DE2246728A1 - NEW SUBSTITUTED ETHYLENE DIAMINES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING SUCH DIAMINES - Google Patents

Description

DIPL.-CHEM.DR. ELISABETH JUNG 8 "J'j; .SEP 1972

DIPL -PHYS. DR. JÜRGEN SCHIRDEWAHN telephone μ 50 6?

¹ ^ - 'TELEGRAM ADDRESS: lisIVEMT / MONCHEN

PATENT LAWYERS. TELEX 5-29 606

u.z .: H 114 G (J / k / hg)

_r ALLEN & HANBURYS LIMITED

London, England

"Heue substituted. 1" ;! Aylendianiine,. Process for their preparation and medicinal preparations containing such diamines ^M

Priority: 23 September 1971, Great Britain-, No. 7 567/71 (post-dated in accordance with Section 6 (3) of the British Patent Act of 1949). "' June 6, 1972, Great Britain, No. 26 24.8 / 72

The present invention relates to new substituted ethylenediamines, which have pharmacological activity as well as a Process for their production and medicinal preparations containing such diamines. ·

The new substituted ethylene diamines have the following general formula

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II ¹ l \ ^J R ⁷ .ft ⁵

JJ -C-C-N

in which the groups R to R aind same or different and each have the following meaning: hydrogen atoms, linear or branched C ₁ _, - alkyl, alkenyl or Alki.nylgruppen or by a cycloalkyl group substituted alkyl or cycloalkyl, alkoxycarbonyl -, aryl, aralkyl or acyl groups, including arylsulphonyl groups, the alkyl radical of the aralkyl groups by one or more optionally esterified hydroxyl groups and the aryl groups or the aryl radical of the acyl or aralkyl groups by one or more halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups , Trifluoromethyl groups, nitro groups, amino groups and / or dialkylamino groups can be substituted,

5 8
in which the groups R to R are identical or different and each represent hydrogen atoms or alkyl groups, with the

5 '8 stipulation that not all groups R to R at the same time V / atomic atoms are, or in which R and R or R and R together a carbonyl oxygen (= 0) and in each pair of groups R / R, R / R, R / R and R '/ R a carbocyclic or heteroeyclisches saturated or unsaturated ring system, which may optionally be replaced by lower alkyl or aralkyl groups.

The expression "acyl group ¹ " used here means the radical of an organic acid, in particular the benzoyl, formyl and acetyl radical. In addition, within the scope of the invention

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BATH ORIGINAL

also understood arylsulfonyl radicals. The term "aryl group" comprises an aromatic or heteroaromatic nucleus.

The invention also relates to non-toxic salts of the. new Ethylenediamines, especially their acid addition salts, for example the hydrochlorides, sulphates, maleates and tartrates *

Some of the new compounds can also exist in optically active forms, and the invention therefore also includes such forms optical isomers and their mixtures.

In particular, this also includes optical isomers of open chain Compounds with at least one asymmetric carbon atom.

In the context of the invention, preference is given to compounds of the above

V R given formula I ,. in which the groups R and R along with. the adjacent carbon atom is a carbocyclisch.es Form ring system, in particular a carbocyclic ring system with 4 to 7 carbon atoms, such as the cyclopentyl group

3 4 and especially the cyclohexy! Group, The groups R and R are preferably alkyl, alkenyl * or alkynyl groups with 1 to 6 Carbon atoms and in particular 1 to 4 carbon atoms if they are alkyl or alkynyl groups. Preferably the groups R and R are a methyl, allyl, propargyl or dimethylallyl group. These substituents R and R but can also mean hydrogen atoms or an aralkyl group, iushesouuere. the phenethyl or benzyl group, or they can represent the cyclopentyl group or together with the

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adjacent nitrogen atom form a heterocyclic ring system. Examples of such heterocyclic ring systems are the piperidyl group, the N-methyl-piperazinyl group and the

1 2 pyrrolidinyl group. The groups R and R are preferably hydrogen atoms, C1-4 alkyl groups, in particular the methyl group or an acyl group, in particular the pormyl group (HGO-) and the benzoyl group, which may be in the aryl radical can be substituted by fluorine or chlorine. The groups

1 2
R and R can also mean an aralkyl group, in particular the benzyl group, which in the alkyl radical (-CH ₂ -) can be substituted by a hydroxyl group or an esterified, in particular acetylated, hydroxyl group. .. R and R preferably denote hydrogen atoms "or a C ₁ , -alkyl group, in particular a methyl group.

In a further preferred group of the compounds according to the invention, R 'and R and R and R are preferably hydrogen atoms or C _1- «-alkyl groups, although not all of these groups may be hydrogen atoms at the same time. Particularly

7 8 preference is given to those compounds in which R and R · each C-. .-Alkyl groups and in particular the methyl group and, while either R or R is hydrogen and the other group R or R is a C | _, - alkyl group, in particular the methyl group, or is a hydrogen atom.

In the context of the invention, compounds are of particular importance with the general formula below

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N - B ⁵
1 CH-
ι J N \ CH. - C - C - E ^{2 /} ή ⁶ ι
«Ι, CH ^

in v / which R the benzoyl group, a chlorine-substituted benzoyl group or the group COOAIk with Alk = a C.. -alkyl group '

2 5 -

"means R hydrogen or the methyl group, R the methyl group and R is hydrogen. '

In the context of the invention, particularly preferred classes of compounds are the following;

1) Compounds according to formula I, in which R has the following meaning Has ; 3,4-dichlorobenzoyl, formyl ,. Benzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl; 3,4-dimethoxybenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, acetyl, p-toluylsulfonyl, 2,3,4-trimethoxy * -. benzoyl, 3,4-dichlorobenzoylsulfonyl, 2,4-dichlorobenzoyl,

'2 is hydrogen, the methyl or ethyl group, while -R is hydrogen

or the methyl group, R ^ the methyl group, R the methyl or Benzy! Group or hydrogen, R and R

7 R

Are hydrogen and / or the methyl group and R and R together form the cyclohexyl group. ■

2) Compounds according to formula I, in which. R has the following meaning has: hydrogen, formyl, acetyl, 4-fluorobenzoyl, 2-chlorobenzoyl, 3,4-mchlorobenzoyl, 2,3,4-trimethoxybenzoyl, 4-nitrobenzoyl, 4-aminobenzoyl, or the ethoxycarbonyl group,

2 the methyl or ethyl group, while R is hydrogen or the

eg VR

Is a methyl group, R. and R are hydrogen, R 'and R together

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3 4 men form the cyclohexyl group and R and R together with the adjacent nitrogen atom form the piperidyl group.

3) Compounds according to formula I, in which R has the following meaning has: hydrogen, formyl, acetyl, 3,4-dichlorobenzoyl, 2,3,4-trimethoxybenzoyl, p-toluylsulfonyl, 2,4-dichlorobenzoyl,

2 the methyl or ethyl group, while R is hydrogen, the formula

5 ■ ι ....

myl or methyl group, R hydrogen or the phenyl group,

f 1 Λ

R is hydrogen, R and R together with the neighboring one

7 8

Nitrogen atom is the 4-methylpiperazinyl group and R and R together form the cyclohexyl group "

4) Compounds according to formula I, in which R is hydrogen, the

3,4-dichlorobenzoyl, 2-chlorobenzoyl, benzoyl or ethoxy

2
carbonyl group, while R is hydrogen or the methyl group,

R * the methyl group, R hydrogen, the methyl, benzyl, Allyl, propynyl, dimethylallyl, cyclopropylmethyl or

5
Phenethyl group, R is hydrogen or the methyl group, R is hydrogen, R is the methyl group and R is the methyl or butyl group. '

Specific representatives of the compounds according to the invention are explained in more detail by the examples.

The compounds according to the invention can be, starting from an aminonitrile.

The inventive method for the preparation of compounds according to formula I is accordingly characterized in that

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- j -

an aminonitrile of the following general formula

' ^GN - ^N v ■: (H)

. ti- · R .j

in which the groups R, R, R and R are those given above Have meaning, converted by direct reduction into an amine of the general formula below. .

NIIwCH _{0 v}

R ⁷ :

5 or that for the preparation of compounds in which R and R together denote a carbonyl group, the aminonitrile of the formula II hydrolyzed to the corresponding amide>

oö.er that one for the establishment of connections, at which R and R each represent hydrogen, the amide for. Amine reduced,

or that for the preparation of compounds in which R is an acyl group, the amine of the formula III is acylated with a corresponding compound,

or that for the preparation of compounds in which R 'denotes an alkyl group, this acyl group is then added reduced to an alkyl group,

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"" ■ ö ~ "

2 or that for the production of compounds in which R " means an acyl group, the monoalkylamine formed with a acylated corresponding compound,

or that for the production of connections, in which so-

1 2
R as well as R mean alkyl groups, the monoacylated monoalkylamine formed reduces,

5 or that for the preparation of compounds in which R is not hydrogen, the aminonitrile of the formula II reacts with an alkyllithium compound R Li and the imine thus formed then reduced to a primary amine,

or that for the preparation of compounds in which R denotes an alkyl group, R an acyl or alkyl group and /

ρ
or R is hydrogen, an acyl or alkyl group, acylates the primary amine (R = alkyl) formed and then optionally reduces the acyl group,

or that for the preparation of compounds in which R

2
or R is an aralkyl group, the alkyl group of which is substituted by a hydroxyl group, which reduces the underlying amide (conversion of the group -G = O into the group CHOH)

or that for the preparation of compounds in which R

2
or R is an aralkyl group whose alkyl radical is substituted by an esterified hydroxyl group, the compound formed above with free hydroxyl groups is esterified with an acylating agent,

or that for the preparation of compounds in which R

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_ Q _
ΐ

or R denotes hydrogen "from the corresponding compounds with Beuzyl groups the latter split off,

or that for the production of compounds in which R ^:

and / or R are not hydrogen, a compound of the formula I,

■ ι 2
in which the group NR R, cannot be acylated or alkylated, is acylated or alkylated,

1 and that each of the groups R

Q.

to R in a different group within the scope of the given definition converts, and that you optionally the end product in the form an acid addition salt isolated. ■

That used as starting material for the process according to the invention Aminonitrile of the formula TI given above leaves by means of the standard synthesis according to Strecker from the basic

I-

produce lying ketone, as below for cyclohexanone specified is:%

KCN

In this synthesis, the underlying ketone is reacted in the presence of HCF or KCN with an amine of the formula EE NH, in which R and R have the meaning given above, or an acid addition salt of such an amine »

The further implementation of the 'formed aminonitrile

Formula II into an amine of the formula III given above can be carried out using two different reaction pathways »As with the first method, the aminonitrile becomes the corresponding amine is reduced, for example with a complex metal hydride such as LiAlII. or by means of Raney nickel and hydrogen However, N & triumaluminium -... ■ bis-methoxyethoxyhydride are used. According to the second conversion method, the aminonitrile first becomes the corresponding one Hydrolyzed amide, this amide itself being a

5 6

bond according to the invention, in which R and R together form a carbonyl oxygen atom «This hydrolysis can carried out for example by means of concentrated sulfuric acid The amide is then chemically converted into the corresponding amine using, for example, lithium aluminum hydride reduced.

In this way, for example, compounds according to the invention can be used produce in which R, R, R and R are hydrogen. In order to prepare compounds according to the invention in which R and / or R are not hydrogen atoms, these compounds can acylated <> The acylation can be carried out in the usual way be carried out »If, for example, R is an acyl group, the amine can be mixed with an appropriate acylating agent, for example an acid chloride, or, if R is an arylsulfonyl group, it is used for the acylation the corresponding arylsulfonyl chloride. The acylation, for example jiae formylation, but can also be used be carried out by formic acid and acetic anhydride,

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1 1

whereby the group R. = hydrogen into the group E = OHC- (formyl) is convicted. If the formyl compound formed in the process reduced, for example by means of lithium aluminum hydride, the formyl group is converted into the methyl group, and in this way a connection according to the invention can be achieved produce in which H is an alkyl group. The so educated Monomethylamino compound can then be formylated again, whereby a compound is obtained in which E is the methyl

group and R is the OHG group. This reaction scheme will

explained below; .

HCOOII

(CR ₄ Ca) ₂ O

HCOOH

(CH CO) ₂ O

H, C OHC-

.NCH.

