DE2145154A1 - Indanyl, naphthyl and benzosuberanyl derivatives, their pharmacologically acceptable salts with acids, quaternary ammonium salts and N-oxides, processes for their preparation and pharmaceuticals - Google Patents

Abstract

1375732 Bicyclic cycloaliphatic aminoalcohols and derivatives thereof E R SQUIBB & SONS Inc 10 Sept 1971 [10 Sept 1970] 40337/71 Heading C2C The invention comprises compounds of formulµ wherein R 1 , R 2 , R 3 and R 4 are each H, C 1-8 alkyl or haloalkyl, acyl, amido, (C 1-8 alkoxy)alkyl or (C 1-8 alkoxy)carbonyl; X is a single bond or a C 1-10 straight or branched chain divalent radical; Y is NR 5 R 6 where R 5 and R 6 are each H, C 1-8 alkyl, haloalkyl, alkoxy, hydroxyalkyl, alka. noyl or haloalkanoyl, (monocyclic) cycloalkyl or cycloalkyl-alkyl, (monocyclic)aryl, aroyl or aryl-C 1-8 alkyl, (monocyclic) heterocyclyl or heterocyclyl-alkyl, or N,N-dialkylsulphamoyl, or NR 5 R 6 may be heterocyclyl; R 8 , R¹ 8 are each C 1-8 alkyl or cycloalkyl; m, m¹ are each 0-2, and n is 1-3. In examples, which generally specify the particular stereoisomers isolated, these compounds are prepared by (1) oxidation (if necessary first protecting a primary amine by making the acylamino compound) of the corresponding 4,7-dihydro-, 4,5,6,7-tetrahydro-, or 3a,4,7,7a-tetrahydro-indones (or the analogous naphthalene or benzocycloheptene derivatives), and if H 2 O 2 /HCO 2 H is used, hydrolysis of the intermediate ester mixture to the diol or tetrol; (2) O-acylation; (3) hydrolysis of esters or amides; (4) hydrogenolysis of a compound where R 5 is PhCH 2 to give R 5 =H. Intermediates otherwise prepared are indene, indane, tetralin, 1,2-dihydronaphthalene and benzocycloheptene precursors of the abovementioned dihydro- and tetrahydro-amino compounds; 1-(2-hydroxyethyl)indene, 1-(2-ptosyloxyethyl)indene, 3-(3-hydroxypropyl(indene, 3-(2-butoxycarbonylethyl)indene, 1-(2- hydroxyethyl)indane, 2-(2-p-tosyloxyethyl)indane, 3-(3-hydroxypropyl)-4,7-dihydroindene, 1 - (3 - p - tosyloxypropyl) - 4,7 - dihydroindane, 1 - hydroxy - 2 - piperidinomethyltetralin, 1- (3 - diethylaminopropyl) - 1 - hydroxytetralin, 1 - (4 - aminobutylidene)tetralin, 1 - (3 - cyanopropylidene)tetralin, 1 - (3 - diethylaminopropyl) - 1 - hydroxy - 5 - methylbenzocycloheptene and 3 - (4 - cyanobutylidene) - benzocycloheptene. Therapeutic compositions for oral or parenteral administration comprise the tetra-oxy compounds of the above Formula I, which have blood pressure lowering and antibiotic activities.

Description

G 431 C (j / Pi / pi)

Oasis 71229-S

EESQIBB & SONS, Inc.
Iiew York, NY, V.St. A.

"Inüanyl, ITaphthyl and benzosuberanyl derivatives, their pharmacologis cn compatible salts with acids, quaternary ammonium salts and K-oxides, processes for their production and "ArKneimittel" Priority: September 10, 1970, V..St.A., Lir, 71229

The invention relates to indanyl, liaphthyl and benzosuberanyl derivatives of the general formula I.

OR,

(D

R ₂ O OR ₄

- (CH ₉ )

2'n

in which R ^, Rp, R-z and R. are identical or different and

Carbon ρ
Hydrogen atoms, / amide groups (p5 ^ N-CO-) or lower alkyl,

ty

Halo-lower-alkyl-, lower-alkoxyalkyl-, lower-alkoxycarbonyl- or acyl radicals, X is a single bond or an unbranched or branched divalent aliphatic bond

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~ ² ~ 2H5154

Represents a hydrocarbon radical with 1 ε etv / a 10 carbon atoms, Y represents a radical -LC ^ 5 or -CT-n ^, where the pests R, - unu ii _r

ο R "6
■ are identical or different and are hydrogen atoms or nonaero-alkyl, lower alkoxy, halogen-lower-alkyl, ivionocyclic cycloalkyl, monocyclic cycloalkyl-lower-alkyl, lower alkanoyl, halogen-lower-alkanoyl, kyaroxy-lower alkyl, monocyclic aryl, monocyclic aryloyl, monocyclic aryl-lower-alkyl radicals, nonocyelishe heterocyclic radicals, alkyl radicals substituted by monocyclic heterocyclic radicals or K, li-I) ialkylsulfamoyl radicals or together "Diit the nitrogen atom form a heterocyclic radical _ and R'g are identical or different and represent corresponding radicals such as Rp or R, - or pyridine, quinoline or isoquinoline groups or together with the carbon atom form a heterocyclic radical, and R _{7 is} a 7 / hydrogen atom means lower alkyl, aralkyl or lower alkoxy radical, with the proviso that at least one of the radicals R ¹ C, R'g and / or R ₇ contains a nitrogen atom, and R _g as well as E ' _{8 contains} a lower one en denotes an alkyl or cycloalkyl radical, and η is 1, 2 or 3 and m, like m ', has the value 0, 1 or 2, and their pharmacologically acceptable salts with acids, quaternary ammonium salts and K oxides. The substituted car

bonamid groups (tJ ^ IT-CO—) the radicals R _K and R _{c have the} same

h R do

Meaning as with the remainders -! ICj * 5.

Examples of aliphatic ^ hydrocarbon radicals X in the general formula I are alkylene radicals of the general formula Ι ^χ

- (CH ₂ ) - _n,. (Ix)

in which n ^{1 is} an integer from 1 to 10. Specific examples of alkylene radicals Ix are the methylene, ethylene, propylene, tri-ethylene, butylene and dimethylethylene groups. the

209812/1875

ilf'f-itii X köraiui; furthermore, any of the rii ο listed below correspond to their alkyl esters. The radicals R ₁ , R ", R_ and / or K ^ soviic E ₁ and / or Rr can be Ac, rl radicals, which derive from carbonic acids kit less than 12 CA" tones. Examples of these carboxylic acids are lower saturated aliphutic carboxylic acids, such as anicic, acetic, propionic, butyric, valeric, trimethylacetic or caryronic acid, lower ethylenic

Crotonic, aliphatic carboxylic acids, such as acrylic, methacrylic, vinyl glycine or β-methylcrotonic acid, monocyclic aromatic carboxylic acids such as benzoic acid or methyzoic acids, substituted by monocyclic arylic esters lower saturated aliphatic carboxylic acids, such as phenyl acetic, β-phenylpropionic, α-phenylbutyric or 5- (p-ethylphenyl) valeric acid, carboxylic acids derived from cycloalkanes, such as cyclobutane, cyclopentane or cyclohexanecarboxylic acid, such as cycloalkenene-derived carboxylic acids - or 3-Cyclopentenecarboxylic acid, and also lower saturated aliphatic carboxylic acids substituted by cycloalkyl or cyeloalkenyl radicals, such as cyelohexyl acetic, α-cyclopentylbutter, 2-cyclopentanylacetic or 3- (3-cyclohexenyl) pentenoic acid. from which the abovementioned acyl radicals are derived can also be substituted by halogen atoms, an example of such halocarboxylic acids is trifluoroacetic acid. Other acyl radicals _{suitable as radicals R 1} to Rg are Angeloyl, Veratroyl, Vanilloyl, erythra ^ -hyaroxy ^ -methyl ^ -acetoxybutyryl-,

(1) '- 2-methylbutyryl-, Ö) -2-hydroxy-2-methylbutyryl-, (d) -threo- -2,3-dihydroxy-2-methylbutyryl and (1) -erythro-2,3-dihydroxy- -2-methylbutyry! Group.

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-4- 2U5154

"Lower alkyl radicals" are here unbranched or branched To understand radicals which preferably have up to 8 carbon atoms. Specific examples of suitable C.o-alkyl radicals are the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -, Isobutyl ,. Pentyl, hexyl, isohexyl, heptyl, 4,4-diruethylpentyl, Octyl and 2,2,4-trimethylpentyl groups. The halogen -Lower-alkyl radicals can have fluorine, bromine, chlorine or iodine atoms as halogen atoms. The trifluoromethyl group will preferred as halo-lower-alkyl radical.

W The "lower alkoxy radicals" can likewise be unbranched or branched and are derived from the aforementioned lower alkyl radicals.

"Monocyclic aryl radicals" are to be understood here as carbocyclic aryl radicals, such as the phenyl group or substituted phenyl radicals, for example lower-alkylphenyl radicals, such as the o-, m- or ' p-Tolyl, ethylphenyl or butylphenyl groups, di- (lower-alkyl) -phenyl radicals, v / ie the 2,4-dimethylphenyl or 3,5-diethylphenyl group, halophenyl radicals, such as the chlorophenyl, brpmphenyl -, iodophenyl or Pluorphenylgruppe, the o-, m- or p-■ nitrophenyl, dinitrophenyl, such as the 3,5- or 2,6-dinitrophenyl) or 'Trinitrophenylgruppen how the Pikry group!.

Examples of suitable monoeyelis aryloyl radicals are those Radicals derived from the aforementioned aryl radicals.

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The monocyclic cycloalkyl or cycloalkenyl radicals are preferably 3 to 6 members. Specific examples of these radicals are the cyclopropyl, cyclobuty}, cyclopentyl, cyclohexyl or cyclobutenyl or cyclohexenyl group. The rest

R JR '

-Ν ^ τ, 5 or -C ^; ,, 5, as mentioned, can be a heterocyclic

^R 6 * ^R 6

Form rest '. The radicals R _c and R / - or R ¹ , - and E ¹ ^ can

ρ b 5 b

together represent the carbon (and hydrogen) and the oxygen, sulfur or nitrogen atoms which form a 5-, 6- or 7-membered radical with the nitrogen or carbon atom of the aforementioned radicals, which mi.:d ^j 3rd a nitrogen atom, but apart from the nitrogen atom of the radical -N ^ 5 [additionally has at most one heteroatom and fewer than 21 atoms (with the exception of the hydrogen atoms). The heterocyclic radicals can have 1 to 3 substituents, such as lower alkyl or lower alkoxy radicals, trihalomethoxy radicals, for example the trifluoromethoxy group, trihalomethylmercapto radicals, for example the frifluoromethylmercapto group, H, N-dialkylsulfamoyl radicals, such as the Μ, Ν-dimethylsulfamoyl groups, such as the Μ, Ν-dimethylsulfamoyl groups , eB the acetyl or propiony group, hydroxyl groups, hydroxy-lower-alkyl radicals, such as the hydroxymethyl or 2-hydroxyethyl group, hydroxy-lower-alkoxy-lower-alkyl radicals, such as the 2- (2-hydroxyethoxy) -ätlay! group Alkanoyloxy radicals, the alkanoyl content of which corresponds to the above-mentioned alkoxy radicals, alkanoyloxy lower-alkyl radicals with up to about 14 carbon atoms in the alkanoyl content, e.g. or carbopropoxy group or 2- {alkanoyloxy-lower-alkoxy) -lower-alkyl radicals with up to about 14 carbon atoms in the alkanoyl moiety, for example the

209812 / 1SfS

⁶ ~ 2H515A

2- (Dekanoyloxyäthoxy) -äthyl £; ruT «pe. The lower alkyl, lower ones Alkoxy and lower AlkanoyXreste correspond to the residues described above (Fornel I).

r.sli,

Examples of suitable heterocyclic radicals Rj-, R _r , -Y ^ Ji'j b »· /

p ι · ^D

"^ Cp" 5 are the piperidino group, (lower-alkyl) -piperidino-reacts, such as 2-, 3- or 4- (lower-alkyl) -piperidino-groups, e.g. the 2-ethylpiperidino group, or 4- (II-lower-alkyl) piperidino radicals, for example the 4- (N-isopropyl) piperidino group, di- (lower-alkyl) piperidino radicals, v / ie 2,4- _f 2,5- or 3,5-di (lower alkyl) piperidino radicals , for example the 2,4-diiaethylpiperidino or 2,5-ki-tert-butylpiperidino group, (ülieder-alkoxy) piperidino radicals, such as the 2 _r methoxypiperidino or 3-liethoxypiperidino group, hydroxypiperidino groups such as the 3-hydroxy or 4-hydroxypiperidino group, aminomethylpiperidino groups, such as the 4-aminomethylpiperidino group, the pyrrolidino group, lower-alkyl-pyrrolidino groups, such as the 3-methylpyrrolidino group, pi- (lower-alkyl) -pyrrolidinores1; e, such as the 3 »4-diniethylpyrrolidino group, lower-4-diniethylpyrrolidino group, lower pyrrolidino group , such as the 2-methoxypyrrolidino group, the morpholino group, lower-alkyl morpholino radicals, such as the 3-methyliaorpliol / laio group, di- (lower-alkyl) -morphol Ino radicals, such as the 3 * 5-difiethylmorpholino group, lower alkoxy / boropiiolino radicals, such as the 2-metiioxymorpholino group, the thiamorplioliiio group, lower-alkylthiainorpliolio radicals, such as the 3-methylthianiorphoropholino group, di- (lower-alkyl) 3 »-tlaiamorph1 ; fciajaorpholino group €, lower alkoxythiamorpliolinoreste, such as the 3-metlioxythiamorp3aolino group, the piperazino group, lower alkylpiperazino radicals',

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2H5154

like the Il ⁱ -! - ['. ithyl piperazinogruvpe, I) i- (lower-alkyl) -piperazinG-

the
reute, v. ^f ie _/ ^/ _2> ii-Mii: ethylpiperazino- or 2,6-Oiraethylpiperazino ~ group, Kieder-alkoxyjr'iperazinoreste, such as _2-t Hethoxypiperazirio -ruppe, Ilydroxy-lower-alkylpiperazinoreste, such as the K - (2- Iiy (iroxyäthy 1) -piperaainogruppe, alkanoyloxy-lower-alkylpipuraüinoreste kit with up to 14 C-atoms in the alkanoyloxy, v / ie the Ii - (2-heptanoyloxyethyl) -piperasino- or U- (2-dodecanoyloxyethyl) -piperasinogrujipe, Hydroxy-lower -alkoxy-rdeder-alkylpipei'azino radicals, such as the hydi'oxymctlioxymethylpiperazino group, carbo-lower-alcoholic piperazinox'este, such as the *} ^f - (carbomethoxy) -, H - (carboethoxy) - or H - (carbopropoxy) piperazino £; group that

Homopiporazinofjruipe, K -hydroxy-lower-alkylhomopiperazino radicals, like the N - (2-hydroxyethyl) homopiperazino group, the Piperidyl group, lower-alkylpiperidyl radicals, such as 1-, 2-, 3- or 4- (lower-alkyl) -piperidyl radicals, e.g. the 1-li-methylpiperidyl- or 3-ethylpiperidyl group, di- (lower-alkyl) piperidyl radicals, v / ie 2,4- »2,5- or 3,5-di (lower-alkyl) piperidyl radicals, in which the alkyl radicals are methyl, ethyl, n-propyl or isopropyl groups, lower alkoxypiperidyl radicals, such as 3-methoxypiperidyl or 2-ethoxypiperidyl group, hydroxypiperidyl groups, like the 3-hydroxy or 4-hydroxypiperidyl group,

Aminoalkylpiperidyl groups, such as the 4-aminoethylpiperidyl group, the Pyrrolidy! group, llieder-alkylpyrrolidylreste, like the 1-N-Hethylpyrrolidylgruppe, di- (lower-alkyl) -pyrrolidylreste, like the 2,3-DiniethylpyrrQlidy! group, lower-alkoxypyrrolidylreste, like the 4-H-methoxypyrrolidyl group, the morpholinyl group, lower alkylmorpholinyl radicals, such as the 3-methylmorpholiny group, Di- (lower-alkyl) morpholinyl radicals, such as

209812 / 18.75

2H5154

3-methyl-4-N-ethyl korpholinyl £; rui) pe, lower alkoxyinorpholinyl residues, such as the 2-ethoxymorpholinyl group, the thiiamox'pholinyl group, lower alkyl thiarnorpholinyl, such as the 3-ethylthiarnorphilinyl group, di ~ (lower- alkyl) -thiamorpholinylreate, such as the 3-HetLyl-4-H-äthylthiamorphol: Lnylgruppe, liieder-alkoxythiamorpholjnylreste, such as the 3-Methoxythiamorpholinylgr ⁱ Jppe, the piperazinyl or alkyl-, dialkyl-, alkoxy or hydroxy-alkyl-substituted piperazinyl radicals rrieder-.

| Preferred compounds of the invention v / iron as radicals R ₁ , Rp,

R ;, and R, have hydrogen atoms. Furthermore, compounds of the general formula I are preferred in which at least one of the radicals RJ, R ₂ , IU and R is an acyl radical and the radical (s) that may remain (a) hydrogen atom (s) ) is (are).

As mentioned, the invention also relates to the N-oxides of the compounds of the general formula I.

As mentioned, the invention also relates to the salts of the compounds of the general formula I with acids. Since these salts are insoluble in various media, the compounds will of the invention often via the salts from the mixtures * or solvent extracts obtained during their production isolated. The compounds can be precipitated, for example, in the form of an insoluble salt and this salt can be methods in the free base or another soluble or insoluble

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convert lich.es salt. The salts of the compounds of the general Formula I are derived from inorganic acids, e.g. hydrohalic acids such as hydroiodic or preferably

or ■

Hydrochloric / hydrobromic acid, phosphoric, sulfuric or nitric acid, or organic acids such as oxalic, tartaric, apple, maleic, citric, pamoic, fumaric, camphorsulphonic, methanesulphonic, benzenesulphonic, toluenesulphonic , Salicylic, benzoic, ascorbic or mandelic acid. < _%

As mentioned, the invention also relates to the cjuartary Ammonium salts of the compounds of general formula I. Examples are salts with lower alkyl halides, such as Methyl bromide, ethyl bromide or propyl iodide, benzyl halides, such as benzyl chloride, and di-lower alkyl sulfates such as dimethyl sulfate .

The invention relates to all of the general formula I corresponding Stereoisomers and their mixtures, the following compounds fall under the general formula I: a) Compounds according to the general formula Ia

(R ₀ )

Ö ^; ni

-th η ) _m , i Or ₄

(la)

in which all 4 costs R ^ Ö, RgO, R ₅ O and RO are axially arranged, the radicals RaO and R ₂ O are trans-configuration and the radicals OR, and ÖRj, also have trans-Kohfiguratioh.

/ 209812/1075

2H5154

b) Compounds according to the general formula] Ib

in which the remainders R..O and K _? 0 trans configuration and the residues ORv and OR. also have the trans configuration, the radicals R ^ O and R, 0 arranged diaxially and the radicals R..0 and RpO arranged diequatorially .3ind.

c) Compounds according to the general formula Ic

X-Y

(Ic)

in which the radicals R ₁ O and R ~ ö have the cis configuration and the radicals OR, and OR, have the trans configuration, one of the radicals R ₁ O and RpO is equatorial and the other radical is arranged axially and the radicals OR ^ and OR ^ are arranged diaxially.

