

Example 8.

By analogy as described in Example 7, using equivalent amounts of starting material, the following compounds are obtained: a) 1- [3- (2-Chloro-5-methylphenoxy) -2-hydroxypropyl] -4- (1-oxo-iso- indolino) -piperidine hydrochloride, m.p. 206-20 # ° C, b) 1- [3- (o-Allylphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 205-207 ° C, c) 1- [3- (2-Allyl-3-acetylaminophenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 177-180 ° C, d) 1- [3- (2-cyclohexylphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 214-216 ° C, e) 1-C3- (p-carbamoylmethylphenoxy) -2-hydroxypropyl] -4- (1-o-isoindolino) -piperidine hydrochloride, m.p. 266-270 ° G, f) 1- [3- (2-methoxy-3-methoxyphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 161-163 ° C, g) 1- [3- (o-allyloxyphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 1 & 5-136 ° C, h) 1-D- (o-propargyloxyphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 173-175 ° C, i) 1- [3- (p-Bromophenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 253-257 ° C, 1- [3- (o-cyanophenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 203-205 ° C, and k) 1- [3- (5-indanyloxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. 270-272 ° C.

Example 9

To a solution of 3.96 g of 1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4- (1-oxo-isoindolino) -piperidine (prepared from the hydrochloride of Example 7 by reaction with 2N sodium hydroxide solution, extraction with a mixture of ethyl acetate and evaporation of the extract in vacuo) and 2 ml of pyridine in 50 ml of methylene chloride are added dropwise 1.32 g of pivaloyl chloride in 10 ml of methylene chloride under stirring and ice-cooling over 20 minutes. Stirring is continued for 4 hours at room temperature, for an additional 46 hours at reflux temperature, and again for 4 hours at room temperature. The reaction mixture is washed with a 10% fs cold aqueous sodium carbonate solution and water, dried, filtered and evaporated in vacuo. The residue obtained is dissolved in 20 ml of ethanol, the solution is acidified with ethyl acetate saturated with hydrochloric acid gas and the precipitate formed is collected. The precipitate obtained is dissolved in 50 ml of hot ethanol, to which is added 50 ml of ethyl acetate. After cooling the solution with ice, the precipitated precipitate is collected. There is obtained 1- [3- (o-methoxyphenoxy) -2-pivaloyloxypropyl] -4- (1-oxo-isoindolino) -piperidine hydrochloride, m.p. at 206-212 ° C.

141752 17

Example 10.

A mixture of 28 g of 1- (β-naphthoxy) -2,3-epoxypropane and 18.8 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in 40 ml of isopropanol is heated for 4 hours. hours at reflux for boiling. Upon completion of the reaction, the precipitated crystals are filtered off and washed with ether.

There is thus obtained 2-jl- [3- (β-naphthoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone which, after recrystallization from chlorophora, M ethanol melts at 180-183 ° C.

Dissolve 24 g of the above base in 250 ml of warm chloroform and add 30 ml of 2N ethanolic hydrochloric acid. Thereby, the hydrochloride of 2-jl- [3- (β-naphthoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone is precipitated at 269-271 ° C.

Example 11.

A mixture of 26.9 g of 1- (2-methoxy-4-chlorophenoxy) -2,3-epoxypropane and 25.8 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in 30 ml of isopropanol are refluxed for 4 hours. After completion of the reaction, rub with ether, whereupon 2-jl- [3- (2-methoxy-4-chlorophenoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H ) -isoquinolinone precipitates, which after recrystallization from isopropanol melts at 108-110 ° C.

Dissolve 22.8 g of the above base in 60 ml of hot isopropanol and add 10 ml of 8.7 N ethanolic hydrochloric acid. After rubbing with ether, the hydrochloride is precipitated by 2-jl- [3- (2-methoxy-4-chlorophenoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone melting at 210-212 ° C.

Example 12.

A mixture of 11.55 g of 1- (o-cyanophenoxy) -2,3-epoxypropane and 14.95 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone in 30 ml of isopropanol is boiled. for 6 hours at reflux. After completion of the reaction, the reaction solution is diluted with 150 ml of isopropanol, heated to boiling and filtered hot. Upon cooling and rubbing with ether, 2- [C3- (° -cyanophenoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone is precipitated, melting at 138-140 ° C.

Dissolve 16.5 g of the above base in 100 ml of hot ethanol and add 5 g of maleic acid. On cooling the solution, the maleate is precipitated by 2-jl- [3- (o-cyanophenoxy) -2-hydroxy-1-propyl] -piperidyl- (4) j-3,4-dihydro-1 (2H) -isoquinolinone which melting at 183-184 ° C.