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The implementation described above is also acylated to other Connections applicable. You can, for example, carry out an acetylation, whereby you get the corresponding acetyl compound which can then be reduced, thereby converting the acetyl group to the ethyl group. The above explained reaction is therefore generally applicable to

12th
Compounds in which R and R are each acyl groups in

1 2

To convert compounds in which R and R are each alkyl groups are",

For the preparation of compounds in which R is an alkyl group and R is a hydrogen atom, the nitrile of the above formula-II with a metal alkyl, for example a lithium alkyl compound, whereby an imine is obtained as an intermediate product, which is then followed by ^ d by chemical or catalytic reduction, for example using lithium aluminum hydride or Raney nickel and hydrogen, is converted into the corresponding primary amine. Pese reaction runs according to the following scheme:

nht m β'c N ^ β ⁵

Nitrile X ^Ά - - * NW - GH -., Fi - N

1 2 In this way, compounds are obtained in which R and R each- | because they are hydrogen. The compounds obtained in this way can subsequently aylated in the manner described above

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and are alkylated ο compounds in which any of the Groups R to R are alkoxycarbonyl, can be produced, by acylating with an ester of a halogen-substituted acid, for example with chloroformic acid ester, and

'' Acylation ",
within the scope of the invention, the term T is also understood to mean such a conversion «

1 2 If in the compounds according to the invention R or R a Aralkyl group, especially a benzyl group, which contains a hydroxy substituent in the alkyl radical, the corresponding compound can be reduced by reducing the underlying Prepare amides, with the group -C = O 'in the group CHOH is converted. The "group OH can then subsequently acylated to the corresponding ester.

The groups R and R can be identical to the corresponding Groups in the source material "However, it is also possible convert these groups into other groups of the given definition, after the compound according to the invention is established has been. So, if R and R are hydrogen atoms,

1 '2 these compounds in that described for R and R above Acylated or alkylated manner, provided that the "

12 ·

Groups NR R are not themselves alkylatable or acylatable.

The alkylation can also be carried out with an alkyl halide or aralkyl halide are carried out, whereby then the groups R or

R are no longer hydrogen atoms. Connections * in which R and / or R are hydrogen atoms, but can be very can be easily produced by

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fertilize, in which these groups Benzylgruppeti bind, the benzyl groups splits off «If the corresponding acyl group contains a nitro group as a substituent, for example if it is If a p-nitrobenzoyl group is involved, this nitro group can then also be reduced to an amino group will"

The compounds according to the invention show very good activity as oral analgesics.

They can be used in medicinal preparations along with a usual pharmacological compatible = ^ carrier material can be combined · It can these are preparations in liquid or solid form which are suitable for oral or parenteral administration. These medicinal preparations are preferably in the form of capsules, optionally coated tablets, injection liquids, liquid dosage units for oral administration or suppositories. For parenteral administration are doses of 10 to 500 mg of the active ingredient and for oral administration doses of 8 to 500 mg of the active ingredient are preferred.

The examples illustrate the invention.

example 1

Production of 1- (3> 4-dichlorobenzamidomethyl) -cyclohexyldimethylamine .

^a ) Production of I-cyanocyclohexyldimethylamine

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VJ fci JT * ti ti Ω

98.0 g (1.0 mol) of cyclohexanone and 81.5 g (1.0 mol) of dimethylammonium chloride in 150 nl Walser »Then is

rapidly a solution of 68.0 g (1, O45 ^": Möl) of potassium cyanide to 150 ml of water in 5 minutes add set Das: Beaktionsgemiseh is stirred for 24 hours, and it tilden _colorless; crystals The crystals are filtered off, with-. Washed 2.00 ml of ice water, dissolved in 150 ml of benzene and washed again with 1.00 ml of water. The aqueous layer is extracted with 100 ml of benzene, the benzene solutions are then combined, dried over anhydrous sodium sulfate and reduced under; ?. !! Pressure-evaporated to 144 g of I-cyanoeyclohexyldimethylamine are obtained in the form

an oily residue which turns into a product with a melting point of 36 ° C solidified. "-

"b) - Production of: 1 -A.minomethyleycl.ohexyldimethylami.n

22.7 g (0 ^ 15 mol) of 1-gyano-1 τ-cyclöhexyldimethylamine are dissolved in 200 ml of dry ether and - drip env ^ eise, - a stirred suspension of 11> 37 g; (Ο, ^ ΐΜοΙ) iithium aluminum hydride in 300 ml ^; added to dry ether. ~ The .Sus / pensipn. will · about

Night' ,

stirred: and 'excess; Liifehiumaluminiumhydridi.dupch

dropwise addition of 28 _v ml'Wasser, and; .21 ,, ml-3pprpzentig.er sodium hydroxide solution and 5.0 ml ansehliessend · ^ Wapser z, prBetzt. The ether layer. vird separated, .about ^ anhydrous ^ m sulfate dried = and- eingMampft.-Many Avail- ^ _i>} 4 ^ cent of the theory) of low viscosity colorless one; oil _0: With / - adding lOprozent.igem ethanolic hydrogen chloride · to an essential solution of the oil, a solid product is obtained _; which is recrystallized from a mixture of ethanol and ether »

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Is obtained 1-Aminomethylcyclohexyldimethylamin dihydrochloride from Pp. 25'1 to 253 ⁰ C in the form of colorless needles.

Example 2

Preparation of 1 - (3,4-dichlorobenzamidomethyl) - cyclohexyl ~ dimethylamine

A mixture of 1.0 g of I-aminomethylcyclohexyldimethylamine, 2 ml of 3,4-dichlorobenzoyl chloride and 10 ml of pyridine is left to stand for 1 hour at room temperature. The pale yellow crystals forming the calibration are filtered off and recrystallized from a mixture of ethanol and ether. There is obtained 1- (3,4-Dichlorbenzamidomethylj-cyclohexyldimethylamine hydrochloride from Pp. 215-216 ⁰ C in the form of colorless, very feiner- needles.

Example 3 Preparation of N-formylaminomethylcyclohexyldimethylamine

A stirred and cooled solution of 5 ^ 0 g of 1-aminomethylcyclohexyldimethylamine in 30 ml of chloroform, a solution of 4.7 g of chloral in 30 ml of chloroform is added dropwise. The mixture is stirred for 64 hours and then heated on the steam bath for 0.5 hours.

The excess chloroform is removed under reduced pressure ~ evaporated and the oily residue under greatly reduced pressure

distilled. L'to obtain 6.0 g N-Formylaminomethylcyclohexyldimethylamin of boiling »120 ⁰ C at 0.7 mm Hg"

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Be i .. & pi e 1
Ordering ,,.

One £ emiseh of 1.5 g 1 -

3 ml of benzoyl chloride and TO ml of pyridine were ΐ &tund; e · free " temperature-at ^ Hen-g-ellaßiiö The sieve Mlddfrde Kristailmaß will

filtered off and ffie & rmalB from "^ Spro ^ eTitigem Ithänöl iji

slert * th received .i-ie ^ zämi ^ ometkylcy ^^ kydrpöiilorid vom Fpo 245 ^ ^isi 246 ⁰ G in - "E & m- färKtö®6; i?

i. s; .p-

tiergteiiiing. from ΐ ~ ffegluorbe ^ iza ^^

diffletiiylamine

from 1.0 g 1

!. 2 ml of 4-'flüör'bängoylchlörid and 10 ml, "yridiin f frfeüiiüe-Räumtemperätür left * Up sidti biidende i C2 ^is?; täliläiaS'S ^r & is: aiäiiätriert ¹ and ffiehrmais ätts eifieiü (iemascii of ethanol and? Ither, Ufflkristaliisieit. Maü e.rhalts, = ■ 1 ^ (4 ^ fluör ^ e% zäMld ^; ometlfl) ϊα;:

öy & löhexylaime ^^ J ¹ ^ -V, - & 58-Ms = UI ^ in

form of colorless Eaile: ln «.. _; .; ^; . '■ / ■;> -. ".., -. · -. .. ■■". "- .:

B fe i S 'ρ- ϊ e 1 6.: -. ::. · - ■■■■ ^:

ajimejthyiamin . . ..,, - ■ .._. ... -. '. ■ -. ■ \ -.,. '' ■ '■ ..,.': · '■' ■ · -. '

^ Solution of. f, 0 g ^ 4 ^ Ghiorbenzöyichiöri: d- 'and 1> 8> g: i-i

in "'in 10O-ml benzene is 0.5 hours

; J8 / 121 ^:

heated under reflux on the steam bath «The excess

. under reduced pressure ■. . .

Benzene is / is distilled off. The oily residue is dissolved in water and extracted four times with 40 ml of chloroform each time. The chloroform extracts are combined and dried over anhydrous sodium sulfate. The chloroform v / ill under reduced pressure separated ο obtained 1.6 g of a white solid product from Pp. 97 to 99 ⁰ Co

The product is dissolved in 60 ml of chloroform and washed twice with 40 ml of 2N sodium carbonate each time. Per OMoiofOrniextrakt is chloroform tind ge'troöknetf · when wasserfreieni »sodium sulfate attenuated under reduced pressure * The fes-te Küökstand is from petroleum ether (60 to SO ⁰ C) uinkrist & llislert and obtained 1.5 g of 4-Chlorbenzämidomethylcyölohexyldi ^ n9thylamin mp. 105 to 107 ⁰ C. / -

Example 7 Preparation of 3r ^ -pimetiioxybenzamidomethylcyclohexyl-

A solution of 1.2 g of 3v4-Bimethoxyben2oylchlörid and 1.0 g of I ^ Amiriomethylcyclöhexyldiiaethylamin in 100 ml Benaöl is heated under reflux for 1.5 hours. The überohüöslge Böhzöl is divided. evaporated under reduced pressure and dissolved the residue in water and made alkaline. The aqueous iösüng is extracted four times with 40 ml of chloroform _r the Ghloi? Oform löaung is washed twice with 15 ml of 2N hydrochloric acid jeweilB, and the excess water is under verminder-

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- / 19 -

learn pressure ^at) ge.dampf t. The solid residue is ated urakri.stallis-from ethanol, obtaining · Ό, 5 g of 3, 4 ~ D'im'ethoxybenzainJ domethylcyclohexyldimethylamin-hydrqchlorid mp "227" to 229 ⁰ C.

Example 8

Production of 4-methylbenzamidomethylcy el ohexyldimethylamine hydrochloride

A solution of 1.0 g of p-toluyl chloride, 1.0 g of 1-aminomethyl-cyclohexyldimethylamine and 0.65 g of triethylamine in 60 ml of benzene is refluxed for 1.5 hours. The excess benzene is evaporated off under reduced pressure , the residue is dissolved in water and extracted with chloroform. The chloroform extracts are combined and dried over anhydrous sodium sulfate. The chloroform is evaporated off under reduced pressure, and an oil is obtained which solidified on cooling. An ethereal solution of the solid product is treated with excess ethereal hydrogen chloride and the excess ether is evaporated off under reduced pressure. The solid residue is recrystallized from a mixture of isopropanol and petroleum ether (80 to 100 ° C., and 0.7 g of ^ -MethylbenzamidomethyleyclQhexyldimethylamin-hydrochloride -p. 199 to 201 ⁰ Co .... · ^.: _: . =. ".,

Example; 9 ■. ., .

Production of 3-chlorobenzamido methylcyelohexyldimethylamine

li.hydrochloride -

A solution of 1.0 g of 1-AminomethyIcyelohexyldimethylamite and

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1.12 g of m-chlorobenzoyl chloride in 60 ml of benzene is refluxed for 3 hours. The precipitated product is filtered off and recirculated from a mixture of ethanol and isopropanol. 2.0 g of 3-chlorobenzamidomethylcyclohexyldimethylamine hydrochloride with a melting point of 233 to 235 ^° C. are obtained

Example 10 y

Manufacture of 2-ChlorbenzamidomethyIoyclphe ^ hydrochloride .

A solution of 1.0 g of 1-aminomethylcyelahexyldiittethylarain and 1.12 g of oZ-chlorobenzoyl chloride in 60 ml of benzo} is refluxed for 1 hour. The product which has precipitated out is filtered off and recrystallized from isopropanol. 1.3 g of 2-chlorobenzamidomethylcyclohexyldimethylamine hydrochloride of pp. 229 to 231 ^° C. are obtained.

Example 11 Preparation of Acetamidomethylcyclohexyldimethylamine

A mixture of 50 ml of acetic anhydride and 6.0 g of 1-aminomethylcyclohexyldimethylamine is heated on the steam bath for 1 hour. The excess acetic anhydride is evaporated off under reduced pressure. Then the mixture is mixed with 75 ml of ether, 10 ml of 5N sodium hydroxide ^{- s} uW 1.0 g of sodium hydroxide '. Then Na ^ i ^ mc ^ rlfonat is added and the mixture is filtered after 60 minutes. The excess ether is evaporated under reduced pressure and 7.1 g of one are obtained

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ο oily residue 3.0 g of this oily residue is distilled under highly reduced pressure _and} are obtained 2.6 g of boiling Acetamidomethylcyelohexyldimethylamin 120 ⁰ C at 0.1 mm _Hg..; .

Example 12

Production of p-toluenesulfonamldomethylcyclohexyldlmethyl- ' amln-hydroichlorld

A solution of 1.22 g of toluene-4-sulfonyl chloride w & d. 1.0 g of 1-amino methylene, yel; oiiexyldimet] 3.ylamine in 60 ml of benzene is refluxed for 45 minutes. The precipitated product is filtered off and crystallized from ethanol! 1.9 g of p-toluenesulphonamidomethylcyclohexyldimethylamine hydrochloride of pp. 226 to 228 ^° C. are obtained.