.d) Compounds according to claim 1 to 5 according to the general Formula Id

(R ₈ )

R ₂ O '

OR,

(Id)

OR,

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2U5154

in uer the radicals R ₁ O and R ,, 0 have trans corification and the radicals 0R _v and 0R _/ cis configuration, the radicals R ₁ O and R ₀ O are equatorial or diaxial and one of the radicals OR, and OR, equatorial and the other remainder is arranged axially.

e) f) \ erbindungen according to claim 1 to 5 according to the general Formula Ie or If

(Ie).

9ττ ⁽ ν ^} ι

in which the radicals R-O and

as well as the residues OR, and

OR * have cis configuration and the pair of radicals R..O

and RpO to the pair of residues

and

cis configuration (Ie)

or trans configuration (If).

In each of the general formulas Ia to If, the radical -X-Y be directed upwards or downwards.

Preferred compounds of the invention have as radicals R-, Ro » R, and R. acyl radicals, as radical X a trimethylene group, as

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2H5154

Remainder Y is an amirio group, for ri the value 1 and for m as well as for m ¹ the value 0. However, if m has the value 1 or 2,

8 is (are) the remainder (s) preferably in the 5- and / or -6-position.

Specific examples of compounds according to the invention are the compounds of formulas A to E.

HO OH

.HO OH

U)

HO OH ^ (CH ₂ ) ₂ -]

(B)

HO OH

HO OH

(G)

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H ₃ CCO OH

H_ CCO OH
³ I!

21A515A

The invention also relates to a process for the preparation of .Verbindungen, the general formula Iä (RVO and R ^ O = trans, üK ~ and OR ₄ = trans, all radicals R _r O = axial), their salts with acids, quaternary ammonium salts and N ~ Oxide, which is characterized in that a diene of the general formula III

in which X, Y, m, m ¹ 'and η are as defined above, / asserstoffperoxid at temperatures of about 20 to about 4O ⁰ G with formic acid and aqueous V and the Estergemisch obtained by heating with a base at temperatures from about 40 to about 8O ⁰ C in the presence of a below etv / a 100 ⁰ C boiling solvent saponified and, optionally, the obtained tetravalent alcohol of the general Pormel Ia ¹

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2U5154

HO OH

^K 8

(Ia ')

ι ι
HO OH

fully or partially esterified and optionally the alcohol or esters with an inorganic or organic acid, a

with
Quaternizing agent or / a peracid in the presence of a

Reacts solvent. The salts with acids, quaternary ammonium salts and IT oxides of the compounds of the general formulas Ia to If prepared according to the processes described below can be prepared analogously.
A monohydric alcohol with up to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol or butanol, is used as the solvent for the saponification of the ester mixture. An alkali or alkaline earth metal hydroxide can be used as the base for the saponification

ier alcoholate, such as sodium, potassium, barium or calcium hydroxide, sodium methylate or calcium diethylate, can be used. When converting the diene of the general formula III, a molar ratio HpOp / diene of about 2.2: 1 to about 15: 1, in particular from about 2.2: 1 to about 5: 1, is preferably used. In the hydrolysis has a molar ratio base / Estergemisch of about 2.2 is preferably: 1 to about 10: 1, and in ^particular: sondere of about 2.2: 1 to about 5 applied '· 1>.

The tetravalent alcohol of the general formula Ia ¹ can be converted into the corresponding tetraester (R ₁ , R ₂ , Rz and R. = acyl) by treating it at temperatures from about -20 to about ⁰ ° C. in the presence of an acid, such as Perchloric acid, acts as a catalyst with an acylating agent. as

209812/1875

Acylating agent is, for example, one of the aforementioned carboxylic acids with less than 12 carbon atoms, their anhydride or acid halide, are used. In the esterification, a molar ratio is preferably used Acylating agent / alcohol from about 4: 1 to about 20: 1, in particular from about 4: 1 to about 10: 1, applied / ends. Furthermore, "is preferably an acid catalyst / alcohol molar ratio of about 1.1: 1 to about 2: 1, in particular from about 1.1: 1 to about 1.5: 1 »are used.

To convert the alcohol of the general formula Ia '"to the corresponding diester (R ₁ and R ₂ = acyl; R ~ and R ₄ = H), the alcohol is dissolved, for example, in an organic base such as pyridine, and the solution is at temperatures from about 0 to about 20 ° C. with an acylating agent using an acylating agent / alcohol molar ratio of from about 2.1: 1 to about 10: 1, preferably from about 2.2: 1 to about 6: 1. The esterification is preferably carried out at temperatures from about 5 to about 15 ° C. An acid anhydride of the type described above or a corresponding acid halide can be used as the acylating agent.

To convert the alcohol of the general formula Ia ¹ to the corresponding triester (R ₁ , Rp and R ~ = acyl; R. = H), where X preferably represents a single bond and the nitrogen atom of the radical Y is a position suitable for acylation on v / eist, the alcohol is mixed, for example, with a base, preferably pyridine, and the mixture is mixed at temperatures of about 5 to about 40 ^° C., preferably about 10 to about 30 ^° C.,

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Rait an acylating agent using a! • goal ratio Aylating agent / alcohol of about 3 ί 1 Mb about 10: 1 preferably from about 3: 1 to about 5: 1. as Acylating agents can be an acid anhydride or the like Acid halide of the type described above is used. The obtained! '! "! Ester of the general formula XVII

Acyl O O acyl

8'm

X-Y

(XVII)

ι OH

(CS _n )

2 ^; n

Acyl O

can in.den corresponding diester of the general formula XVlIl

Acyl O O acyl

'VnT

HO

VX-Y

(XVIII)

ι
OH

be converted by treating the triester with an alcohol / Water * mixture (volume ratio alcohol / water = etv / a 9: 1 up to about 1: 1, preferably about 3: 1 to about 1: 1). For each part by weight of the Trieste, about 10 up to about 100, preferably about 10 to about 50 parts by weight of the ethanol / v / water mixture are used.

The alcohol of the general formula Ia ¹ can be converted into the corresponding monoester (IU = acyl; R ₁ , R ₂ and R = H) by reacting the alcohol at temperatures of about 20 to about 60 ° C., preferably of about 25 to about 35 ° C, with a halogen

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Brings formic acid alkyl ester to the implementation. The obtained monoester has the general formula XIX

HO O acyl

X-Y.HX "

I ^v ι

HO

in which X "represents a halogen atom. In the reaction, it is preferred an alkyl haloformate / alcohol molar ratio of about 1.1; 1 to about 100: 1, in particular from about 10: 1 to about 50: 1, used.

The invention also relates to a modification of the method described above for the preparation of compounds of general formula Ia, which is characterized in that

if a diene of the general formula III is dissolved in a carboxylic acid, the solution is dissolved with a silver salt of this carboxylic acid ! Temperatures of about 60 to about 110 ° C heated, the obtained. Diester of the general formula IHa

(HIa)

Acyl θ '

in which the Acvlreste derive from the carboxylic acid, in Presence of a proton-active solvent with überex'schüssiger saponified aqueous base, the resulting dihydric alcohol is reacted with formic acid and hydrogen peroxide and the dated

209812/1875

2H5154

Solvent-free conversion product kit with an alcohol and treated a base.

The carboxylic acid used to dissolve the diene of the general formula III preferably has up to about 8 carbon atoms (for example acetic acid). Silver acetate, for example, is used as the silver salt. A molar ratio of diene / silver salt of about 1: 2 to about 1: 4, in particular of about 1: 2, is preferably used. Furthermore, a diene / iodine pick-up ratio of 1: 1 is preferably used. The solution of the diene ψχτη preferably heated to about 10O ⁰ C to temperatures of about 80th As a proton-active solvent, ethanol can be used as an aqueous base

Sodium or
Saponification of the diester / potassium hydroxide can be used. The reaction with formic acid and hydrogen peroxide is carried out in the manner described above, ie at temperatures from about 20 to about 40.degree. C., preferably about 35.degree. The treatment with an alcohol and a base is also carried out in the manner described above.

The compounds of general formula Ia can also like. will be produced. A diene of the general formula III is reacted with formic acid and 1 equivalent of an oxidizing agent such as aqueous hydrogen peroxide. To After separating off the solvent, the residue becomes a diololefin in the manner described above with alcohol / base of the general formula XVIa

'209812/1875

(ZVIa)

4:

saponified. This diol can divan in the manner described above with formic acid and hydrogen peroxide to the corresponding tetravalent alcohol (tetrol) of the general formula Ia are converted ^1.

The invention also relates to a process for the preparation of compounds corresponding to the general formula Ia ¹ , in which Y is a radical -li

pit

and at least one of the radicals R ₁

and Rg is an aromatic radical or an aromatic radical which is characterized in that can is a hydroxyalkyl compound of the general formula IY

in which X is an unbranched or branched alkylene radical represents up to about 10 carbon atoms in liquid ammonia in present a proton-active compound r-iit a metal to corresponding hydroxyalkyldien of the general formula V

209812/1875

(V)

reduced, the hydroxyalkyldiene of the general formula V dissolves in a basic organic solvent, the solution ^{cools to below O 0} C, Liit a solution of

Treated p-toluenesulfonic acid chloride in pyridine and the mixture is cooled, the diene tosylate obtained is cooled and reacted with an optionally substituted aryl- or aryl-lower-alkylamine or an amine of the formula R ₅ IINRg ₁ to form an aminoalkyldiene of the general formula VI

(VI)

in which RV and RV are the same or different and optionally substituted aryl or aralkyl radicals or have the same meaning as R ^ - and Rg, the aminoalkyl diene general formula VI reacts with formic acid and an oxidizing agent, the reaction product is freed from the solvent ' and the residue is saponified with a base.

The metal with a reducing effect can be lithium or sodium metal can be used, while a lower alcohol can be used as a proton donor. For the solution of the hydroxyalkyldiene of the general formula V, for example, pyridine is used. When reacting the diene of the general formula V with p-toluene

209812/1875

- 21 - 2U5154

sulfonic acid chloride is preferably a molar ratio of diene / Chloride of about 1: 1 "to about 1: 1.5 is used. When the tosylate is not reacted with an amine, a wood ratio is preferred Tosylate / amine from about 1: 2 to about 1: 5 is used. This implementation is preferably carried out in a below

aromatic
about 120 G boiling / solvent such as toluene or benzene performed. Optionally substituted arylamines, optionally substituted aryl-lower-alkylamines or amines of the formula Rf-IiHR, - can be used as amines for converting the tosylate. In the implementation of the Awinopli / Idiens of the general formula VI, hydrogen peroxide, for example, is used as the oxidizing agent. The saponification can be carried out in the manner described above with an alcohol and a base. The aryl radicals suitable as radicals R ¹ V and R "g in the general formula VI can have the same substituents as the aforementioned heterocyclic radicals. If the radical RV or R ^{(l is} a benzyl group, this group can be treated by treating the tetravalent alcohol with Convert hydrogen to hydrogen in the presence of a reduction catalyst such as palladium on strontium carbonate.

According to a modified process, compounds of the general formula Ia ¹ are prepared by adding an aminoalkylindene (prepared by reducing the corresponding cyanoalkylene cylinder) or an aminoalkyltetrahydronaphthalene with, for example, lithium metal in the presence of liquid ammonia, diethyl ether and a proton-active compound such as a lower alcohol a service of the general formula VII

209812/1875

reduced, the diene of the general formula VII in the presence a "basic solvent such as pyridine, triethylarain or a dilute alkali with an acid halide of the aforementioned type, e.g. benzoyl chloride, to a diene of the general Formula VIII

(VIII)

converts the diene of the general formula VIII with formic acid and an oxidizing agent, v / ie Wassex'stoffperoxid, for the reaction brings and the reaction product in the above-described Way saponified with a base. When reacting the diene of the general formula VII with an acid halide is preferably a molar ratio of diene / halogenide of about 1: 1 to about 2: 1 applied.

The invention further relates to a process for the preparation of compounds of general formula Ib (R ₁ 0 and R ₂ O = trans;. OR, and OR = watery; R ~ 0 R, 0 = diaxially; R ^ O and R ₂ O = diequatorial),. which is characterized in that

209812/1875

- ²⁵ - 2U5154

onnjüittel reacting one nit oin Diesterolefin the general Poriuel IHa at temperatures of etv / a 20 to etv / a 4O ° C formic acid and a Oxidati and the reaction product with an alcohol and a base at temperatures of from about 40 to etv / a saponified 100 ⁰ C. . Hydrogen peroxide can be used as the oxidizing agent in this reaction. The reaction with formic acid and the oxidizing agent is preferably carried out at temperatures from about 25 to about 35.degree. For the saponification v / iru, for example, a monohydric alcohol and any of the abovementioned bases are used; The saponification is preferably carried out at the reflux temperature of the mixture.

The invention also relates to a process for the preparation of compounds of the general Porrael Ic (R-.0 and RpO = cis; OR ₇ and OR. = Trans; R ₁ O or RpO = equatorial; the other remainder = axial; OR-, and OR. = Diaxial), which is characterized in that a diene of the general formula III in the presence of a saturated aliphatic carboxylic acid containing about 2 to 10 ° ί- V / ater with a silver salt of this carboxylic acid and iodine at temperatures of about 50 to 110 ° C heated and the obtained monoester of the general Porxiel IX

Acyl O

or reacts the dihydric alcohol obtained therefrom with formic acid and an oxidizing agent and the conversion

209812/1875

" ²⁴ " ■ 2H5154

product saponified with a base. As a solvent for the Diene of the general formula III used carboxylic acid preferably has 2 to 10 carbon atoms (e.g. acetic acid) and contains preferably about 5 7 'of water. As the silver salt, sorr.it is e.g. Silver acetate used. The intermediate olefin of the general formula IX is a new compound It can be converted into the diol with a base, e.g. in the presence of an alcohol in the manner described above, Hydrogen peroxide can be used as the oxidizing agent for the oxidation of the olefin or diol. The individual stages of the The aforementioned processes correspond to the stages in the preparation of the compounds of the general formula Ia.

The invention further relates to a process for the preparation of compounds of general formula Id (R.0 and RPO = trans; OR and OR * · ^ = ice; R ₁ 0 and RPO = diequatorially or diaxially;. OR, or OR = equatorial, the other remainder = axial), the

⁰ e.g.

is characterized by having a / in the above-described Way prepared diester of the general formula UIa in the presence of a basic organic reacting Brings solvent with osmium tetroxide to the reaction and the ■ 'obtained diester alcohol of the general formula .X

Acyl 0_ ^. , .j

- ^(R 8 ^} m '

Acyl O-

saponified with a base. When implementing the diester of

209812/1875

general formula IHa can be used as a solvent a mixture from pyriine and benzene can be used. A molar ratio of ossium tetroxide / diester of about 1: 1 is preferably used up to about 4: 1, in particular from about 1: 1, used.

The invention also relates to a process for the production of Vei'bindungen of the general formulas Ie and If (R ₁ O and RpO = = cis; OR, and OR, = cis; Ie: pair R..0 and RpO / pair OR-, and OR. = cis; Ifj pair R ₁ O and R ₂ 0 / pair OR ^ and OR. = trans), which is characterized in that a mono ° ster of the general formula XX in the presence of a basic solvent 'with the afthydride a saturated aliphatic carboxylic acid with up to about 6 CWitomen converts the Did.e ?? generalB Fopmel

and

l with OsirdymtetrDxid to implement

BEFORE

the

(ΧΪΪ)

2H5154

OH

(ZlII)

rait a base saponified. The basic ice solvent used in this method is B, pyridine. The acid anhydride used can be, for example, acetic anhydride or an anhydride derived from the aforementioned alkanecarboxylic acids. A ratio of the monoester of the general formula IZ to the acid anhydride of about 1: 1 to about 1 is preferably used; 5 * in particular from about 1; 1 to etv / a 1 s 2, applied.

To prepare the lower alkyl ethers of the general formula I (Rj, Rg » Uz and R = lower alkyl), z> B. A tetravalent alcohol of the general formula I is dissolved in a suitable non-proton-active fluid such as benzene, dioxane, diethyl ether or tetrahydrofuran, the solution is per equivalent of the alcohol with at least 4 equivalents, preferably about 5 to about 7 Equivalents of a metal hydride, such as sodium hydride, or jiat ^ iujnamide, and then slowly, with stirring, with about A equivalents of a lower alkyl halide, such as methyljo44-d, methyl bromide or ethyl iodide, added and then at 1 temperatures of about 20 to about 60 C preferably about 30 biö about 4O ⁰ G kept. Then the non- ¹

. .. alkyl

r-converted laae jqit Athanpl and / or V / aaaer decomposed and the / Other are isolated by evaporation of the solvent,

2Q9812 / 187S

²⁷ 2U515A

The preparation of compounds of general Porniel I, the products of which are R-, Jl ,, * K ₇ and R halo-lower-alkyl radicals, takes place analogously to the preparation of the alkyl ethers, but instead of an alkyl halide a dihalogen alkane such as trircethylene chlorobromide is used or pentane ethylene fluoride iodide.

The preparation of the compounds of general formula I whose radicals R, R ₂ , R ^ and R represent lower alkoxycarbonyl radicals, is carried out analogously to the preparation of the alkyl ethers, but instead of an alkyl halide, a ¹ xialkylcarbamoyl halide, v / ie dircethylcarbainoyl chloride or diethylcarbamoyl bromide is used , 'or an organic isocyanate, such as an alkyl or aryl isocyanate, is used.

The preparation of the compounds of general formula I,

in which the radicals R-, R ₂ * R ^ ^{un <} * R / lower alkoxyalkyl radicals (2 to 5 carbon atoms in the alkyl radical) are analogous to the preparation of the alkyl ethers, but instead of the alkyl halide, an alkoxyalkylene halide such as ethoxypropyl chloride is used or ethoxyethyl tromide is used.

The preparation of the compounds of the general formula I, in which the radicals R-, R ₂ , R ^ and R. are lower alkoxycarbonyl radicals, are also carried out analogously to the preparation of the alkyl ethers, but using an alkyl haloformate, such as methyl chloroformate or - ethyl ester, instead of the alkyl halide.

BAD ORJGfNAL

209812/1875

The 1,2,3> 4, b , 8-hexahydronaphthalenes of the general formulas XXa and XXb which can be used for the preparation of compounds of the general formula I

(XXa)

< ^R Vm <

(XXb)

can be prepared from tetrahydronaphthalenes by several known methods getting produced. Compounds of the general formula XXa can be prepared by reacting an α-tetrahydronaphthalene

-ons with an aminoalkyl Grignard compound and subsequent Birch-Hückel hydrogenation (Ha in liquid NIL) of the obtained Amino alcohols can be produced directly. The 2-substi-.tuierteh Compounds (general formula XX.Td) can be derived from B-Te-: trahydronaphthalen-ons are prepared by removing the alcohol group before the Birch-Hückel hydrogenation with the aid from acids such as hydrochloric acid in acetic acid. According to another method, tetrahydronaphthalenes are reacted with a ylide of the Wittig type to form side-chain nitriles, which in turn are reduced to primary amines. The primary amines are then in a conventional manner by sub-

209 812/187 5

stitution converted into secondary or tertiary amines . A third process is via the tetrahydronaphthalene

-onen derived Mannich bases (ie reduction with lithium aluminum hydride and subsequent Birch-Hückel hydrogenation to form a compound of the general formula XZb with n * = 1). According to a modified method, a quaternization is carried out. The anschliei3ende reaction with potassium cyanide or Cyanessigsäureäthylester in the presence of a base provide intermediates which are easy to side-chain amine groups aufwei- • send dihydronaphthalenes convertible ¹¹ J ^- Vbei are compounds analogous to the Pormel XXa or XXb obtained in which 'n is 2 or .3 has. These compounds are converted to the hexahydronaphthalenes in the aforementioned manner by a Birch-Hückel hydrogenation.