Example 13

A mixture of 18 g of 1- (o-methoxyphenoxy) -2,3-epoxypropane, 27 g of 4-phthalimidopiperidine hydrochloride, 60 ml of triethylamine and 300 ml of isopropanol is heated at reflux for 4 hours. The reaction mixture is evaporated to dryness and the residue is digested with 2N sodium hydroxide solution. The aqueous suspension is extracted with methylene chloride, the organic phase is dried over sodium sulfate and freed from solvent in vacuo. To the residue is added 11.6 g of maleic acid. The maleic acid salt of 1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-phthalimido-piperidine is crystallized by ethanol / ether and melts at 201-202 ° C with decomposition.

Example 14.

Dissolve 10.8 g of o-cresol in 250 ml of dimethylformamide and drop the solution with stirring in a solution of 5.0 g of sodium hydride in 250 ml of dimethylformamide. Then heat for 30 minutes to 50 ° C. 28.6 g of 2- [1- (2,3-epoxypropyl) -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone are then added in 300 ml of dimethylformamide and heated to 50 ° C for an additional three hours. . It is decomposed under cooling with plenty of ice and water and shaken with ether. The ethereal solution is extracted twice with 2 F sodium hydroxide solution and dried, and then the ether is evaporated. Evaporation gives 2- [1- (3- (o-tolyloxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone as a crystalline product which melts at 104-105 ° C. The resulting maleic acid salt melts at 165-166 ° C.

Example 15

a) 4.6 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone are added to 1.85 g of epichlorohydrin in 35 ml of benzene and stirred for 15 hours at room temperature. Then, the solvent is evaporated at 40 ° C under vacuum and the residue is extracted several times with benzene to crystallize. The crystallize is stirred with acetonitrile and filtered off with suction. The 2- [1- (2,3-epoxypropane) -4-piperidyl] -3,4-dihydro-1 (2H) -isoquonolinone hydrochloride obtained melts at 173 to 174 ° C.

b) Heat 1.08 g of o-cresol together with 2.9 g of the 2- [1- (2,3-epoxypropane) -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone obtained above and 2.8 g of potassium carbonate in 20 ml of acetonitrile for 15 hours at reflux. Then, potassium carbonate is filtered off and the filtrate is evaporated under vacuum. The residue is recrystallized from ethanol-water. After recrystallization from ethanol-water, 2- {1- [3- (o-tolyloxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone melts at 104-105 ° C.

The maleic acid salt of this compound melts after recrystallization from ethanol-ether at 165-166 ° C (dec.).

Example 16.

5.2 g of 1- (o-methoxyphenoxy) -2-hydroxy-3-bromo-propane are heated together with 4.6 g of 2- (4-piperidyl) -3,4-dihydro-1 (2H) -isoquinolinone and 2 6 g of E-ethylisopropylamine in 80 ml of dimethylformamide for 12 hours at 80 ° C. Then the dimethylformamide and amine are distilled off under vacuum. The residue is dissolved in water and the solution is made alkaline with aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried and evaporated and the hydrochloride is prepared by ethanolic hydrochloric acid. Pra ethanol ether crystallizes 2- {1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl] -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride, m.p. 174-176 ° C.

Example 17

a) 10 g of 1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4- (3,4-dihydro-1 (2H) -isoquinolinon-2-yl) -pyridinium bromide is hydrogenated with platinum oxide at room temperature 100 ml of ethanol in the presence of concentrated hydrochloric acid. The reaction mixture obtained is made alkaline with 2N aqueous sodium hydroxide solution, extracted with chloroform, dried and evaporated. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in water. The hydrochloride is prepared by ethanolic hydrochloric acid. 2- {1- [3- (o-Methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl | -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride is recrystallized from ethanol-ether and has a melting point of 174-176 ° C.

B) The above-mentioned quaternary salt is prepared from 1- (o-methoxy-phenoxy) -2-hydroxy-3-bromo-propane and 2- (4-pyridyl) -3,4-dihydro-1 (2H) - isoquinolinone in dimethyl formamide with the addition of IT-ethyl diisopropylamine at 80 ° C and we are treated in the crude state as indicated under a).

Example 18.

To 4.1 g of 1- (3-o-methoxyphenoxy) -2-hydroxy (propyl) -4-amino-piperidine and 3 g of potassium hydroxide in 50 ml of acetone, drop a solution of 2.6 g of 2- (2). (chloroethyl) -benzoyl chloride in 50 ml of acetone and the reaction mixture obtained is heated at reflux for 9 hours. The precipitated material is filtered off and the filtrate is evaporated to dryness. To the oil thus obtained is added 2 IT hydrochloric acid and extracted with methylene chloride. The combined extracts are dried and evaporated. The residue is recrystallized from methylene chloride-ethyl acetate to give 2- {1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl} -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride, m.p. . 174-176 ° C,

Example 19.