Example 13

Preparation of 1- ^ T- (3,4,5-Ti "ifflethoxybenzamidomethyl) -cyclohexylj-dimethylamine-hydrochloride

A solution of 1.5 g of 3,4,5-trimethoxybeuzoylechloride in 25 ml of benzene is mixed with a solution of 1.0 g of aminomethylcyolohexyldimethylamine in 25 ml of benzene and refluxed for 1.5 hours. The crystals that form are filtered off , washed with benzene and recrystallized from isopropanol to give ₀ 1.6 g (65 percent of theory) of 1- / ⁵ H- (3,4,5-Trimethoxybenzamidomethyl) -cyclohexyl7-dimethylamine-hydrochl.orid mp ^"0 to 199 C. , _; ■,,.

309818/121 ^, ^,

Example 14

Production of 3, 4-dichloro- ^ ~ (dimethylamine) -cyclohexanmethyl7-sulfonamide hydrochloride

A solution of 1.0g 1- (Dimethylamine) -cyclohexanole thy I in 15 ml of dry benzene is mixed with a solution of 1.57 g of 3 »4 ~ di ~ chlorobenzenesulfonyl chloride in 15 ml of dry benzene and refluxed on the steam bath for 1 hour. The reaction mixture is cooled, filtered, and the residue is washed with benzene and dried. The solid product is recrystallized from isopropanol, and 1.9 g (74 percent theory) 3 »4-dichloro - ^ - (dimethylamine) -cyclohexanmethyl7-sulfonamide hydrochloride of m.p. 206 ° C.

Example 15

Preparation of 1-1'-hydroxybenzylmethylaminomethylcyclohexyldimethylamine

6.3 g (0.025 mole) of I-benzamidomethylcyclohexyldimethylamine dissolved in 100 ml of dry benzene and added dropwise to a stirred suspension of 1.9 g (0.05 mol) of lithium aluminum hydride

added in 200 ml of dry ether. The suspension is over night

Heated under reflux and remove excess lithium aluminum hydride by dropwise addition of 4 ml! 'water, 3 ml of a 30 percent sodium hydroxide solution and 14 ml of water again decomposed. The ether / f-nsol layer is separated off, washed with water, dried over anhydrous sodium sulfate and evaporated. 5.43 g (86.2 percent of theory) are obtained

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. 23 - 2248728

amber-colored thin liquid oil. After treatment with a mixture of ν cm of ethanol and methyl iodide, after recrystallization from a mixture of ethanol and ether, 1-1'-hydroxybenzylmethylaminomethylcyclohexyltrimethyllaTnmoniumdi ^ mp. 194 to 195 ⁰ C (decomposition) in the form of colorless crystals.

B e i s ρ i e 1 16 ·

Production of 1-1'-acetoxybengylmethylaminomethylcyclOhexyldimethylamine ■ ■

1.5 g (0.0057 mol) 1-1'-hydroxybenzylmethylaminomethylcyclohexyldimethylarain will ' Heated under reflux for 3 hours with 5. ml of acetic anhydride in 5 ml of pyridine. · The solvent is evaporated under reduced pressure and the residue was azeotropically distilled. You get 1.1g (63 »2 percent of theory) of a brown viscous oil. After treatment with TO percent Ethanolic hydrogen chloride and 2 days storage in the refrigerator as well as recrystallization from a mixture of ethanol and ether one gets weak reddish-brown prisms of 1,1'-

Acet
/ oxybenzylmethylaminomethylcyclohexyldimethylamino hydrochloride from pp. 177 to 178 ⁰ C.

Example 17 Preparation of I-methylaminomethylcyclohexyldimethylamine

9.0 g (0.05 mol) of N-pormylaminomethylcyclohexyldimethylamine prepared according to Example 3 is dissolved in 100 ml of dry ether and added dropwise to a stirred suspension of 3.8 g

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(0.1 mol) lithium aluminum hydride in 200 ml dry ether was added. The suspension is refluxed for 24 hours and excess lithium aluminum hydride is decomposed by adding 8 ml of water, 6 ml of 30 percent sodium hydroxide solution and 28 ml of water dropwise. The ether layer is separated using Na ₂ SO. dried and evaporated. 7.8 g (94.2 percent of theory) of a colorless, low-viscosity oil are obtained. A portion of this oil is treated with lOprozentigem äthanoltschen hydrogen chloride, and, after Umkrißtallieation from a mixture of ethanol and ether N-Methylaminomethyleyclohexyldimethylamin dihydrochloride, mp. 232 ⁰ G bit 233 in the form of colorless needles.

Example 18

Production of 1- ^ dimethylamine -cyclohexyl / - N-ethylmethylamino-dihydrochloride

A cooled and stirred suspension of 1.0g lithium aluminum. Nium hydride in tetrahydrofuran is added dropwise with a solution of 4.0 g of acetamidomethylcyclohexyldimethylamine in 30 ml Tetrahydrofuran is added and the mixture is refluxed for 24 hours heated. The suspension is then cooled in ice and excess lithium aluminum hydride by adding decomposed by water.

The suspension is then dried over anhydrous sodium sulfate. The mixture is made using a filter aid filtered and the residue washed thoroughly with ether. the

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combined ether extracts are extracted three times with 15 ml of 2N hydrochloric acid each time, the acid solution is evaporated under reduced pressure and the solid residue is recrystallized from a mixture of ethanol and isopropanol. This gives 3.5 g of 1- ^ Tfl) imethylamino) -cyclohexyl7-l! I-äthyldimethylaminhydrochlorid of mp. 239-241 ⁰ O.

Example 19

Preparation of 1- (N-formyl-1-methylamino-methyl) -cyclohexyldimethylamine ; '

6.9 g (0.15 mol) formic acid and 15.3 g (0.15 mol) acetic anhydride are mixed without cooling and 1 hour "at tree temperature held. 5.9 g (0.034 mol) 1-methylaminomethyl-

will
cyclohexyldimethylamine. . dissolved in 12 ml of formic acid and slowly added the formylation mixture (16 ml). The mixture begins to foam vigorously and the temperature rises to 75 ^° C. The mixture is then left to stand for 2 hours at room temperature and then ^{heated on a water bath at 55 °} C. for 0.75 hours. The solvents are removed under reduced pressure, obtaining 5.32 g (77.7 percent of theory) of an amber oil which after the addition of petroleum ether (60-80 ⁰ C) of 1- (N-formyl-1-methylaminomethyl) -cyclohexyldimethylamine of melting point 59 ° to 60 ° C. results in the form of colorless prisms.

.B e 1 s ρ ie 1 20

Preparation of U-methylacetamidomethyl-I-dimethylaminocyclohexane . .

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A solution of 2.0 g prepared according to Example 17 i-Methylaminomethylcyclohexyldiniethylamino-dihydrochloride in 5 ml of 5N sodium hydroxide solution are added to 2 ml of water. Then 50 ml of benzene and anhydrous sodium sulfate are added in excess and the mixture is filtered *

40 ml of acetic anhydride are added to the benzene solution and the mixture is refluxed for 1 hour. Excess acetic anhydride and benzene are evaporated under reduced pressure to give a solid residue. This residue is made alkaline with an excess of saturated sodium carbonate solution, and 50 ml of ether and excess anhydrous sodium carbonate are added to remove the water. The mixture is filtered and excess ether is evaporated under reduced pressure. An oily residue of g after recrystallization from petroleum ether (80 to 100 ⁰ C) 0.45 N-Methylacetamidomethyl-1-dimethylamino cyclohexane is obtained, mp. 69 to? 1 ° results in G.

Example 21

Manufacture of 3 , 4-dichloro-N-methylbenzamidomethylcyclohexyldimethylamine hydrochloride

A solution of 1.16 g of methylaminomethylcyclohexyldimethylamine

Weigh ty c% γ *

dihydrochloride in 1 ml / is mixed with 3 ml of 5N sodium hydroxide solution offset. 50 ml of benzene and anhydrous sodium sulfate in excess are added, the mixture is filtered and the Benzene solution to a solution of 1.0 g of 3,4-dichlorobenzoyl chloride added in 20 ml of benzene. The solution obtained is

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Heated under reflux for 45 minutes and left to stand for two days ο The crystals that form are filtered off, and 1.1 g of ^^ - dichloro-N-methylbenzemidomethylcyclohexyldimethylamine hydrochloride of pp. 189 to 192 ⁰ CO is obtained

B e i s ρ i e 1 22

Preparation of i- / ~ 1- (3,4,5-trimethoxy-li-methyl-N -> ^ ~ 1- (dimethylaminoJ-cyclohexylT'-methyl (-benzamide hydrochloride

1.5 g / ~ "1- (methylaminomethyl) -cyclohexyl7-dimethylamine-dihydro-

will

Chloride made alkaline with 5 »0 ml of 5N NaOH» It will be

/ wix * cl

Added 20 ml of benzene, and the basic solution ^ over anhydrous NapCOnz dried The solution is then filtered, the benzene washed with Natriumcarbonatrückstand UTID / mix \, 4

■ -sr-

3,4,5-trimethoxybenzoyl chloride in 25 ml of dry benzene was added. The mixture is refluxed for 1.25 hours. The crystals which separate out are filtered off, washed with benzene, and after recrystallization from benzene, 1.5 g (61 percent of theory) 1- / ~ 1- (3,4,5-trimethoxy-N-methyl-N-; £ ~ are obtained Λ - (dimethylamine ^ -cyclohexyl / '- methyl (-benzamide hydrochloride of pp. 197 ° C.

Example 23 '' ■

Production of I-dimethylaminomethylcyclohexyldimethylamine

2.88 g (0.014 Hol) of 1- (N-pormyl-. I-methylaminomethyl-cyclohexyldimethylamino- ⁶¹ 'prepared according to Example 19) dissolved in 40 ml of dry ether and added dropwise to a stirred suspension of

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1.14 g (0.03 mole) lithium aluminum hydride in _; 150 ml of dry ether added. Excess lithium aluminum hydride is decomposed overnight by adding 3 ml of water, 2 ml of a 30 percent sodium hydroxide solution and 10 ml of water dropwise to the suspension. The ether layer is separated off _{, dried over anhydrous Na 2} SO and evaporated. f§an receives 2.34 g (87.6 percent of theory) of an oil that is slightly stone-colored. Treatment of this oil with 10 percent ethanolic hydrogen chloride gives, after recrystallization from ethanol and ether, i-dimethylaminomethyl-i-cyclohexyldimethylamine dihydrochloride of pp. 232 to 234 ^° C. in the form of colorless needles.

Example 24

Production of 3,4-dichloro- ^ i- (dimethylamine) -0 (. ~ Methylcyclohexanmethyl ^ -benzamide

A suspension of 12.0 g of lithium aluminum hydride in about 40 ml of dry dioxane is mixed with 35.8 g of 1- (dimethylamine) -cyclohexyl-

methylimine is added and the mixture is refluxed for 5.5 hours. Excess lithium aluminum hydride is neutralized with water and the residue is filtered with a filter aid. The piltrate is extracted with 50 ml of 2N hydrochloric acid and the acid extract is evaporated to dryness. The residue is dissolved in 10 ml of water, the solution is made alkaline with 10 ml of 5N sodium hydroxide solution and an _{excess of 30 ml of ether and anhydrous Na 2} CO are added. The solution obtained is filtered, the piltrate is poured over water

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- 29 - ': ■

Wi ITa ₂ SO ^ eingedampft.- The oil is' dried and distilled to an oil, and one obtains 10,7 g (30 percent of the. theory) of i-CDimethylaminoJ cl methylcyclohexanmethylamin, bp. 105 to 115 ⁰ C at 12 mm Hg.