The 1 ^, ojTjS ^ -hexahydro-SH-benzocycloheptenes which can be used for the preparation of compounds of the general formula I general formulas XXc, XXd and XXe

(XXc)

^<CH 2> Xj

(XXd)

209812/1875

2H5154

can be prepared by several conventional methods from the corresponding tetrahydro-5, obzw.TH-benzocyclohepten -!?, 6 or 7-ones of the general formulas XXc ', XXd ¹ or v /. XXe '

(XXC)

(XXd ¹ )

^(R

(XXe ¹ )

getting produced. The ketones are linked to an aminoalkyl -Grignard compound implemented, the implementation product is

- if necessary, after dehydration - reduced to the corresponding aminoalkyl-6,7, 8,9-tetrahydro-5H-benzocyclohepten and this compound is described above in the

209812/1875

- ⁵¹ ~ 2U515A

V / else subjected to the Birch-Hückel hydrogenation. The ketones of the general formulas XXc ', XXd' and XXe 'can also be reacted with a ylide of the Vittig type to form a side-chain kitrile, the nitrile can be reduced to a primary amine and this optionally converted into a secondary or tertiary amine in a conventional manner before the Birch ~ Huckel Hydz ⁱ ation makes. The compounds of the general formulas XXc, XXd and XXe can also be obtained in the above-mentioned manner by oximation of the aforementioned ketones, reduction of the oximes to the corresponding primary amines (n "= 0) and reduction of the amines. ■

The following compounds used in the preparation of the compounds of the general formula I or formed as intermediates are new: the compounds of the general formulas XIV and XV

< ^R ₈ y

OR

° R'2

209812/1875

in which. R ¹ - and R'p denote hydrogen atoms or iicyl radicals and X and Y have the meanings given above, the. Diesters of the general formula IHa, the beasts of the general formula XI

Cxi)

^{the dololes of the general formula IIIa f} derived from the beasts of the general formula lilac

(purple ¹ )

IX

the compounds of the general formula XVI

OH

(XVI)

-OH

as well as the dienes of the general formula III and the monoesters of general formula IX.

The dienes of the general formula III can be obtained by Birch-Hückel -Hydrogenation of aromatic compounds of the general formulas XXI or XXII ''

209812/1875

2U5154

(XXII)

produced v / earth. E ^ ne aromatic compounds suitable as starting compounds Indeny! Compound of the general formula XXIII

(XXIII)

is produced, for example, by indening the general Formula XXIV

(XXIV) '

(.ft «1)

X ¹ is a reactive halogen atom or another displaceable group such as a tosylate group, and is all η'eine number from 1 to 10, at temperatures of from about 75 to about 150 ⁰ C, preferably about 100 to about 120 ⁰ C, in the presence of a solvent with a boiling point below about 150 ^° C., such as toluene or xylene, with an amine of the general formula XXV

209812/1875

₅₆ (XXV)

in which Rj and Rg have the meaning given above, under

Use of an inene / amine molar ratio of about 1: 2 "to

about 1:10, preferably about 1: 2 to about 1: 4, for reaction brings.

The compound of the general formula XXIII can be reduced to the corresponding indanyl compound, for example with the aid of hydrogen in the presence of a catalyst such as platinum oxide. The aromatic indeny compounds of the general formula XXIII can also be prepared by adding indene at temperatures of about 40 to about 75 ° C, preferably about 45 to about 55 ⁰ C, in the presence of, on the one base, such as a concentrated aqueous iürdalkalilauge, was added a methanolic solution of letramethylammoniumhydroxid, with a Aminoalkylenhalogenid of the general formula XXVI

' ^R 5

(XXVI)

in which X ¹ , Rr, Rg and n 'have the meaning given above, brings about the implementation. In this reaction, an iridene / halide molar ratio of about 1: 1 to about 10: 1, preferably about 2: 1 to about 4: 1, and a base / halogenide molar ratio of about 3: 1 to about 10: 1, preferably about 3: 1 to about 5: 1 »applied.

Indeny! Compounds of the general formula XXVII

209812/1875

2H5154

. (XXVII)

can be prepared by indening the general Formula XXIV in the presence of liquid ammonia with a compound of the general formula XXVIII

\ _R. ■ (XXVIII)

^R 6

^R 7

in which H is an alkali, such as sodium or potassium atom, .using an indene / alkali compound molar ratio from about 1: 1 to about 1:10, preferably about 1: 2 to about 1: 4, to react. As an alkali compound of the all For example, general formula XXVIII can be a compound of general formula XXIX

(XXIX)

are used, in which Rq corresponds to any radical P. ¹ , -. The indenyl compound of the general formula XXVII can then be reduced to the corresponding indanyl compound with hydrogen in the presence of a catalyst such as platinum oxide.

209812/1875

2H5154

Indeny! Compounds of the general formulas XXX or XXXI

(XXX)

(XXXI)

can be prepared by using a 1- or 2-indanone at temperatures from about 80 to about 125 ° C, preferably at

the reflux temperature of the mixture, as opposed to a subaromatic one
half about 150 G boiling / solvent, such as toluene or benzene, and of p-toluenesulfonic acid with a 1min of the general formula XXV using an indanone / amine boiling ratio of about 1: 1 to about 1: 4, preferably about 1: 1, 1 to, approximately ψ 1: 1, *? , brings to reaction, then separates off the water, solvent and unreacted amine, dissolves the residue in an alcohol boiling below about 100 C, such as methanol, adds an alkali borohydride to the solution, and adds the unreacted borohydride an organic acid such as acetic acid, and finally treating the product with a base.

The dihydronaphthalene and dihydrobenzosuberanverbin-

209812/1875

fertilize the general formula XXXII

« ^RI 8» m

(XXXII)

one can be prepared by / "Tetrahydronaphthalen-1-one" at temperatures of about 80 "to about 140 ⁰ G, preferably about 110 to about 140 ⁰ C, in the presence of an aromatic solvent boiling ^{below about 150 0 C and of} brings p-1'oluenesulfonic acid with an amine of the general formula XXV using a molar ratio of tetrahydronaphthalene-1-one / amine of 1: 1.1 to about 1: 1.5. A dihydronaphthalene obtained in this way can then pass through Reduction in the form of its salt has for example "" lithium- ^ "~~ aluminum hydride converted into the corresponding tetrahydronaphthyl compound.

By Birch-Hückel hydrogenation of the aromatic compounds of the general formulas XXI and XXII, as mentioned, the diene of the general formula III is obtained. To carry out the .. ^: Birch-Hückel hydrogenation, the aforementioned aromatic compounds in the presence of liquid ammonia, a proto-. nen-active compound, e.g. of a lower alkanol, and of diethyl ether in a known V / eise with lithium metal using a molar ratio of aromatic compound / lithium metal of about 1: 2 to about 1:50, preferably about 1:10 to about 1:20, implemented.

209812/1875

- ⁵⁸ - '' 2U5154

Specific examples of aromatic compounds of the general formula XXIV, which can be used to prepare the compounds of General formula I are suitable, can be seen from Table I.

Table I.

m ^f = 0

a) ΐί ^ Ι, X '= Cl

b) i £ = 2, X '= Br

c) rf = 2, X '= J
d). n = 4, X

e) ϊ * = 5, X '= C1

f) ΐέ = 6, X '= Br

g) rv = 7, X '= C1 h) n = 8, X' = J

n = 1 m = O

n = 3

^R 8 ^{= 6} "" ^C 2 ^H 5

Rq = 5-CH ₃ , 6-CH ₃

^R ₈ ^{= 5-0}

Table II shows amines of the general formula XXV, which are used in
the preparation of the compounds of general formula I can be used.

209812/1875

T a b e ^R 5 lie II -Qh R ₆ a) CH ₃ - H b) H C ₂ H ₅ c) ClCH ₂ - CH ₃ d) Q ClCH ₂ - e) α H f) Q-CH ₂ - he G) Πγ Q-C, H) CH ₃ i) CH j) C ₂ H ₅

Examples for the preparation of the compounds of the general Compounds of the general formula XXVI which can be used for formula I are shown in Table III.

Br
Cl tab n * hurry III R ₆ Br 2
2 ν CH ₃
CH ₃ 2- a)
b). J
Cl 3 C ₂ H ₅
CH ₃ -C- ^H Ö "' O J 4th
5 hQj- HIGH ₂ CH ₂ d)
e) 10 - ^CH 2 -
HO-CH ₂ CH ₂ - η f) η

209812/1875

~ ⁴⁰ ~ 2143154

Table IV shows compounds of the general formula XXVIII which are used in the preparation of the compounds of the general formula I can be used.

Table IV

p "Ff, R- - '■ -.- ■

. M __2. - «■

a) KC ₂ H ₅ 'C ₂ H ₅ H

, / b) Na "Φ ^HH

_c ) Li -ΓΓΧ * Tr3 < H

d) Na / ^ ^HH

e) KH ι - "- ' ^H

f) Na · '» ¹ ^" - ^CH '

. For the preparation of the li-oxides of the compounds of general

(Y = nitrogen-containing heterocyclic radical) Formula I / these compounds are, as mentioned, in the presence

a solvent reacted with a peracid. Specific * examples of suitable peracids are m-chloroperoxybenzoic, perbenzoic and monoperphthalic acid. A suitable solvent is, for example, chloroform.

For the preparation of the quaternary ammonium salts of the compounds of the general formula I, the free base per equivalent is at least 1 equivalent of the alkylating agent in question implemented.

The invention also relates to medicaments by a

209812/1875

Content of at least one compound of the general formula I, their pharmacologically acceptable salt with acids, quaternary Ammonium salt and / or IJ oxide are labeled as active ingredients.

The compounds of the invention are antihypertensive

People and others
Effect on / warm-blooded animals such as rats and dogs. They are also suitable as antibiotics. The compounds of general formula I and their pharmacologically acceptable salts can be processed into conventional preparations that can be administered orally or parenterally, such as tablets, capsules, elixirs, injection preparations or powders. The compounds of the invention are administered in the form of 2 to 4 divided doses in amounts from about 100 mg to 400 mg / day, preferably from 125 to 175 mg / day.

Finally, the invention relates to the use of the compounds of the general formula I, their salts with acids, quaternary ammonium salts and IT oxides as water softeners.

209812 / 187S

The examples illustrate the invention.

example 1

1- / 3- (4-7-dihydro-l-indanyl) -propyl7-piperidine- hydrobromide Yield by Bireh-Hückel hydrogenation of 1- / 3- (3-indenyl) ~ propy! / - piperidine prepared as follows:

A solution of 13.5 g (0.056 mol) 1- / 3- (3-indenyl) propyl7-piperidine 100 ml of ether is added to a mixture of 1 liter of liquid ammonia and 100 ml of ether. Then be within from 15 minutes with stirring 20 g (2.85 urammatom) lithium metal added in several partial amounts. The lithium metal is used in tape form, as in the following examples. A greenish-bronze colored mixture is obtained, which is stirred for 90 minutes and then dropwise until it disappears anhydrous ethanol is added to the arbe. The ammonia is then evaporated off. The residue is mixed with water made up to a volume of 1500 ml and extracted twice with ether. The ether extracts are dried over potassium carbonate, and then the solvent is evaporated off under reduced pressure. 13.9 g of 1- / 3- (4,7-dihydro-i-indanyl) propy / piperidine are obtained; Yield 100 percent of the "theory."

5 g of this compound are then converted to the hydrobromide by, man! .In a solution of the compound is added dropwise a hydrobromic acid solution until it reaches a value of ~ p _H. 4 When the solvent is evaporated off, a yellow solid crude product is obtained which, after recrystallization from ethanol / ether, contains 3.8 g of des

209812/1875

2U6154

crystalline hydrobromide supplies; Yield 56 percent of theory. After a second recrystallization from the same solvent mixture to obtain 2.4 g of the desired compound from the Pp löü to 196 ⁰ C (decomposition). Yield 35 percent of theory.

C H N Br

C ₁₇ H ₂₇ N.HBr; calc .: 62.57; 8.65; 4.29; 24.49

Found: 62.70; 8.60; 4.04; 24.51.

Example 2

3a, 7a-trans-5,6-trans-hexahydr o -1- (2-piper idinol t; hyl) -3a, 5,6,7a indantetrol

2- (1-indenyl) ethanol

The compound is described in the method described by Howell & Taylor, J.C.S., (1957), "On page 3OI3 prepared in the manner described.

Butyl lithium, which was prepared by reacting 20 g of lithium metal with 234 g of butyl bromide in ether is added indene at -1O ⁰ C with stirring, and using nitrogen as a protective gas with 116 g (1 mole). After standing for 1 hour at -10 ⁰ C a solution of 88 g of ethylene oxide in 300 ml of ether is added within 30 minutes. The mixture is then: heated for 10 ⁰ C, treated cautiously with 500 ml of v / ater and stirred "until no lithium is longer exists After layer separation, the organic layer is washed once with dilute hydrochloric acid and then washed three times with water.. After drying, the ether is evaporated off and the residue is distilled, giving 76 g of 2- (l-indenyl) ethanol with a boiling point of 125 to 135 ° C / 0.2 Torr; yield 48 percent of theory.

The nance spectrum available shows that there is a double bond in the 2,3-position /.

20981 2/1875

2U5154

2- (1-indenyl) ethyl tosylate

4-9 g (0.306 mol) of that prepared in the aforementioned manner 2- (l-Indenyl) ethanol are combined with 64.8 g (0.35 mol) of p-toluene- ' sulfonic acid chloride added. The paste obtained is cooled to 0 C, and 49 g (0.62 Hol) are added within 1 hour. Added dropwise pyridine. The resulting cold solution is

about chüssifjer Stirred for 4 hours and then with / dilute hydrochloric acid offset. The product is then extracted with ether

over 95 g of the viscous tosylate; Yield / 99 percent of theory. That Nuclear magnetic resonance spectrum shows that the double bond is in the 2,3-position. ■

1- Z2- (3-indenyl) -ethyl7-piperidine

41.5 g (0.13 mol) of the crude tosylate are refluxed with 28 g (0.33 mol) of piperidine in 200 ml of toluene for about 15 hours. The warm reaction mixture is then until the onset of crystal formation mixed with ether. After cooling, the pests are filtered off and washed several times with ether. That with the filtrate combined with the washing waters. is freed from the solvents under reduced pressure. This leaves an oily residue which is dissolved in ether. A small amount of insoluble matter is filtered off, and the filtrate becomes the ether evaporated. 29.7 g of a brown oil are obtained. Yield 99 percent of theory. The oil is used to help cleanse distilled under reduced pressure. A yellow oil with a boiling point of 115 ° C./0.5 Torr to 130 ° C./0.1 Torr is obtained; Yield 86 percent of the Theory.

209812/1875

A solution of 15 g (0.066 mol) of l-Z2- (3-indenyl) ethyl7-piperidine in 100 ml of ether "is then in a mixture of 1 liter liquid ammonia and 100 ml of ether entered. Then 20 g (2.5 gram atom) lithium metal are within 15 minutes added with stirring in the form of quantities of rope. The received greenish-bronze colored mixture is stirred for 90 minutes · Then add anhydrous ethanol until the color disappears. For this purpose, 260 ml of ethanol are required, which are added within 100 minutes. The one when evaporating the residue obtained from the ammonia is filled with water to 1500 ml and extracted twice with ether. The ether extracts are dried over potassium carbonate and then freed from the solvent under reduced pressure. 13.1 g are obtained an amber oil; Yield 86 percent of theory.

A comparison of the IR and UV spectra of the oil with the corresponding spectra of the starting material / shows that no unreacted starting material has remained. The product is identified as 1- / 2- (4,7-dihydro-l-indanyl) ethyl7-piperidine. 11 g (0.048 mol) of this compound are then added dropwise to 100 ml of cold 98 percent strength formic acid over the course of 15 minutes. Then within 40 minutes 57 ml (about 0.5 mol) 3Oprozentiges hydrogen peroxide, the temperature being kept at 20 ⁰ C are added dropwise. The temperature of the mixture is then allowed to rise to 35 ° C. and kept at 30 to 35 ° C. for 4 hours with the aid of a large water bath. The mixture is then stirred for about 15 hours and then evaporated to almost dryness. The performic acid that is still present is removed by adding water twice.

2 09812/1875

and evaporation removed at reduced pressure »

The yellow oil that remains is dissolved in 100 ml of anhydrous ethanol. The solution is made with a solution of 30 g of potassium hydroxide added in 50 ml of water. The resulting mixture is refluxed for 1 hour and then cooled and with 500 ml of water diluted. Then it is extracted four times with ether. The ether extracts are dried over magnesium sulfate. To After filtering off the magnesium sulfate, the ether is reduced at a reduced rate Pressure evaporated. 7.2 g of a brown-yellow solid substance are obtained; Yield 51 percent of theory, after two times Recrystallization from ethyl acetate gives 4 »25 g of 3a, 7a-trans-5,6-trans-hexahydro-1- (2-piperidinoethyl) -3a, 5,6, 7aindantetrol mp 179 Ms 182 C; Yield 30 percent of theory.

C ₁₆ H ₂₉ NO ₄ ;

* Example?

3a, 7a-trans-5,6-trans-hexahydro-1- (2-piperidinoethyl) -3a, 5,6,7aindantetrol-S ^ -diacetate hydrochloride

A solution of 2 g (0.0067 mol) of prepared according to Example 2 3a, 7a-trans-5,6-trans-hexahydro-1- (2-piperidinoethyl) -3a, 5 »6,7a-indantetrol in 35 ml of pyridine, while cooling in an ice bath, 18 ml of acetic anhydride are added dropwise over the course of 30 minutes offset. After stirring for about 15 hours at room temperature, the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and the solution

209812/1875

64 C. 9 H 4th N ber .: 64 , 18; 9 .79; 4th , 68; found i , 21; .82; , 68.

extracted twice with 5 percent potassium carbonate solution. The chloroform extract is dried over magnesium sulfate. After filtering off the magnesium sulphate, the chloroform is evaporated off under reduced pressure. The residue is freed from the remaining pyridine by adding benzene twice, which is then evaporated off under reduced pressure. The foam-like residue is dissolved in isopropanol / ether and converted into the hydrochloride by adding a solution of hydrogen chloride in isopropanol. 1.5 g of the crude desired compound are obtained with a melting point of 2 <32 Vis 263 ° C .; Yield 54 percent of theory. After recrystallization from ethanol / isopropanol, 1 g of the pure compound of melting point 262 to 263 ^° C. is obtained; Yield 36 percent of theory.

CHN Cl C ₂₀ H ₅₃ MO ₆ .HCl; calc .: 57.21; 8.16; 3.33; 8.44;

Found: 57.13; 8.27; 3.18; 8.66.

Example4

3a, 7a-trans-5,6-trans-hexahydro-1- (5-piperidinopentyl) -3a, 5 «6, 7a-indantetrol

3,5 * -Brompentylinden ".

The compound is in the manner described by Makoska in "Tetrahedron Letters", Volume 38, (1966) at pages 4621-4624 as described is made as follows:

A mixture of equimolar amounts of indene and 1,5-dibromopentane is in 50 percent aqueous sodium hydroxide solution, which is a methanolic solution of TritonJB ^ (Trimethylbeiizylaninoniumhydroxid)

209812/1875

was added. This forms an oil that is purified by distillation. The temperature at 141 to 147 ° C / 0.1 torr-boiling compound is identified as 3> 5'-bromopentylindene

etv / a
certified; Yield / 50 percent of theory.

1- / 5- (Inden-3-yl) -pentyl7-pyridinium bromide A solution of 85 g (0.32 mol) of the 3 »5'-bromopentylinder and 28 g (0.35 mol) of pyridine in 100 ml of acetonitrile is refluxed for 20 hours. "The warm reaction mixture is then mixed with a small amount of ether until it becomes cloudy. After further cooling, the crystals formed (10.5 g» yield 98 percent of theory) are filtered off and washed with ether. The product melts at 142 to 146 C and is identified as 1- / 5- (inden-3-yl) pentyl7-pyridinium bromide.