1.5 g of isocoumarin and 2.8 g of 1 - [(3-o-methoxyphenoxy-2-hydroxy) propyl] -4-amino-piperidine are heated in 30 ml of ethanol for 3 hours at reflux. To the reaction mixture is added 0.5 g of palladium / coal and hydrogenated until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness. To the residue is added ethanolic hydrochloric acid and the 2- {1- [3- (o-methoxyphenoxy-2-hydroxy) propyl] -4-piperidyl} -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride is recrystallized by grating with ether. After recrystallization from ethanol-ether, the product melts at 173-175 ° C.

Example 20

a) 9.1 glT-1- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl} -2-aminoethyl-benzoic acid ethyl ester is heated in 100 ml of ethanol with 2.6 g of K-ethyl diisopropylamine for 6 hours under reflux. Then the amine and alcohol are removed in vacuo and the residual oil is transferred with ethanolic hydrochloric acid to the hydrochloride.

Pra ethanol ether is recrystallized from 2-fl- [3- (o-methoxyphenoxy) -2-hydroxypropyl] -4-piperidyl} -3,4-dihydro-1 (2H) -isoquinolinone hydrochloride, m.p. 174-176 ° C.

Claims (1)

B) The above ester is obtained by reductive amination of 1- [3- (o-meth-oxyphenoxy) -2-hydroxypropyl] -4-piperidone with 2-aminoethyl-benzoic acid ethyl ester mite platinum / carbon catalysis in methanol and is reused in the unclean state under a). Claims. Analogous process for the preparation of piperidines of general formula H? , B5 R * E3 R2 -X A, I ._. R '-O-CH2-CH-CH2-ir XN | - R "1 (i) s-O wherein R4" means a phenyl, indenyl or naphthyl group optionally substituted once or twice by C ^-C ^ alkyl, C ^-C ^ alkoxy, C1-C ^ alkenyl, C ^-C ^ alkenyloxy, hydroxy-C ^-C ^ alkyl, hydroxy, halogen, cyano, C C--C ^ alkanoylamino, 2- (C --C ^ alkoxy) ethyl, C ^-C ^ alkanoyl, carbamoyl, cycloalkyl of 5-7 ring link, carbamoyl-C--C ^ alkyl or C C 1 -C 4 -alkoxycarbonylamino-C 1 -C 4 -alkyl, R 1 is hydroxy or C 1 -C 2 -alkanoyloxy, R 1 represents hydrogen, C 1 -C 3 -alkyl or C 1 -C 2 - alkoxy, halogen, trifluoromethyl, hydroxy, C ^-C ^ alkanoyl amino, nitro or amino, n is 0 or 1, and R ^ is hydrogen, C ^-C R-and R ^ together represent an additional bond and R ^ and R ^ each hydrogen, or R ^ together with R ^ is an oxo group, R ^C ^-C ^ alkyl or hydrogen and R R hydrogen, or R together with R 1 is an oxo group, R 2 hydrogen, C 1 -C 2 alkyl or hydroxy and R 2 hydrogen, or salts thereof, characterized in that a) reacting a compound of formula R1-0-Y "*" (II) with a compound of formula n6 T? 5 rj4 * n 3 y— J2- ^ y XN Ti - R "'(III) ^ Χ / R1 II o 141752 22 where R1, n, R, M, R3, R4, R ^ and R6 have the given meanings, one of the groups y! and Y 2 is hydrogen and the other is a group of the formula -ch 2 -ch-ch 2 -z X 2 2 wherein X is the group R forming an epoxy group, or b) in a compound of formula R6 R5 r! .R3 -> o <. ii © / 'VN R-O-CH 2 -CH-CH 2 -r XE | --R, M (V) ^ - "\ A® 0 wherein R ^, R2, R3, R4, R ^, R ^, R , M and n have the above meanings, and A® is an anion, reducing the pyridinium ring to a piperidine ring or c) intramolecularly condensing a compound of formula R6 R5 R4 ^ e2 - (CQ-H3 -II -CH 2 -r 2 | --E "1 (VI) o wherein r 1, R 2, R 1, n, R 3, R 4, R 2 and R 2 have the meanings indicated and X 1 is a reactively esterified hydroxyl group, or d) for compounds of formula I, wherein R 3 and R 2 together are another bond when n = 1, a compound of formula R2 reactes R1-Q-CR2-CH-CH compound of the formula R4 R4, C. Show, I I - R "· (VIII)