A solution of 1, 0 g of 1- (Dirnethylamino) -Pt-methylcyelohexanmethylamin in 15 ml of dry benzene is treated with a solution of 1, 23 .g ^{3J4-liiehlor:} benzoyl chloride in 15 ml of dry benzene, and the mixture i hour on the steam bath heated under reflux. The benzene is evaporated and the residue made alkaline with 2N FaOH and extracted three times with chloroform. The combined chloroform extracts are dried over anhydrous HagSO * and evaporated to an oil. The oil is dissolved in hot petroleum ether (up to 8O ⁰ C), decolorized with charcoal, and after cooling 1, 25 g (62 percent of theory) 3,4-dichloro- ^ ~ "1- (dimethylamino) -oC-methylcyclohexanemethyl7-benzamide from mp ₀ 111 to 114 ⁰ Co

B e i a ρ i e 1 25

Preparation of 2,4-dichloro - ^ "l - ( dimethylamino) - C ^ -methylcyclohexanmethylj-benzamide

A solution of 1.0 g of i-i-dimethylamino-cC-methylcyclohexanemethylaman in .15 ml of dry benzene is mixed with a solution of 1.23 g of 2,4-dichlorobenzoyl chloride in 15 ml of dry benzene and the mixture is heated under reflux for 1 hour is evaporated and the residue is made alkaline with 2N NaOH and extracted three times with chloroform. The Ver-

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Certain chloroform extracts are dried over anhydrous ^ and evaporated to an oil. The oil is dissolved in hot petroleum ether (60 to 80 ⁰ C), decolorized with charcoal, and after cooling 0.9 g (44 percent of theory) 2 _{tons of} 4-Diehlor- / T- (dimethylamino) -öi- -methylcyclohexanmeiihylJZ-benzamide from Ppο 123 to 126 ⁰ Co

Example 26

Preparation of 3 »4-dichloro ^ 1- (dimethylamino) -Oi.-methylcyclohexanemethyl ^ -sulfonamide

A solution of 1.0 g of 1- (dimethylamino) -oC-methylcyclohexanemethylamine in 15 ml of dry benzene is treated with a solution of 1.23 g of 3,4-dichlorobenzenesulfonyl chloride in 15 ml of dry benzene and the mixture under reflux for 1 hour Steam bath heated. The benzene is evaporated and the residue is made alkaline with 2N NaOH and extracted three times with chloroform. The combined chloroform extracts are dried over anhydrous Na ₂ SO. dried and evaporated to an oil. The oil is dissolved in hot petroleum ether (80 to 100 ⁰ O) , decolorized with charcoal, and after cooling, 0.88 g (40 percent of theory) 3, 4-DiChIOr - / ""! - (Whore thylamino) - ¹ * -methylcyclohexanemethyl7-sulfonamide from bp 111 to 115 ° C

Example 27

Production of 2-CHH.or- ^ ~ 1- (dimethylamino) - «> t-methylcyclohGxan-

methyl / benzamide hydrochloride

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A solution of V ₅ Og 1- (dimethylamino) -c ^ -methyl.cyelohexanemethylamine in .15 ml of dry benzene and a solution of 1.03 g of 2-chlorobenzoyl chloride in 15 ml of dry benzene are mixed and refluxed for 1 hour. The. Crystals that form on cooling are filtered off and recrystallized from so'propanol. 0.9 g (45 percent of theory) 2-chloro - ^ "1- (dimethylamino) -o6_methylcyclohexanmethyl7-tenzamide hydrochloride of melting point 227 to 228 are obtained ⁰ C.

Example 28

Manufacture of 3,4-dichloro-N-methyl-H -, / "1 - (dimethylamine) ~ oc methylcyclohexanemethyl / '-' benzamide hydrochloride · ·. ,

A solution of 1.0 g of 1- (dimethylamino) -N, oC-dimethylaminocyclohexanemethylamine in 15 ml of benzene is mixed with 1.14 g of 3,4-dichloro-benzoyl chloride in 15 ml of benzene and refluxed for 1 hour Crystals which separate out on cooling are filtered off, dried and recrystallized from isopropanol, giving 0.5 g (24 percent of theory) of 3j4-dichloro-N-methyl-li-f "i - (dimethylamino) - Ct-methyleyclohexanemethyl7 Benzamide hydrochloride of mp. 212 ⁰ G.

Example 29

Production of 2-chloro-NHnethyl-N- / ~ 1- (dimethylamine) -eimethylcyclohexanraethA'-lJZ-benzamid-hyäroehloriä :

A solution of 1.0 g of 1- (dimethylamino) -1,2-dimethylcyclohexane

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methylamine in benzene is mixed with a solution of 0.97 g of 2-chlorobenzoyl chloride and refluxed for 4 hours. The crystals which separate out on cooling are filtered off, and a hygroscopic solid is obtained which is dissolved in 50 ml of water and made alkaline with 5N NaOH. The suspension is extracted three times with 50 ml of chloroform each time, the combined chloroform extracts are washed with 50 ml of water and _{dried over anhydrous Ma 2} SO /. 'The chloroform is evaporated, the residue is dissolved in hot petroleum ether (80 to 100 ⁰ C), treated with charcoal and evaporated to dryness. A solution of the residue in ethyl acetate wiua subjected to a chromatograph with aluminum oxide filling and eluierf with Xthylacetat. A suspension of the oil in dry ether is mixed with essential HCl drop by drop until the solution is acidic. The supernatant liquid is separated off and the solid residue is rubbed with dry ether and washed. A white powdery product is obtained. The residue is recrystallized from a mixture of ethanol and ether, and 0.24 g (13 percent of theory) of 2-chloro-N-methyl-N - / ^ 1- (dimethylamine) - «* - methylcyclohexanmethylZ- benzamld hydrochloride of m.p. 214 C.

Example 30

Preparation of 1- ^ f "3,4-dichlorobenzoylaminoinethyl 7-ii-methyl-N-benzylcyclohexylamine

A solution of 2.32 g of 1-aminomethyl-N-methyl-N- benzylcyclohexylamine in 50 ml of benzene is mixed with a solution of 2.095 g

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22A6728

3,4-Di.chlorbenzoylehlorid added in 50 ml of benzene and the mixture. Heated under reflux for 1 hour. The retained solution is cooled, washed three times with 50 ml of 2N sodium hydroxide solution each time and 100 ml of water each time, dried over anhydrous Έ & 2 ^^ μ and evaporated. 4.0 U of white XristaXie, seeds are obtained. Recrystallization from cyelohexane gives 3 »583 g (89% of the theory) 1 ~ ^ 3 _f 4 ~ dichlorobenzene: oylamine © -

* yöm Ep. H39

Ils H45®'Q fn Boaaii welaaex Brismein.

Manufacture yom i - ^^ ninome1; jhyI ^ N- ^ 3netllyl · "N-lDenzylcyclohexyZgmin

A tubed solution of 13, f δ g B
cliiorid and. 9 »3 g in 12 Oyclohexanon; ml water ■.-Is added under ice-water cooling with a solution of 5,145 E of sodium cyanide in 25 ml water dropwise. 2) the resulting mixture is stirred overnight, diluted with water and four times with each

■ *

200 ml of ether extracted. The combined ether extracts are washed four times with 500 ml of water each time, dried over anhydrous NagSO ^ and evaporated. This gives 20.4 g -a '■''orange oil, 10 g of the crude oil are dissolved in 10 ml of benzene and placed on a chromatography column (50 χ 4 _Å ■ *! Cm) filled with silica, a mixture of benzene and Ether in a ratio of 1: 1 is used as an eluant. "";"4 fractions of 250 ml each are obtained.

The praccions 2 and. 3 are combined, evaporated- and again on a chromatography column (50 χ 4.4 cm) with. Alumi-

3Q9ei8 / 1212 -

nium oxide filling given unu with a device _yc ., _} g _en z _C j. _lL ^, j ether separated in a ratio of 4: 1 as Jiluierurusmittel. 8 fractions of -100 ml each are obtained. pie tractions 3 to 6 v / ground united and evaporated. Hau receives

i-i. orange

7.0 g of a colorless 01g. 10.4 g of the remaining Γ ^ ₀ v; ground

"all in all

Purified in a similar manner, and 14 g (61 percent the theory) i-cyano-N-methyl-N-benzylcyclohexylaiain in ίΌπη of a colorless oil.

A stirred suspension of 12.7 g of lithium aluminum hydride in 500 ml of ether, which is cooled in an ice water bath, becomes 57> 0 g i-Cyano-N-methyl-lI-benzylcyclohexylamine in 50 ml of ether drop by drop offset. I) ao obtained mixture v / ird over ft & ßht and under "Ice water cooling V / water in excess drop by drop added to decompose excess lithium aluminum hydride. The mixture is filtered with a filter aid.

,will be

The layers obtained / separated and the aqueous layer extracted three times with 200 ml of ether each time. The combined ether extracts are washed four times with 200 ml v / water each time, over anhydrous lla ^ SO. dried and evaporated. 52.6 g of a colorless oil are obtained. This oil will

distilled, and l-amino-N-methyl-W-benzylcyclohexylamine is obtained from bp 116 to 14 ° C at 0.05 to 0.5 mm Hg.

Example 32

Manufacture ν on H ~ / "~ 1 -He t hy 1 -N -ho t hyl -Ii-bonayl eye lohexyl ar :: hi / ~ benzamide and hydrochloride ^:

A solution of 3.142 g of i-Auinomethyl-N-methyl-Ii-bengylcyclo-

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BATH

Hexylamine in 75 ml of dry benzene is treated with a solution of 2.108 g (1.73 m * -U benzotrichloride in 75 ml of dry benzene and the solution is heated under reflux for 1 hour. The solution is then cooled for two ~ ± washed twice with 100 ml of 2N hydrogen hydroxide solution each time and four times with 200 ml of v / water each time, dried over anhydrous liquid, dried and evaporated. 5.2 g of white crystals are obtained. 60 ⁰ O) in a ratio of 1: 1 you get 4 _} 341 g (86 percent of theory) Έ- £ ~ Λ -Met> y1 - ^ - methyl-lY-benzylcyclohexylamine T'-benz amide of melting point 118 " to "124 ⁰ C in the form of white prisms.

0.673 g of N- ^ T-Möthyl-N-methyl-IT-'benzylcyclohexylaniin / '- benzamide are dissolved in 5 ml of absolute ethanol and 5 ml of ethereal HGl are added. The resulting solution is evaporated to a white semicrystalline solid which is dissolved in a small amount of ethanol. By adding ether drop by drop and grinding and cooling with ice water, white crystals precipitate, which are filtered off. Recrystallization from ethanol with the addition of ether 195 obtained 0.895 g (93 percent of theory) U ^ f ~ 1-methyl-N-methyl-N-benzylcyclohexylamin / ⁷ -benzamide hydrochloride FROM ₁ mp. 200 ⁰ G in Form of a white powder. ·> ^ ■

B e i s ρ i e- 1 33

Production of JT- / ~ 1-methyl-H-ynethylcyclohexylamino7-benzaraid and -hydro chi or id

3.365g li ~ / T-methyl-I'T-iiiethyl- prepared according to Example 32

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BATH ORIGINAL

τ become

Il-bensy] cyclohexylamine-benzamide dissolved in 50 nl Ksaigsäurc. 0.2 g of palladium black are added and the atmosphere is saturated with hydrogen with vigorous stirring for 4 hours at atmospheric pressure. "The catalyst is filtered off through Celite, the filtrates are diluted with water and made alkaline with 5N sodium hydroxide solution. The cloudy solution obtained is extracted four times with 200 ml of ither each time, the ether extracts are washed four times with 200 ml of water each time, _{dried over anhydrous Na 2} SO and evaporated to give 2.4 g of a colorless oil chromatographic column (30 χ 3 "O cm) with Aluminiumoxidfüllunc and 5 100 ml fractions with ether and further 5 100 ml fractions with methanol eluierliSie ¹ ^ 7 to 9 are combined and evaporated. to give 2.253 g (91 percent of theory) of N - / ~ 1-Methyl-N-methylcyclohexylamine7 - benzamide in the form of a pale yellow oil.

0.493 g of N - ^ / fi-methyl-N-methylcyclohexylaminy-benzamicl are dissolved in 2 ml of absolute ethanol, and 1 ml of ethereal HGl is added. The resulting solution is evaporated and the oil dissolved in a minimum of absolute ethanol. White crystals fall by dropwise addition of ether and trituration of the _f are filtered off. After recrystallization from absolute ethanol with the addition of ether, 0.427 g (75 percent of theory) of N- / ~ 1-methyl-N-methylcyclohexylamine-benzarcide hydrochloride with a melting point of 152 ° to 154 ° C. is obtained in the form of white prisms.

3 0 9 818/1212

',' B e i s ρ i -e ΐ 34 "

Production of 2,6-dichloro - ^ / ~ 1 - (diraetliylamino) -cycloac <: MmethylT'-bonzylamine dihydrochloride ...

A solution of 1.25 g of 2,6-dichlorobenzyl chloride in 15 ml of dry benzene is mixed with. a solution of 1.0 g of 1-aminomethylcyclohexyldimethylamine in 15 ml of dry benzene and heated on the steam bath for 1.5 hours. The colorless solution obtained is first evaporated to dryness and then again with ethanol. A basic semi-solid product is obtained. This product is dissolved in 15 ml of water, acidified with 2N HCl and extracted twice with 25 ml of ether each time. The ether extract is discarded, the aqueous acidic solution is cooled, made alkaline with 5N NaOH, and the basic solution is extracted three times with 100 ml of ether each time and dried over anhydrous UapSO «. The ether extract is evaporated to dryness, and you. receives, 1,, 4 g of one. Oil which is converted to ₁₉ 9 g of the dihydrochloride and recrystallized from ethanol. This gives 0.5 g of _2,6-t Di.chlor- / ~ 1- (dimethylamino) -cycloheXc ^ methylT'-benzylamine dihydrochloride from Pp. 216 ⁰ C (decomposition). . . ; . , ... .. ".

At spie 135

Ilerstelluriff of -1- (1-amine-omothylcyclohexyl) - ^ pl peri ^ din ■ - "■ - · -"'

■ become

1.92 g (0.01 lic ^x '- (1-Oyanocyclohexyl) -piperidine in 50 ml

dissolved in dry ether and added dropwise to a stirred üuüpension of 0.76 g (0.02 mol) of lithium aluminum hydride in 100 ml

added to dry ether. The suspension is stirred overnight and more precisely; Example 1b worked up. I-Ian received; 1.4 "," (74.4 percent of theory) of a colorless oil. Treatment with ethanolic HCl gives 1- (I-aminomethylcyclohexyl) -pipderidine dihydrochloride with a pp. 256 to 257. ^U C in Foriü colorless needles.