1- / 5- (indan-1-yl) pentyl7-piperidine

106 g (0.31 moles) of 1- / 5- (inden-3-yl) pentyi7-pjridini'ambromid become Hydrogenated in a Paar device as follows: The bromide is separated into four portions and these are filled in four bottles. In; each bottle is also 200 ml of methanol and 0.6 g of platinum oxide are added as a catalyst. Hydrogen is then passed in at room temperature. The hydrogen recording ends after 75 minutes. The amount of hydrogen absorbed corresponds to the reduction of four double. bonds calculated theoretical amount. The catalyst is then filtered off and the filtrate is freed from the solvent. The residue is recrystallized from a mixture of 3 parts of ethanol and 1 part of ether. 103.6 g of crystal are obtained!

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2HB15A

nes l- / 5- (indanyl-l-yl) pentyl7-piperidine hydrobromide vom M.p. 147 to 152 C; Yield 96 percent of theory. The hydrobromide is quantitatively converted to the free base by making an aqueous solution of the bromide alkaline, the free base extracted with ether, the ether extract is dried and evaporated under reduced pressure.

5a, 7a-trans-5,6-trans -hexahydro-1- (5-piperidinoperityl) -ga, 5,6, 7aindantetrol

A solution of 16.3 g (0.06 mol) of 1- / 5- (indan-1-yl) pentyl7 ~ piperidine in 100 ml of ether is added to a mixture of 1 liter of liquid ammonia and 100 ml of ether. The mixture is then with stirring within 15 minutes with 20 g (2.85 mol) LithiummetalX, offset in the form of subsets. You get a

blue-bronze colored mixture which is stirred for 45 minutes. Then anhydrous ethanol is added dropwise until the blue color disappears. 375 ml of ethanol are required which are added within 2 hours. The ammonia is then evaporated. The residue is made up to 1500 ml with water filled up and then extracted three times with ether. The ether extracts are dried over potassium carbonate, and the ether becomes evaporated at reduced pressure. 16.2 g of an oil are obtained Yield 99 percent of theory. A comparison of the IR and UV spectrum of this oil with the corresponding spectra of the starting material shows that there is no longer any unreacted starting material.

16.2 g (0.06 mol) of the oil are then added dropwise to 100 ml of cold 98 percent formic acid over the course of 15 minutes. The mixture is then added dropwise ^{at 20 ° C. within 25 minutes}

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2Ί4Β154

with 59 g (0.5 mol) of 30 percent hydrogen peroxide added. The temperature of the mixture is then allowed to rise to 35.degree and 3 hours with the help of a large water bath at 30 held to 35 0. The mixture is then stirred for about 15 hours and then evaporated to almost dryness. Me remaining Performic acid is then removed by adding water twice and evaporating under reduced pressure.

The yellow oil that remains is dissolved in 100 ml of anhydrous ethanol. The solution is with a solution of 30 g of KOH in 50 ml V / ater offset. The resulting mixture, which immediately turns dark, is refluxed for 1 hour,! Times the After cooling, the mixture is made up to 500 ml with water. Extraction with ether gives 12.4 g of a brown, viscous one Raw product; Yield = 61 percent of marriage theory. After recrystallization from ethyl acetate and further recrystallization twice from ethyl acetate using activated charcoal is obtained 3.2 g of white crystals with a melting point of 153 to 156 ° C .; 16 percent yield the theory. The crystals represent the desired connection. '

CH Ji C ₁₉ H ₃₅ NO ₄ ; calc .: 66.82; 10.33? 4.10;

found i 66.90; 10.43; 4.04. ^:

Example

3a, 7a-trans-5 , 6-trans-hexahydro-1- (5-piperidinopentyl) -3a, 5,6,7a-indantetrol-3a, 5,6,7a-tetraacetate 4 g (0.012 mol) of the according to the example 4 prepared 3a, 7a-trans-5,6-trans-hexahydrol- (5-piperidinopentyl) -3a, 5,6,7a- indantetrols are introduced into 80 ml acetic anhydride. Connecting

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5 ml of glacial acetic acid are then added to obtain a clear solution. The solution is then treated dropwise within 30 minutes with 8 ml of 70 percent perchloric acid while cooling with ice / sodium chloride. The mixture is then held at about -15 ° C. for 16 hours. With continued cooling, 80 ml of methanol are then added dropwise over the course of 30 minutes. The mixture is then made alkaline with concentrated ammonium hydroxide and then extracted three times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and filtered. After the chloroform has been distilled off under reduced pressure, 5.2 g of an amber-colored viscous substance are obtained. Most of this substance is dissolved in 200 ml of hot hexane. After cooling, 1.5 g of the desired crystalline compound (main product) with a mp of 123 to 130 ^° C. are obtained, which are filtered off. When the mother liquor is concentrated, several additional product fractions are obtained in a total amount of about 1.6 g. The yield of crude crystals of the desired compound is thus 3.1 g; Yield about 50 percent of theory.

The main product is recrystallized from hexane. 1.3 g of the pure compound of melting point 123 to 128 ^° C. are obtained; yield

21 percent the theory. 63 C. 8th H 2 N 63 .63; 8th , 51; 2 .75; C ₂₇ H ₄₃ NO ₈ ; ber .: .79; , 50; , 82. * found:

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21 4b154

Example 6
3a, 7a-trans-5,6-tran8-hexahydro-1- (5 - piperidinopentyl) -3a,

5,6, 7a-indantetrol-5, 6-diacetate hydrochloride 4 g (0.012 mol) of the 4 prepared according to Example 3a, 7a-trans-5,6-trans-hexahydro-l- (5-piperidinopentyl) ~ 3a, 5,6,7a-indante tetrol are dissolved in 70 ml of pyridine. 35 ml of acetic anhydride are added dropwise to the solution in the course of 30 minutes while cooling on an ice bath. The mixture is then stirred for about 15 hours at room temperature and then evaporated almost to dryness. The residue is dissolved in chloroform and extracted two times with a 5 percent jialium carbonate solution. The chloroform solution is then dried over magnesium sulfate. Including filtering off the magnesium sulphate, the chloroform is evaporated off at reduced pressure. An oily substance is obtained as the residue. To remove the remaining pyridine, this substance is _s treated twice with benzene, and this is in each case evaporated under reduced pressure.

The oil is then dissolved in ether and the solution filtered si.r removal of a small amount of insoluble constituents _o spell is the product by adding a solution of HCl in isopropanol precipitation. nol converted into the hydrochloride. 4 »4 g of the roliea Hydrochloride are obtained. Yield 80 percent of theory. After two recrystallizations from isopropanol / Ä'ther obtained 2 _s 05 g of the desired compound, mp. 209 to 21O ⁰ Cj yield 38 percent of theory.

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53 -
C. 8th H 3 , 03; 2 η S1 54 59 .79; 8th .73; 3 , 00. 59 .75, , 93;

^C 23 ^H 39 ^NO 6 '^HC1;

found:

Example 7

3a, 7a-trans-5 »6-trans-hexahydro-1- (3-morpholinopropyl) -3a, 5, 6,7a-indante tetrol

1- / 3- (3-indenyl) propyl7-morpholine

A solution of 23.7 g (0.1 mol) of 3,3'-bromopropylindene and 22 g (0.25 mol) of morpholine in 100 ml of toluene is refluxed for 2 hours and then cooled. The large amount of pesticides formed is then filtered off and washed with ether. The filtrate is concentrated under reduced pressure. The residue is dissolved in ether and a small amount of insoluble constituents is removed by filtration. The ether is then evaporated off and the residue is distilled. This gives 22 g of l- / 3- (3-indenyl) -propyl7-morpholine of boiling point. 152-162 G ⁰ / 0.05 Torr. Yield 90 percent of theory.

A sample of this base is converted into the hydrochloride from m.p. 192 to 194 C.

C H N 'Cl calcd .: 68.68; 7.93; 5.02; 12.67; Found: 68.92; 8.02; 5.10; 12.41.

3a, 7a-trans-5,6-trans -hexahydro-1- (3-morpholinopropyl) -3a, 5,6,7aindantetrol

A solution of 16.5 g (0.068 mol) 1/3 (3-iridenyl) -propy: L7-morpholine in 100 ml of ether is added to a mixture of 1 liter of liquid ammonia and 100 ml of ether. Within 20 minutes 25 g of lithium metal are then in the form of several partial

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amounts added. A greenish-brown mixture is obtained, which is stirred for 2 hours. Anhydrous ethanol is then added dropwise until it is discolored. 225 ml of ethanol are required and added within 2 hours. The residue obtained after the ammonia has evaporated is made up to 1500 ml with water and then extracted three times with ether. The ether extracts are dried over potassium carbonate. After evaporation of the solvent under reduced pressure | 16.6 g of an amber-colored oil are obtained; Yield 100 percent of theory. The UV spectrum of the oil shows that it does not contain any unreacted starting material. D _a g oil is identified as l- / j- ^(4,7-u ihydro-l-indanyl) -propyl7-morpliolin. 0.068 mol of this crude compound is then added dropwise to 100 ml of cold 98 percent formic acid within 15 minutes. Then 60 ml of 30 percent hydrogen peroxide are added dropwise at 20 G over the course of 40 minutes. The temperature is then allowed to rise to 35 ° C. and then kept at 30 to 35 ° C. for 3 hours with the aid of a large water bath. The mixture is then stirred on a water bath for about 15 hours and finally evaporated to almost dryness. The remaining performic acid is then removed by adding water twice and evaporating under reduced pressure.

The viscous residue is then dissolved in 75 ml of anhydrous ethanol and treated with a solution of 30 g of potassium hydroxide in 50 ml of water are added. After refluxing for 1 hour, the mixture is made up to 500 ml with water. Extraction four times with ether gives 2.3 g of a yellow oil (fraction A). The aqueous solution is then subjected to a continuous explosion

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214S154

subjected to traction with ethyl acetate. After 150 minutes are 7.3 g of substance (fraction B) extracted. After another, about

Extraction for 15 hours gives an additional 3.5 g of substance (Group C). A total of 13.1 g of product are extracted; Yield 61 percent of theory. From the ethyl acetate solution (fraction B) 5.2 g of a crystalline product are obtained which, after recrystallization from ethyl acetate, 4.2 g of the desired compound provides from m.p. 140 to 151 ° C; Yield 20 percent of the Theory.

'CHN

C ₁₆ H ₂₉ NO ₅ ; calc .: 60.93; 9.27; 4.44;

Found: 60.86; 9.03; 4.36.

Example p

• 3a, 7a-trans-5,6-trans-hexahydro-1- (3 ~ morp hQliiiQr; ropyl) -3a ₎ 3 _> 6 _> 7a-indantetrol-3a, 5,6,7a-tetraacetate

1 »5 g (0.004SHoI) of 3a, 7a-trans-5,6-trans-hexahydro-1- (3-morpholinopropyl) ~ 3a, 5,6,7a-indanetetrols prepared according to Example 7 are entered in 30 ml of acetic anhydride, - It is then about 1 ml of glacial acetic acid was added dropwise to obtain a clear solution solution is then added dropwise within 15 minutes with 3 ml of 70proaentiger perchloric acid while cooling with ice / common salt. The mixture is then held at 15 ° C. for 20 hours. Under continued cooling, 30 ml of methanol are then added dropwise over the course of 25 minutes. The mixture is then concentrated with Ammonium hydroxide made alkaline and then extracted three times with chloroform. The combined chloroform extracts are dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. 2.35 g of one are obtained

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2Hb15A

amorphous substance which, after recrystallization from hexane, yields 1.35 g of crude product with a bp. 144 to 147 ° C .; Yield 58 percent of theory. After recrystallization of the crude product from hexane ¹ , 950 mg of the desired compound with a melting point of 145 ° to 148 ° C. are obtained; Yield 41 percent of theory.

CHN C ₂₄ H ₃₇ NO ₉ ; calc .: 59.62; 7.71; 2.90;

Found: 59.89; 7.52; 2.90.

Example9

5a, 7a "tranS" 5 »6-trane-I: J ^ ahydro -» l- (3 -niorpholinoprop y.l) -3a, 5 , 6,7a-indantetrol ~ 5,6-diacetate

1.9 g (0.006 mol) of 3a, 7atrans-5,6-trans-Eexahjdro-l ~ (3-morpholinopropyl) -3a ₉ 5,6,7aindantetrols prepared according to Example 7 are dissolved in 35 ml of pyridine. The solution is 18 ml of acetic anhydride are added dropwise within 30 minutes while cooling with ice. The mixture is stirred at room temperature for about 15 hours and then evaporated to the Tioekene. The residue: is dissolved in chloroform and the solution w »

extracted three times with 5% potassium carbonate solution. The chloroform solution is then dried over magnesium sulfate, _{filtered 9} and freed from chloroform under reduced pressure. The remaining pyridine is removed by adding benzene twice and evaporating under reduced pressure. Most of the product is not soluble in 75 ml of hot benzene. 1.95 g of crystals are filtered off; Yield 81 percent of theory. After two recrystallization from acetone, 900 mg of the desired compound with a melting point of 100 to 125 ^° C. are obtained; Yield 38 percent of theory.

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2U5154

60 C. 8th H 3 N ber .: 59 , 13; 8th , 33; 3 , 51; found: .92; .45; , 53.

Example 10

2, 3a, 5-CJS-6,7-trans-hexaIydro-2-piperidino-3a, 5 , 6, 7a-indantetrol 1- (2-indanyl) -piperidine .

A solution of 79 g (0.6 mol) of ß-indanone and 100 ml of piperidine in 500 ml of benzene is made using a water trap 3 hours under reflux with 0.5 g of p-toluenesulfonic acid gel: ocht. Shortly before this time has elapsed, no more water is caught in the "trap. The solvent and excess The piperidines are then evaporated under reduced pressure. The residue is dissolved in 1 liter of anhydrous methanol.

ο ^A0 S At temperatures below 30 C, sodium borohydride is added to the solution in the form of several partial amounts. The mixture is then stirred for a further 2 hours and then treated with a small amount of acetic acid to destroy the remaining sodium borohydride. The mixture is then made strongly alkaline with sodium hydroxide solution, diluted with 250 ml v / water and freed from the bulk of the methanol under reduced pressure. The product is then extracted three times with ether. The extracts are dried over potassium hydroxide, and then the ether is evaporated off under reduced pressure. The l- (2-indanyl) piperidine obtained in this way is distilled. 107 g of the compound pass from b.p. 125 to 130 ° C./1 Torr; Yield 89 percent of theory. The connection becomes firm when standing.

A small amount of the l- (2-indanyl) piperidine is added to the hy-

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- ™ - 2H5154

hydrochloride transferred. After two urocrystallization 2-Propanol, the pure hydrochloride is obtained with a melting point of 257 Ms

259 C. C H 5 N 14th Cl calc .: 70.72; 8.48; 5 .89; 14th , 91; Found: 70.75; . 8.49; , 93; , 96. 1- (4,7-dihydro-2-indanyl) piperidine

A solution of 40.2 g (0.2 mol) of the distilled l- (2-indanyl) - ^ piperidins in 350 ml of ether is in a mixture of 2.5 liters liquid ammonia and. 250 ml of ether entered, then within 20 minutes 50 g of lithium metal in the form of several Partial amounts added. The "blue-bronze-colored The mixture is stirred for 30 minutes and then anhydrous ethanol is added until it is discolored. To be 475 ml of ethanol are required, which are added within 2 hours. The residue obtained after evaporation of the ammonia is cooled, made up to about 4 liters with water and finally extracted twice with ether. The ether extracts Dry the ground over potassium carbonate and evaporate the solvent under reduced pressure. 41 g of 1- (4,7-dihydro-2-indanyl) piperidine are obtained; Yield 100 percent of theory. : The connection becomes firm when standing. UV analysis shows that no unreacted starting material is present.

A sample of the compound is converted into the hydrobromide. After two recrystallization from 2-propanol, the pure hydrobromide is obtained with a melting point of 244 to 246 ^° G (decomposition).

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- ⁵⁹ - 2H5154

G H Ii Br calc .: 59.16; 7.80; 4.93; 28.11; Found: 59.14; 7.73; 4.87; 28.06.

2,3a, 5-cis-6 _> 7a-trans -hexahydro-2-piperidino ~ 3 ^ _> 5,6,7a ~ indantetrol

37 g (0.18 mol) of the crude 1- (4,7-dihydro-2-indanyl) piperidine prepared in the aforementioned manner are introduced in several partial amounts into 300 ml of cold 90% formic acid. 170 ml of 30 percent hydrogen peroxide are then added dropwise over the course of 1 hour at temperatures of 20 to 25 ° C. The temperature of the equipment is then allowed to rise to 35 ° C. and then ^{kept at 30 to 35 °} C. for 3 hours using a large water bath. The mixture is then stirred on a water bath for about 15 hours and then evaporated to almost dryness. The remaining performic acid is removed by adding water twice and evaporating under reduced pressure. The viscous residue obtained is then dissolved in 300 ml of anhydrous ethanol. A solution of 90 g of KOH in 100 ml of water is added to the solution. After refluxing for 1 hour, the dark brown mixture is made up to 1 liter with water. After four extractions with ether and three extractions with ethyl acetate, the total is obtained

about 32.3 g of a partially crystalline substance; Yield / 66 percent of theory. When the substance is heated with benzene and ethyl acetate, 22.4 g of a crystalline product are obtained; Yield 46 percent of theory. After two recrystallizations from 2-propanol, part of this product gives the desired compound with a boiling point of 238 to 241 ° C

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CHN calc .: 61.96; 9.29; 5.16; found 61.90; 9.28; 5.10.

Example 11

3a, 7a-trans-5,6 ~ trans-hexahydro-2-piperidino-5a, 5 _f 6,7a-indanetetrol-5,6-dibenzoate

2 g (0.0075 mol) of that prepared according to Example 10 2, 3a, 5-C1S-6, 7a-trans -hexahydr o-2-piperidino-3a, 5,6,7a-indantetrols are partially dissolved in 25 ml of pyxidine. Then be 6 ml of benzoyl chloride were added. The dark colored reaction mixture is then heated in the steam bath for 1 hour. The solvent is then evaporated off under reduced pressure and the Treated residue with saturated sodium bicarbonate solution. That Product is extracted with chloroform. After evaporation of the solvent, a dark brown viscous residue is obtained Substance based on neutral aluminum oxide (degree of activity IV) is chromatographed. The product (1.45 g; yield 41 percent of theory) is eluted with ether and from ither / petroleum ether ) recrystallized. 1 g of the desired compound is obtained Mp 146-147.5 ° C; Yield 28 percent of theory,

° 28 ^Η 33 ^1ΪΟ 6ί

found:

Example 12

2,5a, 5-CXS-6,7a-trans-hexahydro-2-piperidino-5a, 5,6,7a-indantetrol-5a, 5,6-triacetate hydrochloride .

4 g (0.0147 mol) of the 2,3a, 5- prepared according to Example 10

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C. 12; 6th H 2 N ber .: 70 12; 7th .94; 2 .92; found: 70 , 08; , 65.