The 1- (1-Gyanocyclohexyl) -piperidin is produced as follows:

24.1 g (0.2 mol) of piperidine hydrochloride and 13.0 g (0.2 hol) of potassium cyanide are dissolved in 80 ml of water and 160 ml of ethanol. A solution of 19.6 g (0.2 mol) of cyclohexanone in 40 ml of ethanol is added dropwise to this stirred solution, and the mixture is refluxed for 24 hours. The ethanol is then evaporated off under reduced pressure and the residue extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous Na SO and evaporated under reduced pressure. 27.0 g (68.8 percent of theory) of a pale amber-colored oil, which crystallizes on standing, are obtained after recrystallization from ethanol iO-CyanocyclohexylJ-piperidin from ίρ. 67 to 68 ⁰ G in the form of colorless platelets.

B e i s ρ i e] 36 Preparation of 1 ~ / ~ 1- (Formamidomethyl) -cyclohexyl7-piperidine

4.65 g of chloral v / ground dropwise to a cooled gob of 5.9 g of 1- _< / ~ 1 - (, lminomethyl) -cyclohe: cyl7-piperidine in 30 ml

309818/1212

~ 39 - / ". ■ -

add dry chloroform. ν The mixture: i v-'ird 16! Stirred for hours at cold temperature and then heated for 30 minutes. The solution obtained is evaporated to dryness and the oily residue is evaporated with ether today. 7 ^ 9 g 9es . '' _ brown oil residue are strong / reduced pressure to distilled ^1, giving "5.1 g i- ^ i- (Formamidomethya -) - cyclo-: hexyl7 PIP © riäin from Kp 170th" to 172 ⁰ C in 1.7 mm Hgv '

; B eis / p ie 1 37 _: -. ■ ~ ■ '

Preparation of 1- / T ^ acetamiäomethyl) -cyGlohexyl7-piperidine.

9.8 g of 1 ~ / ~ 1 - (jtoiinomethyl) -cyGloheXyl7-rpiperidine are added dropwise to 40 ml of ice-cold acetic anhydride with constant stirring. ..- The mixture is stirred for another 1.5 minutes.

Stir and reflux for 1.25 hours. The solution obtained is evaporated to dryness, and the oily liquid is evaporated again with a mixture of ethanol and benzene. * The residue is dissolved in 30 ml of water and treated with 5 ' n NaOH 'adjusted to pH 10. -The solution is washed three times with. 50 ml Chlorof örm extrahiertiUnd., the chloroform extracts / ^^ t. ^ Lasser GeV / ascheii and v / asserfreiem Na ₀ SO, dried "the chloroform solution is evaporated under vermihderteiii. pressure to dryness. and there is obtained 14.8 g of a basic oil, which is treated in Petroiäther '(60 to 80 ⁰ C) and treated with charcoal * After filtering die.Lösung a ~ b ^ is.

"Cooled _v and oils \ \ -: λ> -> l-Dcl2o, Idenden Iris Talle from Petroiäther ..""■ - (60 to 80 ⁰ C) umkristalXisiert Man Avail- 7, airi.idoinetliylO-cyclohexylT'-piperidin from. Pp. 104 ⁰ C:

BATH

Example 38

Preparation of l- (4-fluorobenzamidomethylcyclohexyl) piperidine A mixture of 1.5 g! - (l-aminomethylcyclohexyl) piperidine, 2 ml 4-fluorobenzoyl chloride and 10 ml pyridine is left to stand for 1 hour at room temperature. The crystals which form are filtered off, and 2.55 g (86.6 % of theory) of 1- (4-fluoro-benzamidomethylcyclohexyl) piperidine hydrochloride with a melting point of 243 ° -245 ° C. (decomposition) are obtained in weak form lemon yellow rosettes.

Example / 39

Preparation of 1- (2-chlorobenzamidomethylcyclohexyl) piperidine A mixture of 1.5 g! - (l-aminomethylcyclohexyl) piperidine, 2 ml 2-chlorobenzoyl chloride and 10 ml pyridine is left to stand for 1 hour at room temperature without any visible reaction. The mixture is therefore refluxed for 1 hour, cooled, diluted with water, made alkaline with ammonia and extracted with chloroform. The chloroform extract is washed with water _{, dried over anhydrous Na 2} SO ₂ and evaporated. 3 * 0 g (79 * 2 % of theory) of a viscous brown oil are obtained. After dissolving the oil in ether and passing in dry HCl-Ges in the solution obtained l- (2-Chlorbenzamidomethylcyclohexyl) piperidine hydrochloride, mp. 234-2J6 ⁰ C after recrystallization from a mixture of ethanol and ether as pale r'Jil '. jiibrown rosettes.

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Example 4P ■ · ^: '' .. ■ ■ - '

Preparation of 1- (3? ^ - dichlorobenzamidomethylcyclohexyl) piperidine A mixture of 1.5 g of 1-Cl-aminomethylcyclohexyl) piperidine, -2.0 g of 3i4-flour benzoyl chloride and 10 ml of pyridine is left to stand for 1 hour at room temperature, whereupon the entire reaction mixture solidifies. · After repeated recrystallization from a mixture of ethanol and ether, 1.7 g (54.8 '% of theory) of 1- (^, 4-Dichlorbenzamidomethylcyclohexyl) -piperi "din obtained. Hydrochloride, mp. 235-236 ⁰ C. (Decomposition) in the form of small '.' colorless needles. ■ ■

Example _; 4l ^; :

Production of I- / I- (3 »4,5-trimethoxybenzamidomethyl) -cyclohexy !!, ^ · piperidine-hydrochlori'd . .. ''. ·. > ■ ^:

A solution of 1.2 g of 3 ', 4,5-trimethoxybenzoyichloride and 1.0 g of 1- (aminomethyl) cyclohexy] ^ piperidine in 50 ml of dry benzene is refluxed for 1.5 hours. The crystals which separate out are filtered off, washed with benzene and recrystallized from isopropanol. 1.2 g (58 % of theory) are obtained

_t hydrochloride of mp, 24I ⁰ C (decomposition) V _:

Example 42 ;

Production of / * (l-piperldinocyclohexyl) -methyl / -carbamic acid ~ ethyl ester ■ ~ '.''- ■' -

! A "dissolution of 1.0 g l>/" l- (aminomethyl) -cyclohexyl / -plperidin * Itt -10 iftl dry benzene, is 0 * 6 g / AETJ ^ lchlorf oitii $ it i.rt ^v '10 ml dry benzene, mixed and refluxed for 30 minutes

3 09818/1212

heated. The crystals which precipitate are filtered off and the residue is washed with benzene. After recrystallization from isopropanol, 0.7 g (45 % of theory) / (1-piperidinocyclohexyl) methyl / arbamic acid ethyl ester with a melting point of 208 ° C. (decomposition) is obtained.

example kj>

Production of 1- / Ί- (p-nitrobenzamidomethyl) -cyclohexyl / ~ pipe ridine hydrochloride

Solutions of 2.0 g of 1- / 1- (aminomethyl) -cyelohexyl / -piperldine in 15 ml of dry benzine? ¹ and 1.9 g of p-nitrobenzoyl chloride in 15 ml of dry benzene are mixed and heated on the steam bath for 50 minutes. / The crystals that separate out on cooling become

filtered off and recrystallized from isopropanol. 2.65 g of a solid crystalline product are obtained. The solid product is dissolved in hot ethanol, acidified with ethereal HCl and evaporated to dryness. After recrystallization from ethanol, 61 % of theory (p-nitro-benzamidomethyl) -cyclohexyl7-piperidine hydrochloride with a melting point of 254-256 ° C. is obtained as the residue.

Example 44 Preparation of 1- / Ί- (p-aminobenzamidomethylj-cycloliexy! / »Piperidine

A solution of 2.0 g of l- / l- (p-nitrobenzamidomethyl) -eyclohexyl / -plperidin hydrochloride in 20 ml of water is made alkaline with 5N MaOH and the suspension is extracted three times with 50 ml of chloroform each time. The combined chloroform extracts are dried over anhydrous Na ₂ SO ₁ ^ and evaporated to give 1.7 g of a yellow solid product

309818/1212

suspended in 100 ml of ethanol containing Raney-Niekel dropwise a solution of 5 ml of hydrazine hydrate in 5 ml of ethanol added over a period of 30 minutes. The suspension obtained is stirred for a further 3.5 hours, for 30 minutes heated to the boiling point and filtered with a filter aid, the filtrate is evaporated to dryness, and the formed

will,
white crystals / recrystallized from benzene. 0.95 g (50% of theory) of 1- / Ί- (p-aminobenzamidomethyl) -cyclohexyl / -piperidine with a melting point of 160-163 ° C. are obtained. . '

Example. 45 ■. ',

Preparation of 1- (l-methylaminomethylcyclohexyl) piperidine 4.48 g ((/, 02 mol) 1- (1-formylaminomethylcyclohexyl) rpiperidine are reduced with 1.52 g (0.04 mol) lithium aluminum hydride and the resulting suspension according to Example Ib worked up 4.1 g (93 »0 % of theory) of an amber-colored, low-viscosity oil which, after treatment with ethanolic HCl, 1- (1-methylaminomethylcyclohexyl) -piperidino-dihydrochloride of melting point 259-260 ° C. are obtained in the form of colorless needles.

Example "46 ·

Production of l- / l- (Kthylaminomethyl) '- cyclQhexyl / -piperidin and its dihydrochloride

A solution of 5 »5 g l- / l- (Acetamidomethvl) -cyclohexyl / -piperidine in 50 ml of dry tetrahydrofuran is added dropwise with stirring added over a period of 10 minutes to a suspension of 3> 8 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The eriici .. oüii ^ mixture is refluxed for 5 * 5 hours and stirred for 16 hours at room temperature. 10 ml of water

309818/1212

are added dropwise to remove excess lithium aluminum hydride to decompose (the gray suspension turns white). '

The suspension is filtered with a filter aid, washed with ether and dried over anhydrous NapSOj. The dried filtrate is evaporated to dryness under reduced pressure and 5 g of the remaining oil are distilled under greatly reduced pressure. This gives 3 »5 g l- / l (Äthylaminomethyl) -cyclohexyl / -piperidln, bp, 138-144 ⁰ C at 5" 5 mm Hg.

3 »5 g of this base are added to the Converted dihydrochloride and recrystallized from ethanol. Man thus obtained 2.1 g of l- / l- (ethylaminomethyl) -cyclohexyl / -plperidine dihydrochloride of m.p. 246-247 ° C (decomposition).

Example 47

Preparation of! - (N-Formyl-1-methylaminomethyloyclohexyl) piperidine

13.8 g (0.3 mol) of 98 to 10% formic acid and 30.6 g (0.3 mol) of acetic anhydride are kept at room temperature for 1 hour without cooling. 4.2 g (0.02 mol) of l-(l-methylaminomethyl-cyclohexyl) piperidine are dissolved in 15 ml of formic acid, and 25 ml of the formylating agent are slowly added. This results in vigorous foaming and the temperature rises to 60 ^° C. The mixture is then at overnight

.will a

Let stand room temperature, and the solvent / evaporated under reduced pressure. 3 # 79 g (80 % of theory) of a viscous amber-colored oil which crystallizes on cooling are obtained. After recrystallization from petroleum ether (60-80 ° C)

309818/1212

1- (N-formyl-1-methylaminomethylcyclohexyl) piperidine is obtained from. M.p. 94 ⁰ C. '''' ■

Example 48 Production of! - (l-Dimethylaminomethylcyclohexyl) piperidine

.2, ^ 8 g (0.01 mol) of l-CN-formyl-l-methylaminomethylcyclohexyl:) - piperidine are dissolved in 50 ml of dry ether and added dropwise to a stirred suspension of 0.76 g (0.02 mol ) Lithium aluminum hydride in 100 ml of dry ether added. The suspension is stirred overnight and the product obtained is worked up with lithium aluminum hydride in accordance with the above examples. After the ether has evaporated, 1 * 59 g (72.1 % of theory) of a colorless, thin oil which, after treatment with 10 percent ethanolic HCl, 1- (l-dimethylaminomethyleyclohexyl) piperidine dihydrochloride of melting point 224 ⁰ C results in the form of colorless needles after recrystallization from a mixture of ethanol and ether.

Example 49

Preparation of N-methyl-N - / "(l-piperidinocyclohexyi) -methyl / - ; acetamide

A mixture of 1.9 g (0.005 mol) l- / l - / "(methylamino) -methyl / -cyclohexyl / -piperidine and 10 ml acetic anhydride is heated for> 0 minutes on the steam bath. The solution is evaporated to dryness and 5 ml of water are added to the residue, then a saturated solution of 10 ml of sodium carbonate is added and the alkaline solution is extracted five times with 50 ml of chloroform each time and dried _{over anhydrous Na 2 SO 4}

309818/1212

evaporated to dryness and the oily residue evaporated again with ether. The residue is then dissolved in petroleum ether (60-80 ° C.), decolorized with charcoal and filtered with a filter aid. The combined filtrates are evaporated to dryness, and one obtains \, J> g of N-methyl-N - / "(~ piperidinocyclohexyl) -methyl / -acetamide.