2H5154

cis-6,7a-trans-Hexahydro-2-piperidino-3a, 5,6,7a-indantet'rols are partially dissolved in 70 ml of pyridine. The mixture is mixed with 35 ml of acetic anhydride within 40 minutes while cooling with ice and then stirred for about 15 hours at room temperature. The clear, amber-colored solution is then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and extracted twice with 5 percent potassium carbonate solution. The chloroform solution is dried over magnesium sulfate and filtered and the solvent is evaporated off under reduced pressure. The remaining pyridine is removed by adding benzene twice and evaporating under reduced pressure. After recrystallization from benzene / petroleum ether, 2.05 g of (23, 3aR, 5S, 6S, 7aR) -hexahydro-2-piperidino-3a, 5,6,7a-indantetrol-3a, 5,6-triacetate with melting point. 126 to 141 ⁰ C; Yield 35 percent of theory. Part of this compound is converted into the hydrochloride. After two recrystallization from isopropanol, the desired compound is obtained with a melting point of 236 to 237 ° C. (decomposition).

G H N Cl

C ₂₀ H ₅₁ NO ₇ .HCl; calc .: 55.36; 7.43; 3.23; 8.17;

Found: 55.60; 7.56; 3.32; 8.20.

Example 13

3a, 7a-trans-5,6-trans »hexahydro-2-piperidino-3a, 5,6,7a-indantetrol-5,6-diacetate and _2,3-f 5-cis-6, 7a-trans-Hexahydro ~ 2-piperidino-3a, 5,6,7a-indantetrol ~ 3a, 5,6-triacetate A mixture of 210 ml of pyridine and 105 ml of acetic anhydride is gradually added to 12.5 g (0.046 mol) of Z ^ a ^ -cis-o ^ a-trans

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2Η5Ί5Α

7a-indante tetrol added. After removing the cooling bath the solution is stirred for about 15 hours at room temperature. A Part of the solution is then evaporated to give an oil. This is mixed twice with benzene and reduced Evaporated pressure. After adding ethyl acetate, 10.34 g of 3a, 7a-trans-5,6-trans-hexahydro-2-piperidino-3a, 5,6,7aindantetrol-5,6-diacetate-hydroacetate are obtained in the form of a yellow solid substance; Yield 54 percent of theory.

Another part of the aforementioned solution is threefold Volume of methylene dichloride diluted. Filtration delivers

4.2 g of the hydroacetate of 2,3e, 5-cis-6,7a-trans-

Hexahydro-2-piperidino-3a, 5,6,7a-indantetrol-3a, 5,6-triacetate in Form of a yellow solid substance; Yield 20 percent of theory.

The corresponding base is obtained from the two hydroacetates Treatment with saturated bicarbonate solution, extraction with methylene dichloride and evaporation under reduced pressure.

From 2.95 g of the hydroacetate of 2,3a, 5-cis-6,7a-

W trans-hexahydro-2-piperidino-3a, 5,6,7a-indante trol-3a, 5,6-triacetate, 2.93 g of the crude free base are obtained.

From 7.15 g of the diacetate hydroacetate, after recrystallization from ethyl acetate, 5.33 g of the free base of melting point 126.5 to 129.5 ° C are obtained; Yield 87 percent of theory. 3.65 g of the base are recrystallized again from ethyl acetate. 2.21 g of the analysis sample with a melting point of 128 to 131 ^° C. are obtained.

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2U515A

Example 14

3a, -7a-trans-5,6-trans -hexahydr o-2-piperidino-3a ₁ 5 , 6, 7 & -indantetrol-3a, 5-diacetate

3.33 g (0.00837 moles) a ^ a ^ -ois-e ^ a-trans-hexahydro-a-piperidino-3a, 5,6,7a-indantetrol-3a, 5,6-triacetate (free base) are about 15 hours at room temperature in 850 ml of a mixture left to stand from 9 parts of methanol and 1 part of water. The solution is then evaporated and the residue, with Me thy lend i chloride recorded. The solution is vigorously washed with saturated sodium bicarbonate solution shaken. The organic layer is separated, dried over sodium sulfate and evaporated. Included the residue obtained is an oil which, after recrystallization, is obtained

Ethyl acetate 1.77 g of crude product, mp. 183 to 185 ⁰ G supplies. After repeated recrystallization from ethyl acetate, the desired compound 184.5 is obtained from Pp. To 185.5 ⁰ C.

Example 15

2,3a, 5-CJS-6,7a-trans-Hexahydro-2-piperidino-5,6,7a-indantetrol- 3a-monoethyl ester hydrochloride

A solution of 2 g of 2,3a, 5-cis-6,7a-trans-hexahydro-2-piperidino-3a, 5,6,7a-indantetrol in 800 ml of diethyl ether is mixed with 80 ml ^:

trades
Ethyl chloroformate /. A precipitate is formed in the process.

The mixture is then stirred for about 15 hours at room temperature. The precipitate (1.7 g) is filtered off. The filtrate is evaporated and the residue rubbed with acetone. There are 0.1 g of a solid substance obtained with the first Precipitation is identical.

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2H515A

The combined pesticides are then ura-.crystallized from methanol / ether. The desired connection from the Fp.

"obtained up to 194 C.

CH Ή Cl

C ₁₇ H ₃₀ NO ₆ Cl; calc .: 53.76; 7.96; 3.69; 9.33;

Found: 53.52; 8.28 ·; 3.61; 9.52.

Example 16

Hexahydro-l- / 3- (l-pyrrolidinyl) ~ propyl7-3a _t 5,6 _> 7a-indantetrol 1-ZB- (3-indenyl) -propyl7-pyrrolidine

A mixture of 35 g (u, 4 mol) 3- (3'-bromopropyl) indene, 64 g (0.09 mol) freshly distilled pyrrolidine and 400 ml toluene is

Boiled under reflux for 2 hours. On cooling, oily crystals of the pyrrolidine hydrobromide precipitate. The toluene solution is decanted and the remaining Hydrobroaiid with ether extracted. The combined organic fractions are evaporated and the oily residue, i.e. l- / 3- (3-indenyl) propylT-pyrrolidine, distilled at reduced pressure. A sample of the compound is converted into the hydrochloride of pp. 134C N Cl 8.41; 5.31; 13.44; '

8.25; 5.19; . 13.66.

l-Z3- (4,7-ßihydro-l-indanyl) -propyl7-pyrrolidine A solution of 27 g (0.119 mol) l- / 3- (3-indenyl) -propyl7-pyrrolidine in 100 ml of ether is in 2 liters liquid ammonia entered. Then 40 g of lithium metal are added in the form of partial amounts within 30 minutes. Stirring is continued for 150 minutes, after which water-

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transforms. ber .: 72 C. found: 72 .84; C ₁₆ H ₂₂ iiCl; .83;

2H515A

free ethanol is added until it becomes discolored. The ammonia 'is then allowed to evaporate and the residue then with Diluted 2.5 liters of water and extracted with ether, liach dem . Drying over magnesium sulfate, the solvent is evaporated. 26 g of 1- / 3- (4,7-dihydro-1-indanyl) propyl7-pyrrolidine are obtained in the form of an oily substance; Yield 94 percent of the

aromatic

Theory. The UY analysis shows that there is no nipht implemented / starting material is available. A sample of the pyrrolidine is converted into the hydrochloride, mp 157 ° C.

CHN. Cl C ₁₆ H ₂₆ ClN; calc .: 71.74; 9.79; 5.23; 13.24;

Found: 71.61; 9.93; 5.19; 12.13.

' Hexahydro-1- / 3- (1-pyrrolidinyl) -propyl7-3a _? 5,6,7a-indantetrol 200 ml of ice-cold 98 percent formic acid is mixed with 22 g (0.095 mol) of the l- / 3- (4-7-dihydro-l-indanyl) propyl7-pyrrolidine prepared in the aforementioned manner within 15 minutes offset. Then 115 ml of 30 percent hydrogen peroxide are added at a rate such that the temperature is kept at 20 C. The temperature of the mixture is then allowed to rise to 35.degree. The mixture is then stirred for about 15 hours at room temperature, then evaporated and finally freed from the remaining performic acid by adding water and evaporating under reduced pressure. The oil obtained as a residue is dissolved in 200 ml of 95 percent ethanol. The solution comes with a

. A solution of 60 g of KOH in 100 ml of water is added. The mixture will then boiled under reflux for 1 hour and then made up to 100 ml with water. After thorough extraction with ether

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mail receives an oil that solidifies when rubbed with ethyl acetate. After recrystallization from ethyl acetate to obtain 188 7 g of the desired compound, mp 19O ⁰ to G. Yield 31 percent of theory.

CH N

C ₁₆ H ₂₉ NO ₄ ; calc .: 64.13; 9.76; 4.68; Found: 64.09; 9.77; 4.60.

Example 17 3a, 7a-trans-5-6-trans-hexahydro-1- / B-Cl-py ^^ olid-in-yl) ~ pp ° pyl7 ~

. 3a, 5,6,7a-indantetrol-3a, 5,6,7a-tetraacetate 1 »5 g (0.005 mol) of the hexahydro-l- / 3- (l-pyrrolidinyl) propyl7-3a, 5 , 6,7a-indantetrols are dissolved in a mixture of 30 ^x ml of acetic anhydride and 0.5 ml of acetic acid. 3 ml of 70 percent perchloric acid are added dropwise to the solution while cooling with dry ice / acetone. The dark colored mixture is then kept at -15 ° C for about 15 hours. 30 ml of methanol and concentrated ammonia are then added with cooling. The product is then P extracted thoroughly with chloroform. After drying and evaporation of the solvent, a brown oil is obtained which solidifies on standing. Recrystallization from hexane yields. 1.07 g of the desired compound, mp 146-147 ° C; Yield 48 percent of theory.

CHNC ₂₄ H ₃₇ NO ₈ ; calc .: 61.65; 7.98; 3.00;

Found: 61.43; 7.99; 2.85.

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Example 18

A mixture of 5 ml of pyridine, 1.5 ml of benzoyl chloride and 0.6 g 3a, 7a-trans-5,6-trans-hexahydro-1- / 5- (1-pyrrolidinyl) -propyl7-3a, 5,6,7a-indantetrol (prepared according to Example 16) is heated in a steam bath for 1 hour. The after evaporation of the excess The residue obtained from the solvent is treated with saturated sodium bicarbonate solution. The mixture is then with Chloroform extracted. The residue obtained after drying and evaporation is chromatographed on neutral aluminum oxide (degree of activity IV). Three fractions are obtained. The third fraction is recrystallized twice from ether. It becomes 3a, 7a-trans-5,6-trans-hexahydro-1- / 3- (1-pyrrolidinyl) -propyl / -3a, 5,6,7a-indane tetrqI-5,6-dibenzoate obtain.

CHN
calc .: 70.98; 7.35; 2.76; Found: 70.80; 7.37; 2.73.

Example 19

3a, 7a-tran3-5,6-trans-hexahydro-2- (2-piperidinoethyl) ~ 3a, 5,6 _> 7a ^ · indantetrol

2-indanethanol

In a suspension of 5 g of lithium aluminum hydride in 200 ml of water

while stirring vigorously Anhydrous ether becomes within 90 minutes / a solution of 17.5 g (0.1 mol) of 2-indanylacetic acid in 500 ml of anhydrous ether dripped in. The mixture is stirred for 2 days at room temperature, then cooled and then with 100 ml of water dropwise . and then treated with 200 ml of 2 η sulfuric acid. the The ether layer is then separated. The aqueous layer becomes

2 0 9 812/18 7 5

2H5154

again extracted with ether. The combined ether extracts .werden dried over magnesium sulfate, and evaporated under reduced pressure "is obtained 16 g of 2-Indanäthanol as an oil;.. Yield 98 percent of theory ^ -JfJ ^{'film 54O} ° ⁰ ^ ¹ (° ~ ^H) ·

p-Toluenesulfenic acid ester of 2-indanethanol 16.2 g (0.085 mol) of p-toluenesulfonic acid chloride are added dropwise with stirring with 12 g (0.074 mol) of 2-indanethanol. 12 ml of pyridine are added dropwise to the mixture in the course of 25 minutes while cooling with ice. The mixture is then kept at low temperature for 4 hours, then acidified and extracted with 600 ml of ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. This gives 19.4 g of a yellowish-white solid of mp. 59 to 65 ⁰ Cj yield 84 percent of theory. After recrystallization from ether, 18 g of the p-toluenesulfoic acid ester of 2-indanethanol are obtained in the form of white crystals with a melting point of 75.5 to 78.5 ° C .; Yield 77 percent of the

Theory. ^ -Sujol ¹⁴²⁰ " ¹³³ ° ^cm » ¹²⁰ ° " ^{1145 cm} (sulfonate), Τ CDCl ^ 8.4 (Ar-CH ₃ ), 7.4 - 9.5 (-CH ₂ -, -CH-) 5, 7 - 6.1 (-CHp- adjacent to -OSO ₂ - / V-CH ₃ ), 1.8 -3 (aromatic protons).

^G 18 ^H 20 ° 3 ^S:

1- / 2- (2-indanyl) ethyl7-piperidine

A solution of 18 g (0.057 mol) of the p-toluenesulfonic acid ester of 2-indanethanol in 100 ml of toluene is mixed with 14 ml (0.143 mol) of pyperidine. The mixture is 11.5 hours under re-

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68 C. 6th H ber .: 68 , 46; 6th .54; found: , 33; , 37.

The organic layer is separated off, washed with water, dried over magnesium sulphate and evaporated under reduced pressure. A dark-colored oil is obtained, which is treated with ethereal hydrochloric acid 15.7 g of 1- / 5- (2-indanyl) -ethyi7-piperidine hydrochloride are obtained, yield 57 percent of theory After recrystallization from ethanol / ether, 11.5 g of gray-white crystals of melting point 204.5 ° to 207 ° are obtained C; Yield 72 percent of theory; Λ ^ ίόΐ ²⁷⁰ ° ~ ²²⁵ °

CHN C ₁₆ H ₂₃ N.HCl; calc .: 72.30; 9.10; 5.28;

Found: 72.28; 9.22; 5.18.

3a, 7a-trans-5 ₁ 6-trans-hexahydro-2- (2-piperidinoäthy1) -3a, 5,6,7 aindantetrol

a) Birch-Hückel hydrogenation

A solution of 7.8 g (0.03 mol) of 1- / 2- (2-indanyl) ethyl-7-piperidine in 100 ml of anhydrous ether is stirred into a mixture of 1 liter of liquid ammonia and 100 ml of anhydrous Ether entered. Then 12 g (1.75 gfamfiatom) lithium metal are added within 15 minutes. The received bronze-blue mixture is stirred for 105 minutes. Afterward 175 ml of anhydrous ethanol are added dropwise to decolorize. The solvent is then left for about 15 hours allowed to evaporate. The residue is cooled ^, and with ice water made up to 1500 ml. The aqueous mixture is then extracted three times with 400 ml of ether each time. The combined ether extracts are dried over magnesium sulphate and

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evaporated under pressure. 5.2 g of 1- / 2- (4,7-dihydro-2-indanyl) ethyl7-piperidine are obtained in the form of an oil (crude product); Yield 66 percent of theory; Λ jj ^ * film I65O a ".

b) hydroxylation

5 g (0.02 mol) of 1- / 2- (4,7-dihydro-2-indanyl) ethyl-7-piperidine are added dropwise to 100 ml of cold 90% formic acid over the course of 15 minutes. The mixture is treated with a 30prozentigem so sized speed with 13 g (0.12 mol) of hydrogen peroxide, that the temperature is maintained at 20 ⁰ G. The temperature is then allowed to rise to 30.degree. The solution is then stirred in a water bath for about 15 hours. The mixture is then evaporated to dryness and the last traces of performic acid are removed by adding water and evaporating under reduced pressure. The crude oil is then cooled in an ice bath and a solution of 7 g of potassium hydroxide in 50 ml of water is added dropwise so that the temperature does not exceed 20 ° C. The mixture is then stirred at 45 ° C. for 30 minutes. It is then extracted with chloroform, washed with water / water, dried over magnesium sulphate and evaporated under reduced pressure. 2 g of the crude desired compound are obtained in the form of a white solid substance

Yield 30 percent of theory. of melting point 136 to 145 ° C. -After two recrystallizations Ethyl acetate gives 0.84 g of the pure compound in the form of white crystals with a melting point of 174 ° to 175 ° C .; Yield I4 percent of the

Theory; λ £ ui ίόΐ ³⁵ °° ~ 3400 cm ^L (OH). N C. H 4.68; C ₁₆ H ₂₉ NO ₄ ; ber .: 64, 18; 9.76; 4.61. found: 64, 12; 9.65;

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Example 20

Hexahydro-2- (2-piperidinoethyl-3a, 5 , 6,7a-indante tetrol acetic acid esters

A solution of 5 g (0.016 mol) cooled with ice / common salt 3a, 7a-trans-5,6-trans-hexahydro-2- (2-piperidinoethyl) -3a, 5,6,7aindantetrol in a Geraisch of 80 ml of acetic anhydride and

while cooling rc it egg / table salt

10 ml of glacial acetic acid is added dropwise / with 80 ml of 70% perchloric acid. The dark colored solution is 17 hours kept at -15 ° C. 80 ml of methanol are then added dropwise to the cooled mixture. The solution is concentrated with Ammonium hydroxide made alkaline. The aqueous layer is extracted with chloroform, dried over magnesium sulfate, and dried evaporated at reduced pressure. 5.3 g of solid crude product are obtained; "Yield 68 percent of theory. After recrystallization

white crystals

cation from ether / pentane gives 3.4 g / of the desired compound with a boiling point of 155 ° to 157 ° C .; Yield 44 percent of theory; ο! 1735 cm ^-1 (C = O).

CHN; calc .: 61.65; 7.98; 3.00

Found: 61.90; 7.72; 3.05

Example 21:

trans- 3a, 7a-trans-5, S- / Hexahydro-l- ^ 4- (l-methyl-2 ~ piperidyl) -butyl7-3a , 516,7a-indantetrol 2 -. / Ä- (Inden-3- yl) -butyl7-p.yridine

Sodium amide is produced by adding several portions of 25 g of sodium to 1 liter of liquid ammonia containing traces of Fe (NOO ^. 9H ₂ O. Then, within a few minutes, 186 g (2 mol) of 2-picoline are added dropwise. That

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"The blood-red colored mixture is stirred for 10 minutes. Then

In ether, a solution of 119 g (0.5 mol) 3- (3 ^l -bromopropyl) indene / is added as quickly as possible. The dark brown mixture obtained is stirred for 1 hour and then mixed with 125 g of ammonium chloride in the form of several partial amounts. 500 ml of ether are then added to the gray-colored mixture and the ammonia is evaporated off. The pests are filtered off and washed with ether. The filtrate is evaporated under reduced pressure. Distillation of the brown oil obtained gives 57.4 g of 2- / 4- (inden-3-yl) -butyl7-pyridine in the form of a yellow oil with a boiling point of 154 to 156 ° C./0.1 torr; Yield 46 percent of theory.

2- / Ä- ( 1-indanyl) butyl7-piperidine

A solution of 50 g (0.2 mol) of the aforementioned pyridine derivative in 150 ml of glacial acetic acid, 1 g of platinum oxide is added and the mixture is 5.5 hours shaken while heating to 40 C in a hydrogen atmosphere. The hydrogen pressure is up to about 3.85 kg /

cm. During the last two hours there was no significant hydrogen uptake. The mixture is then filtered and the acid evaporated under reduced pressure. The residue is dissolved in water, the solution is made alkaline and the product is extracted with ether. Provides the distillation of the ether extract 52.8 g of 2-Z4 (l-indanyl) -buty 7-piperidine of boiling point 144 to 146 ⁰ C / 0.2 Torr in the form of an oil!.; Yield 82 percent of theory.