Example 50 Production of N-methyl-N - / "(l-

dichlorobenzamide hydrochloride

A solution of 1.1 g (0.005 mol) 1 ~ / l - / "(Me thy lamina) ~ me thy l / -cyelohexyl / -piperidine in 25 ml of dry benzene and a solution of | 1.0 g (0.005 mol 3,4-dichlorobenzoyl chloride in 50 ml of dry benzene are mixed and heated under reflux for 1 hour on the steam bath. The precipitated product is filtered off, washed with benzene and dried. 1.6 g of a mp 222 ° C. (decomposition) are obtained ).

After recrystallization from isopropanol, 0.9 g of N-methyl-N - / "(1-piperidinocyclohexyl) -methyl / -5,4-dichlorobenzylidyl chloride is obtained of m.p. 2159 ° C (decomposition).

Example 51

Preparation of 1- (l-aminomethylcyclohexyl) -4-methylpiperazine 4.1 g (0.02 mol) of l- (l-cyanocyclohexyl) -4-methylpiperazine are dissolved in 100 ml of dry ether and stirred dropwise. Suspension of 1. ^ 2 g (0.04 mol) of lithium oil iniuiHhy <? RiU in 200 ml of dry ether was added. The suspension is stirred overnight and excess lithium aluminum hydride through

3 0 9 818/1212

dropwise addition of 4 ml of "water, 3> ^ ml of a sodium hydroxide solution and 14 ml of water Oprozentigen decomposed. The A'therschicht is separated, dried over anhydrous und'eingedampft NapSCk. This gives 5.48 g (82.9 f ° of theory ) of a colorless, thin oil. A portion of this oil is refluxed in 10 ml of ethanol and an excess of methyl iodide for 0.5 hours

yellow needles of, ■
heated and one receives / 1- (l-methylaminocyclohexyl) -4-methylpiperazine-dimethyl iodide, -die ^ are recrystallized from a mixture of methanol and ether. Pale yellow needles with a pp. 24> 245 ° C. are obtained.

Example 52

■ / ■ '■ ·

Production of 1- (1-formyläminomethylcyolohexyl) -4-methylpiperazine ,

6.9 g (0.15 mol) formic acid and 15> 3 g (0.15 mol) acetic anhydride are mixed with one another without cooling and kept at room temperature for 1 hour. 8.4 g (0.04 mol) of 1- (1-aminomethylcyclohexyl) -4-methylpiperazine are dissolved in 12 ml of formic acid, ₅ and 16 ml of the polymerization mixture are added. This causes vigorous foaming and the temperature rises to 70 ° C. The mixture is then left to stand for 2 hours at room temperature and then heated on a water bath at 55 ° C. for 0.75 hours. The solvents are removed under reduced pressure, and 6.0 g ( 66.1% of theory) of a viscous brown oil are obtained, which by recrystallization from petroleum ether (80-100 ° G) l- (l-formylaminomethylcyclohexyl) -4- methylpiperazin of mp. 97-98 ⁰ C in the form of colorless plates results.

3098 18/1212

Example 53 Production of! - / "! - (AcetamidomethylJ-cyclohexyl / '- ^ - methylpipe-

10.57 g l - / "l- (aminomethyl) -cyclohexyIU-4-methylpiperazine become slowly to 40 ml of stirred, ice-cold acetic anhydride

and the mixture is stirred for an additional 15 minutes. The mixture is then heated under reflux for 1 hour. The resulting solution is evaporated to dryness and the residue is evaporated ^twice with a mixture of ethanol and benzene. Thereafter, the · residue is dissolved in water, the solution is treated with 5ώ _outward f a pH value of I ¹ I, extracted with chloroform, dried over anhydrous Na ₂ SO. ₁ dried and evaporated. The residue is dissolved in hot petroleum ether (80-10O ⁰ C), decolorized with charcoal and cooled. The crystals that form

₇ 100 ° ΰ

are recrystallized from petroleum ether (80-). C. This gives 8.3 g (65 percent of theory) of l- £ l- (acetamidomethyl) -cyclohexyl7- ¹ imethylpiperazin of mp. 110-111 ⁰

Example 5 ^

Production of! - / "! - (3, ^ - dichlorobenzamidomethyp-cyclohexy 17-4-methylpiperazine

A solution of 1.05 g of 3, ^ - dichlorobenzoyl chloride in 10 ml of benzene a stirred solution of 1.06 g is added dropwise in Ί0 minutes l-n-fAminomethyD-cyclohexyU - ^ - methylpiperazine in 15 ml of benzene admitted. The mixture is refluxed on the steam bath for 1 hour: '. and the resulting solution evaporated. The firm one The residue is dissolved in ethanol, acidified with ethereal HCl and evaporated to a white solid product. This product

309818/1 2 \ 2

'"''Vi ₁₉ _ ■:" 22A67 28

is suspended in water with 5N NaOH. made alkaline and extracted with chloroform '. The combined chloroform _{extracts are dried over anhydrous Na 2} SOu and evaporated. The solid residue is dissolved in hot petroleum ether (80-100 ⁰ C), decolorized with charcoal and recrystallized from petroleum ether (80-100 ⁰ C). 0.95 g ( ² % of theory) of 1-A- (3, M-Oi chlorobenzamidomethyl) -cyclohexyl / ^-1 * ^{-n i-} ethylpiperazine of melting point are obtained.

Example 55 -

Production of l - / "l- (3 _? ^ _> 5-trimethoxybenzamidomethyl) -cyclohexyl7-4-methylpiperazine hydrochloride

A solution of 2.2 g of 3,4,5-trimethoxybenzoyl chloride in 25 ml of dry Benzene is mixed with a solution of 2.0 g of l- / l- (aminomethyl) -cyclohexyU-Jj-methylpiperazine mixed in 25 ml of dry benzene and refluxed for 1 hour. The crystals that form who filtered off, washed with benzene and from a mixture

,and
recrystallized from isopropanol ether. 1.9 g (^ 5> 4 percent of theory) of 1- / 1- (3,4,5-trimethoxybenzamidomethyl) -cyclohexyiy- ^ methylpiperazine hydrochloride with a melting point of 208-209 ° C. are obtained

Example 56 -

Production before x l- (l-tosylaminOmethylcyclohexyl) - ⁱ l-methylpiperazine

5 g! - (l-aminomethylcyclohexylJ - ^ - methylpiperazine are added to a 10 percent strength sodium hydroxide solution and 0.5 g p-toluenesulfonyl chloride, and the mixture is shaken slightly. The crystals that form are filtered off, washed with water and removed from 95 percent strength ethanol recrystallized. This gives 0, ¹ I g

309818/1212

(46.2 percent of theory) of 1- (l-TosylaminomethylcyelohexylJ- ¹ J-methylpiperazine, mp. 128-13O ° C colorless in the form of needles.

Example 57

Production of! - (l-Methylaminomethylcyclohexyl ) - ^ - methylpiperazine

5.97 ß (0.025 mol) of 1-d-formylaminomethylcyclohexylJ - ^ - methylpiperazine are dissolved in 100 ml of dry benzene and / dropwise a stirred suspension of 3.8 g (0.1 Mo Jy lithium aluminum hydride added in 200 ml of dry ether. The suspension is refluxed for 4 days and excess lithium aluminum hydride decomposed by the dropwise addition of 8 ml of water, 6 ml of a 30 percent sodium hydroxide solution and 28 ml of water. the Ether / benzene layer is separated over anhydrous Na ^ SO ^. dried and evaporated. 5.2 g (93.0 percent of theory) of an amber-colored, low-viscosity oil which neither crystallizes, are obtained still forms stable salts. After distilling the oil under reduced pressure, 1- (1-methylaminomethylcyclohexyl) -4-methylpiperazine is obtained as a colorless oil.

Example 58 Production of 1- / 1- (ethylaminomethyl) -cyclohexyl / -4-methy! Pipe-

razine and its dihydrochloride

A stirred solution of 3 g of lithium aluminum hydride in 40 ml of dry tetrahydrofuran is added dropwise with a solution of 3.0 g of IZ * l- (acetamidomethyl) cyclohexyl / -4-methylpiperasine in ^l \ 0 ml.

dry tetrahydrofuran added. The mixture is stirred overnight, and the resulting suspension is refluxed for a further 6 hours

309818/121 2

heated and excess lithium aluminum hydride neutralized with water. The mixture is filtered and the piltrate is _{dried over anhydrous Na 2} SOj and evaporated to an oil which can be dissolved in a. Microdistillation device disconnected. This gives 1.96 g (69 percent theoretical) - / "- (Äthylaminomethyiy-cyclohexylJ - ^ - methyl piperazine, bp 105-109 ⁰ C at 35 mm Hg as a colorless oil. ''.

An excess of ethereal HCl is added to a solution of 1 _S 5 g! - / 1-CAthylaminqmethylJ ^ cyclohexyiy- ^ methylpiperazine in 20 ml of ether. This suspension is evaporated to dryness and

twice
the oil residue evaporated with a mixture of ethanol and ether. ' The residue is then dissolved in a small amount of hot ethanol, the solution is cooled and excess isopropanol is added. The crystals which separate out are filtered off and recrystallized from a mixture of ethanol and isopropanol. One obtains ₉ 15 g! - / "! - (Ethylaminomethyl) -cyclohexyl / - ⁱ J-methylpiperazine dihydrochloride, with melting point 231-

Example 59 .

Production of! - (l-Methylformylaminomethyl-l-cyclohexyl) - ^ - methylpiperazj.n "\. ■ ,, - ..

3.5 g (0.07 mol) formic acid and 7.65 g (0.07 mol) acetic anhydride are mixed without cooling and 1 hour at room temperature held. 2 ^ 25 g (0.01 mol)! - (l-MethylamiriomeUiyl-lcyclohexyD - ^ - n. ^ T hylpiperazine are dissolved in 6 ml of formic acid, and 8 ml of the formulating agent are added. The mixture begins to foam violently and the temperature rises

309 818/1212.

60 C. The mixture is then left to stand for 2 hours at room temperature and then heated on a water bath at 55 C. for 0.75 hours. The solvents are removed under reduced pressure, obtaining 2.13 g (83.3 percent of theory) of a reddish brown oil, which after recrystallization from petroleum ether (80-100 ⁰ C) - (l-Methylformylaminomethyl l cyclohexyD- ^ -methyl-piperazine, mp. 107-108 ⁰ C in the form of yields colorless needles.

Example 60

Preparation of 3, ^ - dichloro-N-methyl-N- / TA-v4 · uidthyl-1-piperazinyl) -cyclohexyl7-methyl7-benzamide

A stirred solution of 0.65 g of l - / "l- (Methylaminom.ethyl) -cyclohexy ^ - ^ - methylpiperazine is added dropwise in 25 minutes with a solution of 0.61 g of 3, ^ - dichlorobenzoyl chloride in 10 ml of benzene. the mixture is heated then for 1 hour on the steam bath and then evaporated to dryness. the residue is dissolved in hot petroleum ether (60-8O ⁰ C) and decolorized with charcoal the separating crystals are recrystallized from petroleum ether (60-8O ⁰ C). . This gives 0.27 g (23 percent of theory) of 3, ¹ l-dichloro-N-methyl-N- / A ⁽ⁱ (methyl-l-piperazinyl) -cyclohexyl7-methyl7-benzamide, mp. 126- 129 ° C.

Example 6l

Preparation of 1- (1,1-dimethylaminomethyl-1-cyclohexyl) -4- methylpiperazine

0.76 g (0.003 mol) of l- (l-methylformylaminomethyl «-l-cyclohexyl) -4-

. will.

methylpiperazm dissolved in 40 ml of dry ether and added dropwise a stirred suspension of 0.23 g (0.006 mol) lithium

309818/1212

aluminum hydride in 100 ml of dry ether was added. The suspension is refluxed for 48 hours and excess lithium aluminum hydride is decomposed by the dropwise addition of 0.4 ml of water, 0.3 ml of a 30 percent sodium hydroxide solution and 1.4 ml of water. The ether layer is separated off and _{dried over anhydrous Na 2} SO 3 and evaporated. 0.4 g, (72.2 percent of theory) of a colorless, thin oil which does not crystallize. After treatment with a mixture of ethanol and methyl iodide, l- (l, l, l-trimethylaminomethyl- l-cyclo-, hexyl) ~ 4,4-dimethylr5uaraziniumjodid from Pp. 171-172 ^Q C as colorless prisms. '·

Example 62 ·. ". '■'"

Preparation of 1- (1,1'-aminobenzylcyclohexyl ) -4-methylpiperazine 5 »7 g (0.02 mol) 1- (1-benzylimidoylcyclohexyl) -4-methylpiperazine are dissolved in 150 ml of dry ether and the solution 52 g (0.04 mol) of lithium aluminum hydride in 150 ml of dry ether were added dropwise to a stirred suspension of I _9. The suspension is stirred overnight and excess lithium aluminum hydride is decomposed by the dropwise addition of 4 ml of water, 3 ml of a 30 percent sodium hydroxide solution and 14 ml of water. The ether layer is separated over anhydrous Na ₃ SO ₁ . dried and evaporated. 5.02 g (87.6 percent of theory) of an amber-colored, low-viscosity oil which solidifies on cooling are obtained. The solid product is recrystallized from a mixture of acetone and water, and one obtains! - (!, l'-aminobenzylcyclohexyl) -4-methylpiperazine from -Pp. 182 ° C (decomposition) in the form of coloring; loose needles. , '

309818 / 1-212

Example 63

Preparation of 2-dimethylamino-2-methylpropionamide 2.0 g of 2-dimethylamino-2-methylpropionitrile * are mixed with 8 ml of concentrated sulfuric acid, heated to 90 ° C. and left to stand for 5 minutes. The reaction mixture is poured into 100 ml of ice water, 32.0 g of barium hydroxide are added to neutralize the acid, and the mixture is filtered with a filter aid. The Piltrat is evaporated under reduced pressure to a solid residue which is recrystallized from petroleum ether (80-100 ⁰ C). 1.0 g (^ 5 percent of theory) of 2-dimethylamino-2-methyl-propionamide of pp. 109-111 C. are obtained.

example

Preparation of 2-dimethylamino-2-methylpropylamine-dihydrochloride A cooled, stirred suspension of 0.8 g of lithium aluminum hydride in 100 ml of tetrahydrofuran is treated with a solution of 2.5 g of 2-dimethylamino-2-methylpropionamide in 50 ml of tetrahydrofuran. The mixture is refluxed for 16 hours, then water is added to decompose excess lithium aluminum hydride. The mixture is then dried over anhydrous sodium sulfate and extracted with ether. The ether extracts are extracted with 15 ml of 2N hydrochloric acid each time. Excess water is evaporated under reduced pressure so that a solid residue forms which is recrystallized from methanol. 2.0 g (56 percent of theory) of 2-dimethylamino-2-methylpropylamine dihydrochloride with a mp of 254-256 ° C. are obtained.

309818/1212

, Example 65

Production of 3,4-dichloro-N- / ~ 2-dirne thy larnino-2- * methylpropyl, 7- b enzamide hydrochloride monohydrate

1.65 ε 2-dimethylamino-2-methylpropylamine dichloride are dissolved in 2 ml of water and made alkaline with 5N NaOH. 150 ml of benzene are added to the mixture and the mixture is dried over anhydrous sodium sulfate. The suspension is filtered and a solution of 1.8 g of 3,4-dichlorobenzbyl chloride in 50 ml of benzene is mixed with the benzene solution. The mixture is refluxed for 5 hours, and the crystals which separate out are recrystallized in a mixture of methanol and isopropanol. 1.6 g (59 percent of theory) of 3 ^ - dichloro-N - / '2-dimethylamino-2-methylpropyl.7-benz amide hydrochloride monohydrate of melting point ^{0 are obtained}

Example 66

Production of ^ -Dimethylamino-l ^ -dimethylpropylamine dihydrochloride

A stirred suspension of 1.9 g of lithium shavings in 100 ml of ether is added dropwise at -10 C under nitrogen with a solution of 15.5 g of methyl iodide in 50 ml of ether. The mixture is stirred for 1 hour, the temperature of -10 ⁰ C to +10 ⁰ C increases. Subsequently, the mixture is filtered under nitrogen, cooled and treated with a solution of 10.0 g of 2- (dimethylamino) -2-methyl-propionitrile in 50 ml ether. the solution is stirred overnight and with 15 ml of water are added to decompose the inorganic complexes. ' The mixture is then dried over anhydrous sodium sulfate and extracted with ether, the ether is distilled and 10.0 g of an imine are obtained.

309818/1212

-56.- 2248728

A solution of the imine in ether is added dropwise to a stirred and cooled suspension of 5.9 g of lithium aluminum hydride in 100 ml of ether. The mixture is refluxed overnight and excess lithium aluminum hydride is decomposed by adding 5 ml of water. The suspension is dried over anhydrous sodium sulfate and filtered. The ethereal solution is extracted three times with 15 ml of 2N hydrochloric acid each time and the acid extract is evaporated to a solid residue which is recrystallized from a mixture of ethanol and methanol. 8.5 g of 2-dimethylamine-1,2-dimethylpropylamine dihydrochloride of Pp. ^{0 are obtained}

Example 67

Preparation of 3, ^ "dichloro-N - / * 1,2-dimethyl-2- (dimethylamino) -propyl7-benzamide hydrochloride

1.6 g of 2-dimethylamino-1,2-dimethylpropylamine-dihydrochloride are dissolved in 5 ml of 5h NaOH. 50 ml of benzene and anhydrous sodium sulfate are added and the mixture is filtered with a filter aid. The combined filtrates are added to a solution of 1.6 g of 3, ^ - dichlorobenzoyl chloride in 30 ml of benzene and the mixture is refluxed for 45 minutes on the steam bath. There fall 2.0 g of a product with melting point ^; ·. ■ 2 * 18-25 ° C from _# that filtered and recrystallized from methanol

will. This gives 1.3 g ¹ I 3,4-dichloro-N- / i, 2-ditoefchyl ~ 2- (dimethylamino) -propyU-benzamide hydrochloride, mp. 252-25 * ^r

V »

-Example 68 . ■. · ' ^:

Production of o-chloro-N - /! -, 2-dimeth, vl-2- (dimethylamino) - propyl / - benzamide hydrochloride . '/

1.5 g of 2-dimethylamino ~ 1,2-dimethylpropylamine dihydrochloride are used dissolved in ^ ml of water and alkaline with 5N sodium hydroxide solution, made lish. The mixture is then mixed with 100 ml of benzene, dried over anhydrous NapSOj and filtered. the Benzene solution becomes a solution of 1.3 g of o-chlorobenzoyl chloride added in 50 ml of benzene, the mixture under reflux for 1.5 hours heated and left to stand overnight. The crystals that form are filtered off and recrystallized from isopropanol. You get 1 »9 g of o-chloro-N- / i, 2-dimethyl-2- (dimethylamine) -propyl / -benzamide ~ hydrochlofid in front of pp. 245-247 ° C.

Example 69 ■.

Production of N- / ~ 1,2-dimethyl-2- (dimethylamino) ~ propyl / -carbajninsäureäthylester-hydrochloride

2.0 g of '2-dimethylamino-1,2-dimethylpropylamine dihydrochloride are dissolved in 3 ml of water and made alkaline with 5η NaOH. 100 ml of benzene are added and the mixture is _{dried over anhydrous Na 2} SO ^. A solution of 1.07 g of ethyl chloroformate in I > 0 ml of benzene is added dropwise to the benzene solution, and the mixture is refluxed for 4 hours and left to stand overnight. The crystals which are formed are filtered off, and 1.5 g of N- / 1,2-dimethyl-2- (dimethylamine) propyl / carbamic acid ethyl ester hydrochloride from Pp.

3 0 9 & V

At. G pi (j 1 70 Manufacture 1 development

d 3 hydrochloric!

2.0 g of 2-dimethylamino-2-methylpropylamine dihydrochloride are dissolved in 2 ml of water and the solution is made alkaline with 5N sodium hydroxide solution. 100 ml of chloroform are gradually added, the mixture is dried over anhydrous NapSOu and filtered. A solution of 1.4-5 g of chloral in 50 ml of chloroform is added to the stirred and cooled chloroform solution. The mixture is refluxed for 40 hours and excess chloroform is evaporated under reduced pressure. 0.9 g of an oily residue is obtained. This residue is dissolved in 50 ml of ether, the solution is added dropwise to a cooled and stirred suspension of 0.45 g of lithium aluminum hydride in 100 ml of ether and the mixture is refluxed for 16 hours. The mixture is cooled and excess lithium aluminum hydride is decomposed by adding water. The mixture is _{then dried over anhydrous Na 2} SOw and extracted with ether. The ether extracts are extracted twice with 20 ml each and once with hO ml of 2N HCl, excess water is evaporated off under reduced pressure and the liquid residue is taken up in a mixture of ethanol and benzene and still

_t The thus obtained,

repeated evaporation dried / residue is recrystallized from ethanol, and 0.9 g of N-methyl-2-dimethylamino-2-methylpropylamine dihydrochloride are obtained.

ti * Jl I i- "» ^ ■,. ν,: ■. ■■ ■

Example 71 Making ^, ^ -

N-methy! Benzamide-hydrochloride .

0.5 S N-methyl-2-diraethylamino-2-raethylpropylamine-'dthydr'Ochloride ^! v; earth. dissolved in 2 ml of water and the solution with 5N NaOH

made alkaline. Then IOP ml of benzene are added, the garrison is dried over anhydrous Na-SO, filtered, and · a solution of 0.5 g of 3 * 4- dichlorobenzoyl chloride in 50 ml Benzene added. The mixture is refluxed for 1 hour

■ - · · from, ■

heated, the precipitating crystals »filtered and washed with benzene. This gives Ö, 95 g ~ 5>, ² ^ -Dichior-N- / 2- (dimethylamino) -2-methylpropyl7-N-methylbenzamide hydrochloride of Pp ₁ ,

Example 72 Production of ■ 2-benzylmethylamino-2-methylpropylamine

a) Preparation of 2-benzylmethylamino-2-meth3 ^ 1pr'opionitril A stirred mixture of 30.0 g of N-benzylmethylamine hydrochloride in 100 ml of water and 11.0 g of acetone, which is cooled ^{to 0 ^ 1 C.} is, a solution of 9/8 g of sodium cyanide in 50 ml of water is added dropwise *. The mixture is stirred for 20 stood, it four times _m in each case 100 ml ether extracted ,, the Itherextrakte are washed once with 100 mL of water, water-■ · serfreiem sodium sulfate, and dried with a filter. Auxiliary filtered. Excess ether is removed under a reduced truck, and 28 * 0 g of a solid residue is obtained. The solid residue -will by column chromatography using silica and / ethyl acetate as'

Purified eluent, and 18.0 g of 2-benzylmethyli.:mino-2-methylpropionitrile are obtained.

b) Horste! ment of 2 Benzylmethvlamino-2-methylpropylamin A stirred solution of 28.5 g of sodium hydroxide-bis- / S-methoxyethoxy-aluininate in 150 nil of water, which is kept at OC, is mixed with a solution 6.7 g of 2-benzylmethylamino-2-methy3 .-- propionitrile in 100 ml of water are added dropwise. The mixture is then gently refluxed for 20 hours and excess reducing agent is decomposed by adding water dropwise to the cooled suspension. The mixture is _{dried over anhydrous Na 9} SO ₁ , with a filter aid

medium filtered, and excess ether becomes "under reduced Pressure evaporated. The remaining liquid will harden Distilled water jet vacuum, and 3.8 g of 2-benzyl ~ are obtained methylamino-2- methylpropylamine of m.p. 158-140 C.

Example 73

Preparation of 3 "^ - dichloro-N- / 2-benzylmethylamino-2-methylpropyl / benzamide hydrochloride

A solution of 0.5 ² g of dichlorobenzoyl chloride in 25 ml of benzene is mixed with a solution of 0.5 g of 2-benzylmethylamino ~ 2-rr) ethylpropylamine in 25 ml of benzene and the mixture is heated on a steam bath for 2 hours. The product which precipitates out on cooling is filtered and recrystallized from ethanol. This gives 0.7 g of 3,4 ~ dichloro-N - / - benzylmethylamino-2-methylpropyl / -benzamide hydrochloride mp 192 ^0th

309 818/1212

.61-

Example 7 ² J-

Manufacture of 2- / N-Benzylme thy! Ami no / -!., G-dimethylpropy Ismin

21.3 g of methyl iodide in 25 ml of ether are added dropwise to a suspension of 2.1 g of lithium shavings in 200 ml of ether kept at -10 ° C. and under a nitrogen atmosphere. When all of the lithium filings have dissolved, the stirred solution of methyl lithium - '"kept at -10 ° C. is added dropwise with a solution of 9 g of 2-N-benzyiamino-2-methyl-propenonitrile in 50 ml of ether is allowed to stand for 20 hours. Excess methyllithium is decomposed by the dropwise addition of water to the ice-cooled mixture. The mixture is _{dried over anhydrous Na 2} SO ₂ , filtered with a filter aid, and the dry, ethereal solution of the imine is added dropwise to an ice-cold stirred suspension of 10 g of lithium aluminum hydride in 200 ml of ether. The mixture is gently refluxed for 16 hours, excess lithium aluminum hydride is decomposed by adding water dropwise to the ice-cold mixture. The mixture is _{dried over anhydrous Na 2} SOh with a filter aid filtered, and excess ether is evaporated off under reduced pressure, giving an f liquid residue. This residue is distilled under water jet vacuum, ind% to 4.1 g 2- / W BenzylTnethylamino7-l, 2-dimethylpropylamiii, mp 151 ⁰ C. '''' -. '. "- ■■

3033 1-0 / 12 * 2 U

Example 75

Manufacture of 3 »4 - Dlc hlor -NZ ^ -bcnzy lmetrylaniino-1,? - tf * ^ £ t JjTl ₁ -

propyiy-benzamid-hvdrQchlorid . · ■■

A solution of 0.51g (0.0024 mol) ^^ - BichlorbenzoylchiorieP in 25 ml of benzene is added dropwise with a solution of 0.5 S (0.0024 mol) 2- / N-Benzylmethylamine-1,2-dijfflethylpropylamine in 25 ml of benzene are added. The mixture is gently refluxed for 2 hours and the benzene evaporated under reduced pressure. A solid product remains. This product is made from a mixture of isopropanol and ^. Ether recrystallized, and 0.8 g of 5,4-Dichlcr ~ N- / 2-N-benzyliiieth.ylainino-1,2-dimethylpropyl / -berizE is obtained mid-hydrochloride.