N-Methy1-2- / 4- (1-indanyl) -butyl7-piperidine

42.8 g (0.166 mol) of the 2- / 4- (l-indanyl) -butyl7-piperidine prepared in the aforementioned manner are mixed with 100 ml of 37 percent strength Formaldehyde solution mixed. The mixture is with 200 ml

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- 7 ^Ύ > -

2Η515Α

98 percent formic acid added. The solution obtained .is then heated in the steam bath for about 15 hours. Afterward' the solution is evaporated under reduced pressure. The residue is dissolved in water and the solution made alkaline and extracted with ether. The ether extracts are dried over NaOH. The distillation gives 36 g of N-methyl-2- / 4- (1-indanyl) -butyl7-piperidine from bp 149 to 152 ° C / 0.3 torr; Yield 80 percent of theory. ·. ·>.

3a, 7a-trans-5 »6-trans-hexahydro-1- / A- (1-diethyl-2-piperidyl) -butyl7-3a, 5 , 6, 7a-inaaix.totrol

A solution of 15 g (0.057 mol) of the N-Methy 1-2- / 71- (l-indanyl) -butyl7-piperidine obtained in the above procedure in 100 ml Ether is added to a mixture of 1 liter of liquid ammonia and 100 ml of ether. After that, within 15 minutes 20 g of lithium metal were added in the form of several partial quantities. That bluish-bronze colored mixture is stirred for 75 minutes. Afterward anhydrous ethanol is added dropwise until it is discolored. 400 ml of ethanol are required, which is within 2 hours to be added. The residue obtained after evaporation of the ammonia is made up to 1500 ml with water and then extracted twice with ether. The combined ether extracts are dried over potassium carbonate and the solvent is evaporated under reduced pressure. 15.5 g of 1- / 3 - (1-methyl-2-piperidyl) -butyl7-4,7-dihydroindane are obtained in the form of a Oil; Yield 100 percent of theory. The UV analysis shows that the product does not contain any unreacted starting material.

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0.057 mol of the crude compound are then added dropwise to 100 ml of cold 98 percent formic acid over a period of 15 minutes. Then are added dropwise 57 g 30prozentiges hydrogen peroxide within 30 minutes while maintaining a temperature of 20 ⁰ G. The temperature is then allowed to rise to 35 ° C. and kept at 30 to 35 ° C. for 5 hours using a large water bath. The mixture is then stirred for about 15 hours and then evaporated to almost dryness. The remaining performic acid is removed by adding "water" twice and evaporating under reduced pressure.

v "skose

The residue is dissolved in 100 ml of anhydrous ethanol. The solution a solution of 30 g of KOH in 50 ml of water is then added. The mixture is refluxed for 1 hour, then cooled and made up to 500 ml with water. After three times Ether extraction gives 10.5 g of a brown oil; Yield 54 percent of theory. From an ethyl acetate / ether solution 1.9 g of the crystalline tetravalent alcohol are then left to stand for 5 months at temperatures below 0 C. obtain; Yield 10 percent of theory. The alcohol can easily be recrystallized from ethyl acetate. One obtains: 1.55g of the desired compound, bp 152-155 ° C; yield

7th percent the Theory. C. H N 10; .82; 10.55; 4, 88 ber. : 66 .88; 10.43; 3, found : 66

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Example 22

3a, 7a-trans-5,6-trart5-kexahydro-l- / 2- (l-methyl-2-piperidyl) - ethyl 7-3a, 5,6,7a-indante tetrol

3- / 2- (2-pyridyl) ethyl / indene

The connection is made in that of Dressler and Kurland, J.O.C, Volume 29 (1964), on page 175 described V / eise produced.

A mixture of 500 g of indene and 5 g of potassium tert-butoxide is

with stirring _o using nitrogen as protective gas / heated to 130.degree. Then 220 g (2 mol) of 2-vinylpiperidine are added dropwise over the course of 1 hour. The mixture is kept at temperatures of 135 to 145 ° C. during the addition and for 2 hours afterwards. The mixture is then cooled, mixed with 25 ml of acetic acid and filtered. A flash distillation gives 395 g of crude product with a boiling point of 160 to 175 ° C./0.3 Torr, yield 84 percent of theory. After another distillation, 353 g of 3- / 2- (2-pyridyl) ethyl7-indene are obtained ^{in the} form of an oil with a boiling point of 135 ° to 140 ° C./0.1 Torr; Yield 75 percent of theory.

1- / 2- (2-piperidyl) ethyl7-indane

A solution of 44.2 g (0.2 mol) of the above derivative indene in 150 ml of glacial acetic acid is treated with 1 g of platinum oxide and shaken in a hydrogen atmosphere under heating at 50 ⁰ C. The hydrogen pressure is up to about 3.85 kg / cm. The reduction is complete after 7.5 hours. 45 g of 1- / 2- (2-piperidyl) ethyl7-indane are obtained; Yield about 100 percent of theory.

N-methyl-1- / 2- (2-piperidyl) ethy! / - indane

45 g of the l- / 2- (2-piperidyl) ethyl7-indane obtained in the aforementioned manner are mixed with 100 ml of 37 percent formaldehyde solution

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. mixed. 98 percent formic acid is added to the mixture while stirring and then left to stand on the steam bath for about 15 hours. The mixture is then evaporated under reduced pressure. The residue is dissolved in water and the solution filtered, made alkaline and extracted with ether. The ether extracts are dried over KOH. The residue obtained after evaporation of the ether is distilled . This gives 42.6 g of N-methyl-l- / 2- (2-piperidyl) -äthyl7-indan Kp from 128 to 13O ⁰ C / 0.2 Torr;. yield 88 percent of theory.

W Yes, 7 & ~ trans-5,6-ϊτeJlL, - ^ l ^ AaiΎyάro-l- / l>. ~ (L-me ■ bhyl ~ 2- ■ pll3eτldyl) -ä ■ thy'iJ-3a ■ _} 5> 6,7a-indante tetrol

A solution of 15 g (0.06 mol) of N-Methy1-1 / 2- (2-piperidyl) -äthyl7-indane in 100 ml of ether is added to a mixture of 1 liter of liquid ammonia and 100 ml of ether. Then 20 g of lithium metal are added in several partial amounts over the course of 15 minutes with stirring. After 45 minutes, anhydrous ethanol is added dropwise until the blue color disappears. This requires 400 ml of ethanol, which are added k within 150 minutes. The ammonia is then evaporated and the residue is made up to 1500 ml with water and extracted twice with ether. The ether extracts are dried over potassium carbonate. When the ether is evaporated off under reduced pressure, 15.6 g of l- / 2- (l-methyl-2-piperidyl) ethyl7-4,7-dihydroindane are obtained in the form of an oil. The UV analysis shows that the product is still around. Contains 10 percent aromatic compounds. The raw product will. then within 15 minutes in 100 ml of cold 98 percent Amei-. sensic acid dripped in. Then within 30 minutes at 2O ⁰ C 57 g (about 0.5 mol) of 30 percent hydrogen per-

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oxide added dropwise. The temperature is then allowed to rise to 35 ° C and then for 3 hours using a large water bath held at 30 to 35 ° C. The mixture is then stirred for about 15 hours and subsequently evaporated to almost dryness. The remaining performic acid is removed by adding water twice and evaporating under reduced pressure.

The viscous yellow oil obtained is dissolved in 100 ml of anhydrous ethanol. The solution is mixed with a solution of 30 g of KOH added in 50 ml of water. The mixture is then refluxed for 1 hour. The dark brown solution is made up with water

filled up
500 ml / and extracted three times with ether. The ether extracts provide a product amount of 10.5 g; Yield about 56 percent of theory. From an ethyl acetate / ether solution of the product separate after standing for two months at temperatures

ο
below 0 C 1.5 g of crystals from. After recrystallization from ethyl acetate, 1.1 g of the desired compound with a melting point of 143 ° to 153 ° C. are obtained; Yield 5.9 percent of theory "

CHN C ₁₇ H ₃ NO ₄ calc .: 65.14; -9.97; 4.47; Found: 65.09; 9.90; 4.28.

Example 23 I-ZJ- (Dimethylamino) 7-3-propylindene

A mixture of 300 g sodium hydroxide, 300 ml of water and 30 ml .One 40 per cent solution of Triton B ^ in methanol is heated with rapid stirring at 50 ⁰ C. The mixture is .then within 1 hour in the form of portions with a mixture of 232 g (2 mol) of indene and that of 264 g (1.6 mol)

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- 70- -

2U5154

) ^ Cl.HGl prepared free base (about 164 g) added. The temperature is kept at 55 to 60 ° C. during this process. The resulting green-colored mixture is contributed 4 hours 60 ⁰ C stirred, cooled, diluted with 1.5 liter V / diluted ater and extracted three times with 400 ml of ether. The combined ether extracts are washed with a mixture of 180 ml of concentrated hydrochloric acid and 600 ml of water. The aqueous phase is separated off, made alkaline with sodium hydroxide solution (100 g NaOH / 300 ml H ₂ O) and extracted three times with 300 ml ether each time. The combined ether extracts are washed with water and saturated sodium chloride solution and finally ψ gewascnen. When the solvent is evaporated, 182 g of a brown colored oil are obtained. In the distillation, a low boiling and then forward 102 88 g of the desired compound, bp. 93 ° C / O, O5 Torr.

Example 24

1- (1-indanyl) piperidine

A solution of 100 g (0.758 mol) of 1-indanone and 125 ml of piperidine in 750 ml of toluene is heated with 0.5 g of p-toluenesulfonic acid for 48 hours using a water trap. The residue obtained after separating off the solvent and excess piperidines under reduced pressure is dissolved in 1500 ml of anhydrous methanol. Into the solution 50 g of sodium borohydride in the form of subsets are .eingetragen below 30 ⁰ C with stirring. After stirring for several hours, the mixture is mixed with a small amount of acetic acid and then made strongly alkaline with sodium hydroxide solution. Then 400 ml of water are added. The ^ main amount of methanol is then at

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evaporated under reduced pressure. The product is extracted with ether, dried over potassium hydroxide and distilled. 119.7 g of the desired compound with a boiling point of 101 to 102 ^° C. / 0.2 Torr are obtained.

Example 25

l- (l-tetrahydronaphthyl) piperidine

(a)! piperidino-3, 4-dihydronaphthalene

Piperidine A solution of 146 g (1 Hol) Tetraliydronaphthalin-i-pn and "150ml / 1 g of p-toluenesulfonic acid is added to 1 liter of toluene and 11 '^ age under reflux and using a water trap heated. 13 »1 ml of water are collected. The fractional Distillation gives 105.3 g of 1-piperidino-3,4-dihydr onaphthalene b.p. 118 to 120 ° C / 0.2 Torr.

(b) 1- (1-tetrahydronaphthyl) piperidine

In a solution of 40 g of the prepared in the aforementioned manner l-Piperidino-3,4-dihydronaphthalene in ether becomes hydrogen chloride gas initiated. The precipitated hydrochloride is quickly filtered off to prevent hydrolysis by moisture. The hydrochloride is then dried over potassium hydroxide in a vacuum desiccator. The thereby obtained white powder is added in the form of partial quantities to an ether suspension of excess lithium aluminum hydride. To Stirring for 1 hour, the excess hydride is separated by carefully adding dropwise potassium carbonate solution until forms a granular white precipitate. The precipitate is filtered off and the filtrate is concentrated. This gives an oil that at fractional distillation. 25 g l- (l-tetrahydronaphthyl) -

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piperidine of bp 102-1O6 ° C / 0.3 Torr provides.

Example 26

3a, 7a-trans-5,6-trans-1- / 3- (Dimethylarnino) -propyl7-iiexahydro- · 5a, 5 t 6,7a-indantetrol

(a) HNN-dimethylindene - ^ - propylamine

The amine is described by M. Makosza, Tet. Letters, Volume 38

(1966) on page 4621.

A mixture of 232 g (2 mol) indene and that of 264 g (1.6 mol) 3-dimethylaminopropyl chloride hydrochloride produced free Base is converted into a mixture of 300 g (7.5 mol) of sodium hydroxide within 1 hour in the form of partial amounts with rapid stirring. 300 g of water and 300 ml of a 40 percent solution

entered by Triton B ^ in methanol. the

The temperature at the start of the addition is 50 ° C. and the rate of addition is regulated in such a way that temperatures of 55 to 60 C are maintained. The green colored mixture then becomes Stirred for 4 hours at 60 ° C., cooled, diluted with 1500 ml v / ater and extracted with ether. The ether extract is in turn jiiit a solution of 180 ml of concentrated hydrogen chloride extracted off acid in 600 ml v / water. The aqueous phase will . separated, made alkaline with 100 g of sodium hydroxide and with. Ether extracted. Evaporation of the solvent gives . 182 g of a brown oil which, on distillation, yields 102 g of an oil with a boiling point of 88 to 93 ° C./0.5 Torr. With repeated Distillation gives 19.6 g of a product with a boiling point of 87.5 to 89.5 C / 0.05 Torr and 71.1 g of a second product from B.p. 89.5 to 90 ° C / O, 0.5 torr.

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(b) 4,7-dihydro-N, N-dimethyl-1-indanpropylamine

A solution of 35 g (0.174 moles) of N, N-dimethyl indene-3-propylamine 125 ml of ether are added to 2 liters of liquid ammonia. Then within 1 hour "at the reflux temperature 44 g (6.3 gram atom) lithium metal added. After a total of 3 hours the mixture turns blue. 550 ml of ethanol are then added over the course of 135 minutes, the blue color disappearing. The ammonia is then allowed to evaporate for about 15 hours and the residue is dissolved in 1500 ml v / water and extracted twice with ether. The ether extract is dried and freed from the solvent. There are 34.5 g of the raw amine obtained; Yield 98.6 percent of theory. That

approximately

Nuclear magnetic resonance spectrum shows that the product contains ⁷ IO percent of the corresponding aromatic compound.

(c) 3a, 7a-trans-5> 6-trans-1- / 3- (dimethylamino) -propyl7-hexahydro-3a, 5,6,7a-indante petrol

34.5 g (0.172 mol) of 4,7-dihydro-N, N-dimethyl-1-indanpropylamine are added dropwise to 300 ml of formic acid while cooling with ice. The solution obtained is then ^{heated to 15 °} C. and then 150 ml of 30 percent hydrogen peroxide (about 1.5 mol of H2O2) are added over the course of 1 hour, the temperature being kept below 20 ^° C. The mixture is ^{then warmed to 30 °} C. for 1 hour and then stirred at room temperature for about 15 hours. Then 200 ml of water are added. Then 300 ml of the solvent are evaporated off under reduced pressure. The addition of water and evaporation of the solvent are repeated until 1400 ml of solvent have passed over. All the solvent is then evaporated off. One receives a

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. Oil which is refluxed for 1 hour with a solution of 80 g of potassium hydroxide in a mixture of 300 ml of ethanol and 150 ml of water / water. The mixture is then cooled, diluted with 200 ml v / water and concentrated to 300 ml. This procedure is repeated three times. The final volume is adjusted to 700 ml with water, and the solution is extracted with ether and chloroform (8 × 150 ml). 14.6 g of an oil are obtained from the chloroform extract, which solidifies when rubbed with 60 ml of ethyl acetate. The solvent is decanted and the pesticide is recrystallized three times from itnylacetat. 3. V g of the desired compound (c) of melting point 136 to 138 ^° C. is obtained.

CHN C ₁₄ H ₂₇ NO ₄ ; calc .: 61.51; 9.96; 5.12;

Found: 61.50; 9.84; 5.09.

Example 27

3a, 7a-trans-5,6-trans ~ l- / 3- (Dimethylamino) -propyl7-hexahydro-3a, 5,6 _> 7a-indanetetrol-acetic acid ester (1: 4)

3.6 g (0.0132 mol) of finely ψ powdered 3a, 7a-trans-5,6-trans-1- / 3- (dimethylamino) -propyl7-kexahydro-3a, 5,6 prepared according to Example 26 , 7a-indantetrol are stirred with a mixture of 60 ml of acetic anhydride and 2 ml of acetic acid until the compound dissolves. The solution is cooled with 2 dry ice / acetone and treated with 4.5 ml of 70 percent perchloric acid. The mixture is then allowed to stand for about 15 hours at -15 ⁰ C, cooled with ice / acetone and treated within 30 minutes with .35 ml of methanol .. The temperature of the mixture is kept below -10 ⁰ C. The resulting solution is then in a

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cold mixture of 100 ml of concentrated ammonium hydroxide and Poured 200 ml of ether. The ether layer is separated, with V / ater and saturated saline solution gev / ash, dried and evaporated. I-Ian receives 5.6 g of the crude product; 95 percent yield theory, two recrystallization from hexane / Ethyl acetate gives 3.21 g of the pure desired compound with a melting point of 169 to 17O.5 ° C.

59 C. 7th H 3 , 17; ber .: 59 .84; 8th .99; 3 , 09. " found: .59; , 22;

Example 28

3a, 7a-trans-5 _> 6-trans-hexahydro-1 ~ (3-aminopropyl) ~ 3a _> 5,6 _> 7aindantetrol

(a) 4,7-Dihydro-1-indanpropylamine hydrochloride A solution of 14 »6 g of lithium aluminum hydride in 1 liter of anhydrous ether is gradually stirred with a solution of 61.4 g (0.379 mol) using nitrogen as protective gas. Indene-3-propiononitrile was added to 500 ml of anhydrous ether. The mixture is stirred for about 15 hours in a nitrogen atmosphere and then gradually mixed with stirring with 14.6 ml v / water, 14.6 ml 15 percent sodium hydroxide solution and a further 43.8 ml water. The precipitate is filtered off and washed with ether. When the ether is evaporated, 61.4 g of indene-3-propylamine are obtained; Yield 95 percent of theory.

A solution of 61.4 g (0.356 mol) of indene-3-propylamine in a mixture of 2 liters of liquid ammonia and 175 ml of anhydrous Ether is mixed with 29.4 g of lithium metal within 1 hour.

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. The mixture is stirred for 1 hour and then within. mixed with 340 ml of anhydrous ethanol for 150 minutes. the The solution turns white. The ammonia is then allowed to evaporate for about 15 hours. The residue v / ird dissolved in 1 liter of water and the solution extracted with ether. Of the . Ether extract is dried twice over sodium sulfate and evaporated. 62 g of 4,7-dihydro-1-indanpropylamine are obtained, yield 92 percent of theory.

A solution of 15 g of 4,7-dihydro-1-indanpropylamine in 70 ml of 2-propanol is mixed with a solution of hydrochloric acid in '2-Propanol acidified. Then ether is added and the precipitate is filtered off. 18 g of crude 4,7-dihydro-lindanpropylamine hydrochloride are obtained. (quantitative yield). 5 g of the crude product are recrystallized from 2-propanol and ether. 1.1 g of the pure compound with a melting point of 114 ° to 115 ° C. are obtained.

CHH Cl C ₁₂ H ₂₀ NCl; calc. 67.43; 9.43; 6.56; 16.59;

Found: 67.27; 9.64; 6.47; 16.37.

(b) N-'Z3- (4,7-Dinydro-1-indanyl) -propyl7-2 _> 2 _> 2-trifluoroacetamide A solution of 15 g (0.085 mol) 4,7-dihydro-1-indanpropylamine: in 255 58.3 g of sodium carbonate are added to ml of anhydrous ether while stirring. The mixture is within 90 minutes with stirring and cooling with 100 g (0.477 mol) of trifluoro-. acetic anhydride added. The cooling bath is then removed and. the mixture was stirred vigorously for 30 minutes. Then it will be. Pour mixture into 400 ml of chloroform and add ice. The mixture is then shaken with water for 20 minutes.

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The organic layer is separated, dried over sodium sulfate and evaporated. The crude compound (b) is obtained in quantitative yield. 5 g of the crude product are made from hexane recrystallized. 1.6 g of the pure compound are obtained

(b) from Pp. 61 Ms 62 ⁰ C.

CHN Έ - C ₁₄ H ₁₈ NOF ₅ ; calc .: 61.53; 6.64; 5.12; 20.86;

Found: 61.29; 6.64; 5.05; 20.60.

(c) 3a, 7a-trans-5,6-trans -hexahydro-1- (3-aminopropyl) -3a, 5> 6,7aindantetrol

The compound (b) is converted into the tetrol (c) analogously to the process described in Example 2.

Example 29

^ a, 7a-trans-5 «6-trans-hexahydro-1- (3- (benzamidο) -propyl) -3a, 5-6,7a-indantetrol

(a) N- / 3- (4i7-dihydro-1-indanyl) -propyl7-benzamide A solution of 7 g (0.0396 mol) 4,7- ^ ihydro-1-indanpropylamine in 100 ml pyridine is at ^{0 0} C. 10 ml of benzoyl chloride were added within 15 minutes. The solution is then left to stand at 0 ° C. for about 15 hours. Then ice and water (about 400 ml) are added. The precipitate is filtered off, washed with water and then dissolved in methylene dichloride. The solution is washed with 10 percent sulfuric acid and then with water. The organic layer is dried over sodium sulphate and evaporated. 9.5 g of the crude compound (a) are obtained; Yield 85 percent of theory.

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2.6 g of the crude product are recrystallized twice from methylene dichloride and hexane. This gives 1.4 g of the pure compound; mp. 112.5 to 113.5 ⁰ C.

81 C. H 24; 4th if ber .: 81 , 10; Ö, 14; 5 , 98; found: .05; 8th, , 20.

(b) 3a, 7a ~ trans-5,6-trans-hexahydr0-1- / 3-0-enzamido) -propyl7-3a, 5,6,7a-indantetrol

The compound (a) is converted into the tetrol (b) analogously to the process described in Example 2.

Example 29 a

5,6-trans-4,5,6,7-tetrahydro-2-piperidino-5,6-indanediol A solution of 50.5 g (0.25 mol) 4,7-dihydro-1-indanylpiperidine in 1 liter Freshly removed anhydrous acetic acid is treated with 83.5 g (0.5 mol) of anhydrous silver acetate using nitrogen as the protective gas. The suspension is then admixed with stirring with 62.75 g (0.25 mol) of iodine in the form of partial amounts over the course of 30 minutes. The mixture is then heated to 90 to 95 ^° C. for 3 hours with stirring, then cooled, filtered and evaporated to dryness. The residue is 5,6-trans-4,5,6,7-tetrahydro-2-piperidino-5,6-indanediol diacetate. The compound is dissolved in 250 ml of methanol and the solution is treated with 50 ml of 50 percent sodium hydroxide solution while stirring. After stirring for about 15 hours, the solution is diluted with water / water and the reaction product is extracted with chloroform. The extract is dried and freed from the solvent. The crude product is taken up in hot isopropanol.

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With the addition of ether a cloudiness forms. It will Received 25 g of a first product. Further product fractions (12 g) are obtained in the work-up. The overall yield of the 149 to 167 C / Melting product is 63 percent of theory. The IR analysis shows that no cis isomer is present is. After two recrystallization of 6 g 'of the first product from benzene you get 2-, 8 g of the pure compound from Pp 156-157.5 ° C.

CHN C ₁₄ H ₂₃ IiO ₂ ; calc .: 7Π.85; 9.77; 5.90;

Found: 70.66; 9.75; 5.94.

The indanediol can be converted to the corresponding tetrol, i.e. 3a, 7a-trans-5, δ-trans-Hsxahydro-1-piperidino- ^ a, 5,6,7a-indantetrol (General formula I a) can be converted by reacting it according to Lieis] iel 2 with formic acid and hydrogen peroxide and the composition is saponified with a base. ~

Example 30

3a, 7a-trans- b , 6-trans-Hexahydro-2 ~ piperidino-3a, 5,6,7a-indantetrol (corresponds to formula Ib)

HO-

trans

trans

(diequatorial) (diaxial) The compound is analogous to the method described in Example 2

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- 08 -

de by reacting 5 »6-trans-4,5,6,7-tetrahydro-2-piperidino-5,6-indanediol diacetate produced with formic acid and hydrogen peroxide and hydrolysis of the reaction product with a base.

Example 31

5,6-CJS-4, 5 1 6,7-tetrahydro-2-piperidino-5, 6-indanediol A solution of 10.1 g (0.05 mol) of 4,7-dihydro-1-indanylpiperidine in 250 ml of acetic acid are mixed with 5 ml of water. The mixture is then treated with 16.7 g (0.1 mol) of silver acetate using nitrogen as the protective gas. The mixture is then admixed with 12.55 g (0.05 mol) of iodine in partial amounts with vigorous stirring. Then the mixture is heated for 3 hours under nitrogen at 9O ⁰ G. After cooling to room temperature, the silver iodide formed is filtered off and washed out with acetic acid. The solvent is evaporated from the combined filtrates. The 5,6-C1S-4,5,6,7-tetrahydro-2-piperidino-5,6-indanediol-6-monoacetate obtained as residue is taken up in 100 ml of methanol. The solution is treated with 25 ml of 50 percent sodium hydroxide solution, stirred for about 15 hours and finally diluted with water. The reaction product is extracted with chloroform. After drying and evaporation of the solvent, the product crystallizes out on standing. 8.5 g of the crude product are obtained which, after previous softening, melts at temperatures from 162 to 16 ° C. By two-fold recrystallization of the crude product of 5 g from benzene to obtain 2.5 g of the analysis sample which sinters at 142 ⁰ G, and melts at 156-168 ⁰ C.

209812/187 5

- 09 -

^c 14 ^il 23 ^li0 2 '

C 70,

H 9.77;

N
5.90;

found

70.94; 10.04; 5.81.

Example 32

5a, 7a-trans-5,6-cis-hexahydro ~ l-piperidino-5a, 5,6,7a-indantetrol (corresponds to formula Ic)

ice (equatorial-axial)

trans (diaxial)

The connection is analogous to the procedure described in Example 2 by reacting the indanediol from Example 31 or its diacetate with formic acid and hydrogen peroxide and hydrolysis of the reaction product produced with a base »

Example 33

3a, 7a-eis-5,6-trans-hexahydro-2-piperidino-3a, 5 »6,7a-indantetrol (corresponds to the general formula I d)

OHH O--

HO '

trans

(diequatorial or diaxial)

ice (equatorial-axial)

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There are 3.21 g (0.01 mol) of 5,6-trans-4,5,6,7- ^f i'etrahydro-2-piperidino-5,6-indanediol diacetate (prepared according to Example 29 a) in 100 ml a mixture of 75 percent benzene and 25 percent pyridine dissolved. The solution is treated with 1.4 g (0.01 mol) of osmium tetroxide. The mixture is then left to stand for 3 to 4 days at room temperature, then ^{cooled to 5 to 10 °} C. and finally saturated with hydrogen sulfide gas. The precipitate formed is filtered off and washed with benzene. The filtrates are washed with water and dried. The liquid is then evaporated to dryness. The residue is purified by recrystallization. 3.1 g of the ¹ ^ a ₁ 7a-diacetate of the desired compound are obtained. The diacetate is then saponified according to Example 2 with ethanol and potassium hydroxide, the free base being obtained.

Example 34 3a, 7a-üis-5 »6 ~ cis- Hexahydro ~ 2-piperidino'-3a , 5,6, 7a-ind ante tr oil

"(Formula" M bsw, II; corresponds to the general formula Ie or If) OH OH

HO

HO-

OH

ice cream

ice cream

trans

(H) A mixture of the isomeric compounds of formula and is prepared as follows. 2.79 g (0.01 mol) of 5,6-cis-4,5,6,7-tetrahydro-2-piperidino ™ 5,6-iadanediol-6-monoacetate prepared according to Example 31 are dissolved in 25 ml of pyridine »The solution is ^{treated at 5 to 10 °} C. with 5 g (0 * 05 mol) of acetic anhydride.

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After standing for several hours at room temperature, the mixture is poured into 200 ml of water. To isolate dey ^ .cbilaeten Iijc.-ai'iioZ.-ί), (i-dii'cc-tat; j, the mixture is then extracted with chloroform and the residue obtained after evaporation of the solvent is brought to crystallization g (0.01 mol) of the diacetata are then dissolved in 100 ml of a mixture of 75 percent benzene and 25 percent P3 ^r ridin, and the solution is treated with If4 g (0.01 mol) of osmium tetroxide, and the mixture is then kept for several days left to stand at room temperature, then cooled to 5 to 10 ° C. and finally saturated with hydrogen sulfide gas. The precipitate is filtered off and washed with benzene. The filtrate is washed with water and dried. The residue obtained after evaporation of the solvent is purified by unicrystallization receives 3 g of a mixture of stereoisomers of the 5,6-diacetate of the desired compound, of the formulas II ¹ and IV

CH ₅ CO

0
CH ^ CO-

OH

CH ^ CO ice

• CIS

ice cream

Oh ice

ice cream

trans Cr) (κ ¹ )

The diacetate mixture is made according to Example 2 with methanol and potassium hydride to a sterec isonerene desired according to cer Connections saponified.

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Example 35

3a, 7a- "fcrans-l- / 3 ~ (^ imetliylamino) -pr opyl7-3a, 4, 7> 7a-1etrahydro- 3a, 7a-indanediol

13 g (0.065 mol) of 1- / 3- (dimethylamino) _r propyi7-4,7-dihydroindarL are dissolved in 130 ml of 93 percent formic acid at below 5 ° C. The mixture is then heated to 23 G and then 8 ml of 30 percent hydrogen peroxide (about 0.078 mol of H ₂ O ₂ ) are added over the course of 15 minutes. The temperature of the mixture rises to 28 ^° C. within a further 15 minutes. The mixture is then heated to 35 ° C. for 2 hours. The formic acid is then evaporated off under reduced pressure. 100 ml of ethanol, 30 ml of v / ater and 20 g of sodium hydroxide are added to the residue. The mixture obtained in this way is refluxed for 1 hour using nitrogen as the protective gas, then cooled and then diluted with 300 ml v / water. The solution is extracted six times with 200 ml of ether each time. The combined ether extracts are dried and evaporated. 11.8 g of an oil are obtained, which partially solidifies when rubbed with hexane / ether. Filtration gives 1.01 g of a yellow-brown solid which gives a main color spot on thin-layer chromatography The mother liquor is left with one containing 400 g of aluminum oxide (3 percent HO)

Pass the chromatography column and then elute with hexane / . Chloroform mixtures. There will be a total of 2.2 g of one. Obtain oil, the same in thin-layer chromatography . Main color spot shows like the aforementioned solid substance. After

in total . crystallization from ether is obtained / 1.1 g of crystals, which after Combination with the aforementioned substance (1.01 g) twice

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. Ether are recrystallized. 99.5 Dpoei obtained 1.14 g of the desired compound, mp. 101 to _f 5 ° C. The compound behaves homogeneously in thin-layer chromatography.

CHN C ₁₄ H ₂₅ NO ₂ ; calc .: 70.25; 10.53; 5.85;

Found: 70.37; 10.56; 5.65.

The indanediol can by reaction with formic acid and V / water

cteü original replacement product substance peroxide and saponification / with a base according to Example 2 in the corresponding tetrol, i.e. 3a, 7a, -trans-5,6-transhexahydro-1- / 3- (dimethylamine) -propyl7-3a, 5,6,7a-indantetrol (general formula Ia).

Example 36

3a _t 7a-tranB-3a, 4,7 _> 7a-tetrahydro-2-piperidino-3a, 7a-indanediol A solution of 30.5 g (0.15 mol) 4,7-dihydro-1-indanylpiperidine in 250 ml 98prozentiger formic acid, which was prepared in the cold, is within 10 minutes at about 6 ⁰ C dropwise with 18 g of hydrogen peroxide 30prozentigem added .. the mixture is stirred for several hours under ice-cooling and then for about 15 hours at room temperature, allowed to stand. Then, the mixture is stirred at reduced pressure to ^dryness: evaporated. The residue is taken up in 250 ml of ethanol. 50 ml of 50 percent sodium hydroxide solution are added to the solution while stirring. The temperature rises to 65 ^° C. during this process. The solution is then stirred for a further 30 minutes, diluted with water and extracted three times with ether. The extracts are dried over potassium carbonate and the solvent is evaporated. The residue is taken up twice with hexane and each time

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2U515A

kri:; ta "'1: 1 non. evaporated. The recrystallization of the residue yields 50 g of the desired compound from pp. 106 to 121 ° C .. ^; .u ^^ cutn 84 percent of theory.

The indanediol can be obtained by reaction with formic acid and hydrogen peroxide and saponification of the reaction product with a Ba-. se according to example 2 into the corresponding tetrol, i.e., 3a, 7atrans-5,6-trans-hexahydro-2-piperidino-3a, 5,6,7a-indantetrol (general formula Ia).

Example 37

3a, 7a-trans-5,6-trans-1- / 3- (benzylmethylamino ) propyl / -hexahydro-3a, 5 , 6,7a-indante petrol

(a) n-Butyl 3- (3-indenyl) propionate

In a heated to 120 ° C mixture of 464 g (4 Hol) indene and

4.5 g of solid potassium tert-butoxide are added within 90 minutes 256 g (2 mol) of n-butyl acrylate were added dropwise at temperatures from 100 to 120 ° C. The mixture is set at 120 for an additional hour Maintained up to 150 °, then cooled, mixed with 25 ml of acetic acid and filtered. The distillation at a pressure of 2 Torr provides 256 g of the ester (a) with a bp, 1 * 3 to 160 ° C / 2 torr; Yield 57 percent of theory.

(b) 3- (3-indenyl) propanol

A solution of 256 g (1.06 mol) of the ester (a) in 1 liter of ether . is in a suspension of 80 g of lithium aluminum hydride in 2 Li-.ter Ether dripped in. The mixture is refluxed for several hours and then with potassium carbonate solution separated. The precipitation will

filtered off. When the filtrate is distilled, 155 g are obtained

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2H515A

3- (3-indenyl) propanol with a boiling point of 125 Ms 130 ° C / l Torr; yield 84 percent of theory.

(c) 4,7-Dihydro-3- (3-indenyl) propanol A solution of 76.3 g (0.434 mol) of the alcohol (b) in a mixture of 1500 ml of liquid ammonia and 500 ml of ether is mixed with 40 g Lithium metal staggered in the form of small pieces. After 30 minutes, anhydrous ethanol is added dropwise to the mixture until it becomes discolored. After the ammonia has evaporated and further ether has been added, the mixture is cooled with ice and then treated with water. The aqueous layer is extracted with ether and the combined extracts are dried and distilled. 75.7 g of compound (c) with a boiling point of 103 to 108 ^° C. / 0.2 Torr are obtained; Yield 9B percent of theory.

(α ·) 4,7-Dihydro-3- (3-indenyl) propyl tosylate A solution of 75.7 g (0.425 Hol) of the alcohol (c) in 200 ml of pyridine is cooled to -5 to -10 ° C and then a solution of 110 g (0.58 mol) of p-toluenesulfonic acid chloride in 400 ml of pyridine is added dropwise. The mixture is then stirred for a further 3 hours at 0 ° C., then left to stand for about 15 hours at 5 to 10 ° C. and finally Poured while still cold into a sufficient amount of a mixture of dilute hydrochloric acid and ice to neutralize the pyridine. After brief stirring, the product is extracted with ether. The ether extract is dried over sodium sulfate and freed from the solvent, finally under reduced pressure. 133 g of the crude tosylate are obtained as residue; Yield 94 percent of theory. The IR spectrum shows a complete one

209812/1875

Implementation to »

(e) Benzyl- / Ä, 7 ~ dihydro-3- (3-indenyl) -propyl / -aethylamine one-i solution of 100 g (0.33 mol) of the crude tosylate (d) and 100 g (0, ö mol) Ethylbenzylamine in 500 ml of toluene is refluxed for about 15 hours. After cooling and filtering, the solvent is evaporated off under reduced pressure. The remaining liquid is taken up in ether and filtered again. The unreacted starting compounds are finally dissolved at 100 ° C. and reduced pressure.

ψ far away. 79.5 g of the crude methylamine (e) remain; Yield 81 percent of theory.

(f) 3a _> 7a-trans-5> 6-trans-1- / 3 - (- Benzylmetnylamino) -propyl7-hexahydro-3a, 5, 6,7a-indanetetrol

The crude compound (e) is gradually introduced into 500 ml of cold 98 percent formic acid with stirring. 100 ml of 30 percent hydrogen peroxide (1 mol) of H ₂ O _{2 are then} added dropwise at 15 to 20 C. Jlach 1 hour, the temperature at 3O ⁰ C allowed to rise, and there are added dropwise 100 ml H ₂ 0 ". The mixture is then stirred for about 15 hours, the solvent is evaporated and the unreacted starting compounds are removed at a pressure of about 5 torr and temperatures of up to 50.degree. Water is then added three times and evaporated each time. The residue is finally in. 250 ml of ethanol dissolved. The solution is mixed with 100 ml. 0% sodium hydroxide solution in the form of partial amounts while stirring. The mixture is then refluxed for 1 hour, after which it is cooled and finally, per part by volume, with three parts by volume.

209812/1875

len water diluted. Extraction with ether gives finally 37 g of the crude product. Extraction with chloroform gives a further 2 g of the product. The crystal formation v / is then excited with a small sample that is passed through

Las i sch rea ^ -i ex ¹ en eggs

Chromatograph the product on alumina (activity grade IV) and elute with chloroform containing 2 to 5 percent methanol. In this way a first product (19 g) is obtained; Yield 19 percent of the theory. Recrystallization of 5.1 g of this product from Äthylaeetat provides 3.6 g of the analysis sample from the Pp 129-13 ⁷ ° C. Overall yield 13 percent of theory.

6ö C. 8th H M. 01; ber .: 68 .74; 9 .94; 4, 99 found: .79; .05; 3,

Example 38

5a, 7a-trans-5> 6-trans-hexahydro-1- / 3-methylamino) propyl7-3a, 5,6,7a-indante petroleum

A solution of 7 g of 3a, 7a-trans-5,6-trans-1- / 3- (benzylmethylamino) -propyl7-hexahydro-3a, 5,6,7a-indantetrol (prepared according to Example 37) in 150 ml of ethanol is added to 1 g of palladium Stronthium carbonate (Engelhardt) added and hydrogen gas

2 hydrogenated. A hydrogen pressure of up to about 3.5 kg / cm is used. The hydrogen uptake is accelerated towards the end by heating to 30 to 40 ^{° C.} About 9.3 kg of H _{2 are} absorbed within 344 minutes. After the catalyst has been separated off and the solvent has been evaporated off, 5 g of the crude product are obtained; Yield 96 percent of theory. The product is recrystallized twice from acetonitrile. This gives 3.75 g

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2U5154

the pure compound of m.p. 128 to 133 C; 72 percent yield the theory.

CHK

C ₁₅ H ₂₅ NO ₄ calcd .: '60.20;9.72;5.40;

Found: 60.29; 10.00; 5.65.

Example 39

2-piperidinomethyldekahydronaphthalintetrol

naphtha! iii-1 - on A solution of 24.3 g (0.1 mol) of 2-piperidinomethyl-tetraLydro- / in 100 ml of ether is dissolved in a suspension of 5 g of lithium aluminum hydride dripped into 250 ml of ether. The mixture is stirred for 1 hour, then separated with potassium carbonate solution and filtered. Evaporation of the piltrate gives 24.1 g of crude 1-hydroxy-2-piperidinomethyltetrahydronaphthalene. The raw product is taken up in 100 ml of ether. The solution is introduced into 500 ml of liquid ammonia while stirring Mixture is mixed with 14 g of lithium metal in the form of partial amounts added and then stirred for 1 hour. Then slow

. anhydrous ethanol was added dropwise until it was completely discolored. The residue obtained after evaporation of the ammonia is cooled and dissolved in water. The solution is repeated several times. Ether extracted. The combined extracts are dried and the solvent is evaporated. As a residue is 1,2,3,4,5,8-hexahydro-2-piperidinomethyl naphthalene in quantitative Yield obtained.

. The naphthalene derivative is made according to Example 19 with formic acid and hydrogen peroxide converted to the desired compound.

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2U515A

Example 40

] »I iäthylaiainopr op yl- d el: aLydronaplithalintetro l

Me by reacting 29 g (0.2 Hol) Oiät ^ ylaiainopropylchlcrid with 5.2 g of I-lagnesiummetall in 200 mN tetrahydrofuran produced Grignard compound is with a solution of 14.6 g (0.1 mol) of 1-indanone in 100 ml of tetrahydrofuran are added. The mixture is refluxed for 3 hours and then separated with ammonium chloride solution. The reaction product is then isolated by distilling off the solvent. The crude diethylaminopropyltetrahydronaphthol obtained is then dissolved in 100 ml of ether. The solution is introduced into 500 ml of liquid ammonia. The solution obtained in this way is mixed with 15 g of lithium metal in the form of partial amounts. After 30 hours
the mixture is anhydrous by slowly adding dropwise
Ethanol completely decolorized. After the evaporation of the
The residue obtained from ammonia is cooled and taken up in water. The solution is extracted with ether. The extracts are dried and the solvent is evaporated. The residue obtained is 1,2,3,4,5,8-hexahydro-1-diethylaminopropylnaphthalene. This compound is converted into the desired compound analogously to the procedure described in Example 26.

Example 41
1-K-Benzamidopropylde ahydronaphthalintetrol

αϊ e (o, i iioi)

A mixture of 14.6 g (0.1 Hol) Ietrahydronaphthalin-1-one unc ../ CyanpropyltriphenylphosphoniuDibromid in 500 ml Dimethoxyäthan
is mixed with vigorous stirring and using nitrogen as protective gas with a 50 percent mineral oil dispersion of

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2U5154

Sodium hydride (0.11 mol NaH) is prohibited in the form of partial amounts. The mixture is then heated for several hours with stirring and reflux, then freed from the solvent and finally extracted with ether. The resulting solution of 1- / 3-cyanopropylidene-7-tetralin is then added to a suspension of 10 g of lithium aluminum hydride in 250 ml of ether. The mixture is heated for several hours with stirring and reflux, then separated with potassium carbonate solution and finally filtered. The filtrate is evaporated to dryness. The distillation of the residue gives 1,3-aminopropylidene tetrahydronaphthalene, which boils at about 135 to 140 ° C. at a pressure of 1 torr. This compound is taken up in 100 ml of ether. The solution is introduced into 500 ml of liquid ammonia. The one with it The solution obtained is mixed with 16 g of lithium metal in the form of small portions. After stirring for 30 minutes the mixture becomes completely decolorized by slowly adding anhydrous ethanol. The one obtained after the ammonia has evaporated The residue is cooled and taken up in water. The solution is extracted with ether and the extract over potassium carbonate dried. After evaporation of the solvent, 1,2,3,4,5,8-hexahydro-1-aminobutylnaphthalene is obtained as residue. The- ' This compound is converted into the corresponding N-benzoyl derivative according to Example 29 and this is converted into the desired tetrol.

Example 42

The reaction of 29.9 g (0.2 mol) of diethylaminopropyl chloride made with 5.2 g of magnesium metal in 250 ml of tetrahydrofuran Grignard compound is with a solution of 17.4 g

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2U515A

(0.1 mole) 9-methyl-6,7,0, 9-tetrahydro-5E-benzocyclohepten-5-one added in 125 ml of tetrahydrofuran. The Geraisch will be 4 hours boiled under reflux and then with ammonium chloride solution separated. Evaporation of the solvent turns it crude 5-Hydroxy-5-diethylaniinopropyl-9-methyl-6,7,0,9-tetrahydro-5H-benzocycloheptene isolated. This compound is dissolved in 100 ml of diethyl ether. The solution is in 500 ml of liquid ammonia registered. The solution obtained is mixed with 20 g of lithium metal in the form of small portions. for 30 minutes the mixture is completely decolorized by slowly adding dropwise anhydrous ethanol. The one after the ammonia has evaporated The residue obtained is cooled and taken up in water. The solution is extracted with ether. The United Ether extracts are dried and freed from the solvent. Crude 5-diethylaminopropyl-9-methyl-1,4,6,7,0,9-hexahydro-5H-benzocycloheptene is obtained. This compound is converted into the corresponding tetrol in the manner described above.

Example 43

A solution of 16.1 g (0.1 mol) 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene in a mixture of 500 ml of liquid ammonia and 100 ml of diethyl ether with 15 g of lithium metal in the form of offset in small pieces. After 15 minutes, the mixture is completely decolorized by adding dropwise anhydrous ethanol. Of the The residue obtained after evaporation of the ammonia is cooled and taken up in water. The solution is extracted with ether and the extract is freed from the solvent. As a return

209 812/1875

2Η5Ί5Α

standing, δ-amino-1 ^, 6,7,8, g-hexahydro ^ H-benzocycloheptene is obtained. This compound is converted into the corresponding U-benzoyl derivative with benzoyl chloride / pyridine in the manner described above and this is then converted into the corresponding tetrol.

Example 44

A mixture of 16 g (0.1 mol) 5,6,8,9-Setrahydr0-7H-CyCloheptabenzen-7-one and 42.4 g (0.1 mol) of cyanobutyltriphenylphosphonium bromide in 500 ml of dimethoxyethane v / ird with stirring and using of nitrogen as a protective gas with a 50 percent Mineral oil dispersion of sodium hydride (0.11 mol NaH) in the form of Partial quantities offset. After several hours, the mixture is freed from the solvent and the reaction product with ether extracted. The crude product is dissolved in ethanol. Ammonia and 10 g of Raney nickel are added to the solution. It will then a hydrogenation at temperatures of 100 to 120 C and one

Hydrogen pressure of 105 kg / cm carried out. After finished Y / ass would only take off, the mixture is cooled and the catalyst gate freed. When the solvent is evaporated off, crude 7-aminopentyl-6,7 »8,9-tetrahydro-5PI-benzoeycloheptene is obtained. The Ver- ' . binding is absorbed in 100 ml of ether. The solution is in 500 ml of liquid ammonia entered. The resulting solution within 1 hour with 20 g lithium metal in the form ' . small pieces offset. Then the mixture is through. Slow dropping of anhydrous ethanol decolorizes. That after The mixture obtained after evaporation of the ammonia is cooled and taken up with water / water. The solution is extracted with ether.

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2U5154

here. Kach your dampening of the solution is obtained as Residue of crude 7-ariinopentyl ~ l, 4,6 »7, b, 9-hexaaydro-5H-ttnzocycloheptcjii. The connection is described in the above Wines in the corresponding II-Benzoy] derivative do this then converted into the corresponding Tctrol.

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Claims (1)

2145 ι 54 Patent claims . 1. "Indanyl, haphthyl and benzosuberany! Derivatives of the general Formula I. - (I) ^H ^ n ' "in which R-, Rp, P., and P _{4 are the} same or different and P "or lower hydrogen atoms, carbonamide groups .. (p ^> u-C0 -) / alkyl, halo "6 gen-nieaer-alkyl-, Nieaer-alkoxyalkyl-, lower-alkoxycarbonyl- or acyl radicals, X is a single bond or a Hydrocarbon off remainder unbranched or branched zv / eivalent aliphatic / with 1 to , represents about 10 carbon atoms, Y is a radical -HTV ^ or -CC ',,, 5 being ^R 6 R * 6 indicates, where the radicals H ₁ - and R, - are identical or different - and are hydrogen atoms or lower alkyl, lower alkoxy, halo-lower-alkyl, monocyclic ^ cycloalkyl-, monocyclic-cycloalkyl-lower -alkyl, lower alkanoyl, halo-lower-alkanoyl, hydroxy-lower-alkyl, monocyclic aryl, monocyclic-aryloyl, monocyclic aryl-lower-alkyl, monocyclic heterocyclic radicals, through monocyclic heterocyclic radicals substituted alkyl radicals or 1T, N-dialkylsulfamoyl radicals or together with the nitrogen atom form a heterocyclic radical, RV and RV are identical or different and represent corresponding radicals such as R ^ or Rg or pyridine, quinoline or isoquinoline groups or together with the'C -Atom form a heterocyclic radical, and R _{7 is} a • '209812/18 75 V / anoxidatom, a lower alkyl, aralkyl or lower alkoxy radical, with the proviso that at least one of the radicals R'c, RV and / or R ₇ contains a nitrogen atom, and Rg just as "as R'-g is a lower alkyl or cycloalkyl radical, and η is 1, "2 or 3 and m, like m ', has the value 0, 1 or 2, and their pharmacologically acceptable salts with acids, quaternary ammonium salts and IT oxides. 2. Compounds according to claim 1, characterized in that the radicals R ₁ , Rp, Rz and R. are hydrogen atoms. 3. Compounds-according to claim 1, characterized in that at least one of the radicals R .., Rp, R, and R. is an acyl radical and the radical (s) optionally remaining is (are) a hydrogen atom (s). 4. Compounds according to claim 1, characterized in that they are radicals R ^, R ₂ -, R · ,, R ₄ , R, - * R'c>Rg>R'g »R ₇ > Rq and / or. R ¹ O C-jo-alkyl radicals and / or radicals with up to 8 carbon atoms in the alkyl portion. '. 5 · Vex 'bonds according to claim 1, characterized in that they have as radicals Er, R ¹ ,, Rg, R'g> Rg and / or R' ₈ cycloalkyl radicals with 3 to 6 carbon atoms in the ring. 6. Compounds according to claim 1 to 5 according to the general Formula Ia .. 209812/1875 R ₁ O ¹ R ₂ O - 106 OR, 2H515A in which all 4 radicals R ₁ O, RoO, R- * 0 and RO are arranged axially, the radicals R ₁ O and R ₀ O trans configuration and the radicals OR ·, and OR. also have trans configuration. 7. Compounds according to claim. 1 to 5 ent "pv? Without the general Formula Ib R ₁ O OR in which the radicals R ₁ O and RpO trans configuration and the radicals OR.Z and OR. also have trans configuration, the radicals - R-, O and RO are arranged diaxially and the radicals R ₁ O and R ₂ O are arranged diequatorially. 8. Compounds according to claim 1 to 5 according to the general Formula Ic < ^R _B W R ₂ O OR-, OR, <jnx-Y. "« ^CB 2> n ro ' 209812/1875 2U515A in which the Keste R ₁ 0 and R _? 0 ice configuration and the residues ORv and OR. have trans configuration, one of the radicals R ₁ O and RpO is arranged equatorially and the other radical is arranged axially and the radicals OR ₇ and OR. are arranged diaxially. 3: Compounds according to claims 1 to 5 corresponding to the general formula Id OR- (CHJf _n in which the radicals R ₁ O and R ^ O trans configuration and the radicals OR-, and OR. have cis configuration, the radicals R ₁ O and R ^ O are arranged diequatorially or diaxially and one of the radicals OR., and OR. equatorial and the other remainder is arranged axially 10. Compounds according to claim 1 to 5 according to the general Formula Ie or If R ₁ O OR 209812/1875 2H515A (if) in which the radicals R-, O and RpO as well as the radicals OR-, and OR. have the cis configuration and the pair of radicals R ^ O and R2O to the pair of residues OR ·? and OR- cis configuration (Ie) or trans configuration (If). possesses. 11. Compounds :: a -h claim 1 to 10 according to the general formula II HO OH <VnT (II) HO OH in which n ^{1 is} O or an integer from 1 to 10. 12. Compounds according to claim 1 to 11, characterized in that η is 1 and m, like rn ^{1, has} the value 0. 13. A process for the preparation of compounds according to claim 1 and 6 corresponding to the general formula Ia, characterized in that a diene of the general formula III (III) 209812/1875 in which X, ^v , m, m ¹ and η have the meaning given in claim 1, are reacted with formic acid and aqueous hydrogen peroxide at temperatures of about 20 to about 40 C and the ester mixture obtained is heated to temperatures with a base 100 ⁰ C boiling saponified from about 40 to about 80 ° C. in the presence of a below about / solvent and optionally the resulting tetravalent alcohol of the general formula Ia ¹ HO OH " ^(R ' ^{8) m} ' (IaM HO OH fully or partially esterified and optionally the alcohol or ester with an inorganic or organic acid, a Quaternizing agent or with a peracid in the presence of a solvent. 14. The method according to claim 13 for the preparation of compounds of general formula Ia, wherein the radicals R ₁ , Rp, R, and R. represent acyl radicals, characterized in that the alcohol of general formula Ia ¹ at temperatures of about -20 to about 0 C in the presence of an acid as a catalyst * with an acylating agent to react. 15. Process according to claim 13 for the preparation of compounds of the general formula Ia, where the radicals R ₁ and R _{2 represent} acyl radicals and the radicals R 1 and R represent hydrogen atoms, characterized in that the alcohol of the general formula Ia ¹ either dissolves in an organic base or treated per equivalent with about 2 equivalents of a metal hydride and the mixture at temperatures of about 0 to about 20 ⁰ C with 209812/1875 an acyl _x ierungümittel using a molar ratio of acylating agent / alcohol of etv / a 2.1: 1 treated: 1 to about 10 degrees. 16.. Process according to Claim 13 for the preparation of compounds of the general formula Ia in which the radicals R., Rp and preferably Ή.-7 acyl radicals, the radical R. is a V / hydrogen atom and X / is a single bond, characterized in that the alcohol of the general formula Ia ^{1 is} mixed with an organic base and the mixture is at temperatures of about 5 to about 4-0 C with an acylating agent using an acylating agent / alcohol molar ratio of about 3: 1 to about 10: 1. 17. The method according to claim 13 for the preparation of compounds of the general formula Ia, in which the radicals R .., Rp and R. denotes hydrogen atoms and the radical R ^ represents an acyl radical, characterized in that the alcohol of the general formula Ia ^{1 is} reacted at temperatures of about 20 to about 60 ° C. with an alkyl ilaloformate. 18. Modification of the method according to claim 13 · »characterized in that that one dissolves a diene of the general formula III in a carboxylic acid, the solution with a silver salt of this Carboxylic acid heated to temperatures of about 60 to about 110 C, the resulting diester of the general formula IHa 209812/1875 2U515A Acyl O ^ / \ ⁽ v -— f ι Acyl 0 - "" \ / (Ilia) in which the aoyl radicals are derived from the carboxylic acid, in Presence of a proton-active solvent with excess aqueous base saponified the resulting dihydric alcohol freed from the solvent is reacted with formic acid and hydrogen peroxide and the / reaction product treated with an alcohol and a base. · 19 · Process for the preparation of compounds according to Claims 1 and 6 corresponding to the general formula Ia ¹ , in which Y denotes a radical -Ii-Cp ₁ , ^, characterized in that a hydroxyalky! compound of the general formula IV «Vm (IV) in which X represents an unbranched or branched alkylene radical with up to about 10 carbon atoms, in liquid ammonia in counter Connection
was a pi ^ otonenactive / with a metal to the corresponding Hydroxyalkylaien of the general formula V (V) 2 'η 209812/1875 - 112 - 21 451 ■ reduced, the hydroxyalkyl ^ ien of the general formulaΎ in
dissolves a basic organic solvent, the solution is ^{cooled to below O 0} C, treated with a solution of p-toluenesulfonic acid chloride in pyridine and the mixture is cooled, the dientosylate obtained is cooled and with an optionally substituted aryl or aryl-lower-alkylamine or a Aiain of the formula Rp-HHRg is converted into an aminoalkyldiene of the general formula VI in which R ¹ V and RV are the same or different and are optionally substituted aryl or aralkyl radicals or have the same meaning as R ₁ - and Rg (claim 1), which reacts the aminoalkyldiene of the general formula \ ^r I with formic acid and an oxidizing agent which The reaction product is freed from the solvent and the residue is saponified with a base. w 20., modification of the method according to claim 19 for the preparation of compounds of the general formula Ia * (Y = -K ^x -r>'5) »
in which at least one of the radicals Rj- and R, - is a hydrogen atom, characterized in that one
Aminoalkylindene or alkyltetrahydronaphthalene of the general formula VIa ' 209812/1875 2U5154 (Via) in the presence of liquid ammonia, diethyl ether and a proton-active one Yerbindurg to a service of the general formula VII (VII) reduced, the diene of the general formula VII in the presence of a basic solvent with an acid halide to one Diene of the general formula VIII (ch: -X-NR-V. (VIII) 2'η converts the diene of the general formula VIII with formic acid and an oxidizing agent to react "and the reaction product saponified with a base. 21. A process for the preparation of the compounds according to claims 1 and 7> characterized in that a diester olefin of the general formula IHa is reacted with formic acid and an oxidizing agent at temperatures of about 20 to about 40 O and the reaction product is reacted with an alcohol and an Base saponified at temperatures of from about 40 to about 10O ⁰ C. 209812/1875 - 114 - 22. A process for the preparation of compounds according to claim 1 and 8, characterized in that a diene of the general formula III in the presence of a ^{saturated aliphatic carboxylic acid containing about 2 to 10 c} f- ″ / water with a silver salt of this carboxylic acid and iodine Temperatures of about 50 to 110 ⁰ O heated and the resulting monoester / general formula IX Acyl O or the dihydric alcohol obtained therefrom with formic acid and an oxidizing agent, and the reaction product with saponified a base. 23. A method for the preparation of compounds according to claim 1 and 9j, characterized in that one Diester of the general formula IHa in the presence of a basic organic solvent with osmium tetroxide brings to implementation and the resulting diester alcohol of the general formula X saponified with a base. 2 'η OH (χ) 209812/1875 2U5154 24. Process for the preparation of the compounds according to claim and 10, characterized in that one is one ilonoester _; he general formula IX in the presence of a basic solvent reacts with the anhydride of a saturated aliphatic carboxylic acid nit "up to about 6 carbon atoms, the obtained diester of the general formula XI (Xl) in the presence of pyridine with osmium tetroxide for reaction brings and the resulting mixture of diesters of the general formulas XII and XIIl OH Acyl Ο ( ^R 8) m acyl 0- X-Y (CH ₂ J _n OH (XII) (XIII) saponified with a base. 25. Medicines, characterized by a content of at least a compound according to claims 1 to 12 as an active ingredient. 209812/1875 2U5154 26. Use of the compounds according to claims 1 to 12 as water softeners. 27. Connections of the general formulas XIV and XV OR ^{1 0Rl} 2 in which the residues E ¹ . and R 'are ₂ hydrogen atoms or acyl radicals and X, Y, m and m' are as defined in claim 1. 28. Compounds of the general formula III in which R _Q , R'o »m» πι ¹ , n, X and Y have the meaning given in claim 1. 29. Compounds of the general formulas IHa and XI 209812/1875 2H5T54 Acyl ⁽ Vm Acyl 6 acyl O Acyl θ ' ^R Vm (Ilia) (XI) in which R _Q , R'g> m, m ¹ , n, X and Y have the meaning given in claim 1. 30. Compounds of the general formula XVI OH (Ro) 8'm m ' X-Y (XVI) in which Rg, R'o, m, m ¹ > n, X and Y have the meaning given in claim 1. 31. Compounds of the general formula IX (IX) 209812/1875 2U5154 in which Ro, R'p>Χ>Υ> m mean. i-'i ¹ and η the in claim 1 ange ^ cl-onc 209812/1875