Ex iel 76

Manufacture of N- / 2-Benzylme thy lamino-SHwethylpropy . / - benzamide A solution of 2.8 g of benzoyl chloride in 25 ml of benzene is added dropwise with a solution of 4.0 g of 2-benzylmethylamino-2-methylpropylamine in 25 ml of benzene. The mixture is refluxed on the steam bath for J> hours. Excess benzene is evaporated off under reduced pressure, and a semisolid residue is obtained which is dissolved in water with 5N HaOH

made alkaline and extracted three times with 50 ml of ether each time will, The combined ether extracts are over anhydrous iiapSOj, dried, filtered with a filter aid, and excess Ether is evaporated off under reduced pressure behind a. solid product made from Cycloliejcan -urrtAriritf 11 "i sLert will. 4.0 g of N- / 2-benzylmethylaniino-2-diethylpropyl / benzamide are obtained.

3 0 9 8 18/1212

BATHROOM 0RK3INAL

_, _{6; 5} ; _ 22A67 28

Example 77

Manufacture].]; Ung von H - / 2-Methyl ':'. Mino-2 "methyln ropyiy ⁷ -bGna?: ITiad" -. . 5.55 g ■ N - ^ - Benzy-l "me;thy.ramino-2-fflet"hy'lpr-D.py-l / -. B; enzamid _; . are dissolved in 30 ml of glacial acetic acid and poured over 14O. mg palladitol chloride hydrogenated ■>;. ;; 52O'ml of hydrogen are absorbed. The catalyst / is filtered off and the filtrate twice with IQO ml of ether each time; "washed." Then the filtrate is made alkaline with 5N NaQB and extracted three times with in each case 'βθ ml. Ether. The Ver-. Some animal extracts are dried over anhydrous Na.gSO ^ and filtered. The bertic-liquid ether is evaporated off under reduced pressure. A liquid of 2.7 g remains, which is dissolved in 50 ml of ether. Ethereal LHCl is added dropwise to the liquid. Excess ether is evaporated off under reduced pressure, and a sticky solid product is obtained, which is refluxed with methyl acetate for 2 hours Crystals of N- / 2-methyl-

-. . . ... '■■■ .- ■ - ■ / ■ "_ ■ - ^■:;. ■■■■■ -

Anrinp-2-methylprop'yl / benzamide hydrochloride in 7% yield. ■ '-.- ■ """; ■ ... -----'- - ■ ..;.: · ■;.' / '. ■;' ■ '..-.. - ' [ '

Production Λ ^ οη 2-allylmethyl · amino- ■ 2.-mVjt, l ^; _: , ^Γ propylamine . .-..- "■

a) Herste l lung 'of the second-Μο ^ ^{"ν.1βΓηίηό-:} 2 x ->, ιηΘ ^^ λ1 ^· ρΓθρ ^ · οήίί-Γ.1Ί' ''. '-. A ^: chilled mixture; of 67.5 S methylamine hydrochloride, 58, Og Acetorj and 150 ml 'V / ater vrj.rd dropwise within ''-I, Stücde with "a solution of 51.5 S sodium cyanide -. iri' iBO n- " ¹ water versotsit .. D5S-.Ge; m.sch'vriKd ül ^ ei night at -." -.- ■ Raumtompi :; i, ^: ; ui .. stirred and ^v danft, by adding. of made; sodium hydroxide against .Laelimus alkaline. dilute ^■■:

■ - - Ϊ -.:. '■'. '.' ■ - '■ * ■ """. ^: ■ -: ■ -.' ■■ BAD

and extracted three times with 100 ml of ether each time. The ether extract is washed twice with 50 ml of water each time, dried over magnesium sulfate, and the solvent is removed under reduced pressure. A colorless liquid of 71.6 g remains. This liquid is distilled at 54-57 ° C./22 mm Hg, and 65.8 g (67 % of theory) of 2-methylamino-2-methylpropionitrile are obtained as a colorless liquid.

b) A mixture of 14.7 g (0.15 mol) 2-methylamino-2-methylpropionitrile, 18.0 g (0.15 Mo]) allyl bromide, 15.9 g (0.15 mol) sodium carbonate, 0, 2 g (0.001 mol) of sodium iodide and 200 ml of methyl ethyl ketone are refluxed for 40 hours. The sodium carbonate is filtered off and the solvent is removed from the filtrate under reduced pressure. A yellow oil is obtained. With the help of thin-layer chromatography and the use of silica and / or ether as eluent, 3 components with the RF values 0.8, 0.4 and 0.0 are isolated. The oil is applied to a chromatography column (40 χ 3 * 5 cm) filled with silica and ether as the eluent, and 10.0 g (48 % of theory) of 2-allylmethylamino-2-methylpropionitrile are obtained.

c) 1,3 β 2-allylmethylmino-2-methylprQpionitrile in 20 ml

_t with dry benzene are added dropwise g / a stirred solution of sodium dihydro-bis 6,7-Z ^ -methoxyathoxyy aluminate in 30 ml of dry benzene are added and kept under nitrogen atmosphere. The mixture is stirred overnight and excess reducing agent is decomposed by adding water dropwise. The phases are separated that

309818/1212

■; - ■ "- * $: * '." ; 2146728

fe phase with water 'getfraselien, the aqueous': phase; .

■ "i ■ ■ ■ ■ - ^ "- _B

washed with benjsol ^ and; The combined / organic extracts are kneaded over magnesium sulphate and the solvent oil under -. diminished ¹ UGk removed »You get 1> 8 g of fine yellow liquid * By distillation at 0O * 90 ° C / 15 m, 0.8 g (; so of theory) Si-AllyirnethylaiTiin methylpropylamine in the form of a foul liquid.

' Example

- Manufacture ^: ..- yon ,, ^; y4 ^ D4chlQ ^ * K ^: -i-2rallyiiriet ^ . _a

A semicircle of 1.3 g ^ -

3 * 15 g of Jj ^ -BichlorbenaoylGhlo ^ id in 150 ml of dry. Benzene will

"-. '" · "-"...' · ■ '-' ■ "'""■■ -. -": -. / ^f '■' ■ '■ "" Ϊ hour under reflux · heated *. Then ^ ird-das Gemiseh ", from«

• chilled ^ twice with each jK) ml / diluted ^ tr.iumhyärö; xid ~

-, ■. * - ■■ - ■ '-.- ■ "- ■ * ■".. ■ · ■■ ■

solution and twice, each with 30 ml water and then dried over ■ magnesium sulfate. ■ That; fösungsmitt'elvrird under reduced pressure entferh'tjUndinan receives 3.9 g.einens gelbefrÖlB ".The Ölvwird a Ghromatographiesäule (40 ä S> 5 öm) with ^ Älüffii--hiumoxidfüllung -. ■ · 'and ■ Äthylaoetat .as elui

given * and you get 2 * 25 g (71 fo _: the theory) vj, 4-H ^ (2 * allylmethylamino-2-methylpropyl) -benzamide in the form of a

gchwseh yellow. Liquid*; - ':, -.

Example; Gust -, - - ■ "■". "-" ■ - · '■; / ■■; '- ^; .. ■ '■' · _ ^{: iv i;} ";"> ■ ''. ^": · '* * ■'. ■ Hersteilung of M * £ i - $ & bhy.lg * '/ meühtä

benzamide ''""" ^: , -; ' ^: ■ ■

Mixture of 0.55 g (0.052 MpI "). Propargyl bromide / Oi 55 g (0 * 0052 mol) sodium darborate and. some sodium edide crystals,

a solution of 1.0 β (0.0052 mol) N- / 2-methylaniino-2-methylpropyl7 "benzsmid in 25 ml methyl ethyl ketone is added dropwise to 50 ml of meth.y.lathy Ike ton i. the mixture is sohwadierhitzt 2k hours under reflux. filtered v / ground the inorganic solid constituents, and evaporated -Überschüssiges methyl ethyl ketone under reduced pressure. There remains behind a liquid, comprising the traces of solids "This liquid is treated with water, the mixture having ¹ 5N NaOH made alkaline and extracted three times with 50 ml · ether each time. The combined ether extracts are _{dried over anhydrous Na p} SO and filtered with a filter aid. Excess ether is evaporated off at atmospheric pressure and it remains

a liquid. The liquid is transferred to a Chromatograph.Lesäule (50 χ 5.5 cm) with aluminum oxide filling and ethyl acetate given as eluent. Fractions of 25 ml each

are removed after they have been determined by thin-layer chromatography : iet ",

placed / that the first of the connections leaves the column. Fractions 1 to 7 are combined and excess ethyl acetate evaporated under reduced pressure. 1.0 g of N- / 2-methyl-2- / methyl- (2-propynal) -aminc ^ -propy ^ -benzamide is obtained.

Example 8l

Production of N- / 2-methyl ~ 2-- _i / methyl- (3-methyl-2-butenyl) -amines / - pr opy! / - benzatrid

A solution of 0.78 g (0.0052 mol) of 1-bromo-3-methyl-but-2-ene in 40 ml of methyl ethyl ketone, the 0.55 g (0.0052 mol) of sodium carbonate and containing some sodium iodide crystals is made with a solution of 1.0 g (0.0052 mol) of N- / 2-methylamino-2-methylpfopyl7 * benz8mide

309 8187 1212.

BAD QfHGtNAL

added to 25 nil methyl ethyl ketone.

heated under reflux.- The-inorganic solid constituents .-. '■

■■■■■ ■ ' _t wii' · ^ "-" ■. ".- '" ■ -'"■; ■ - · '" · .- ■'

are filtered off ^ and the Pil entered / under "reduced pressure a ■ -'_ ■ concentrated * .. A liquid remains". This liquid is poured onto a silica chromatography column using ethyl acetate as the eluent. fractions of 25 ml each are removed and concentrated, * ■ 1.2 g of N - ^ - r'le.th-yi.-2 '- ^ ethyi-X3-'niethyl-2: -buteny ^s i.) -amlno ^ -piopyl / - - ,, benzamid. - -; ',. . . ■ ^ "" ■ '..'"■-," -:. _ ^; . "- -.- ■ .. ■ - ■ _^..->::: -. ;; .. ■ .:.

The oxalate is produced as follows:

A solution of O ₃ 2.6 g of oxalic acid in 20 ml of ethyl acetate is added dropwise to a solution of 0.8 g (0 * 0039 mol) of the base. .

.. ■ 'iii 20 ml of sthylae acetate given. A sticky precipitate falls out, - The Geisse mixture Viird with a g'eringen; Amount of methanol added to ioose the precipitate. After this

■ - ■. '. · -; ■■ "- ■■■: ■■."-.'- ■ - ■ - ■ .- ^ thi ''" Cooling gives ■; Crystals of the N - ^ - m

M.p. 1 ^ M-1

Be ispiel 82 / ^'.V:':; _:: '.''': [[: ■

Herste ! Ιυη, ς von N-Zg - Z ^ Cyclopropy! Methyl) -rnethylamiri (^ - 2 ^ nTe 'thy 1- pro.pyl ^ b ' A solution of 0.66 g of cyclopropylcarbinol bromide inJO ml of methyl * ethyl ketone., which contains 0.55 g of sodium carbonate and a few sodium odide crystals, is mixed with a solution of 1.0 g _; (0/0052 'mol) ^:

N- / 2-Methy] .amino-2 ..metb.ylp_röpy-l / -ber.i-.zamid: in 50 ml Me thy la thy I- ■ "" - ketone pozed. . The mixture vrird, 24 hours -under return flow ER, hltst and · -; ^ · · / f ■ ¹ I rVifi'ri ;.! Ub ^c r> schu! ..,: ^v .) Xe & methylethylteton: v; is evaporated under reduced pressure. A "liquid"remains.;.'

3 0 9 818/1 2.1 2

kai Ό. This liquid is applied to an AJturainLnjnoxidchrcinatcgraphJ.e gauze and eluted with ethyl acetate. One obtains 0.9 S N- / 2 - / "(Cy clopropyIrnethy 1) -methyla.nuno ^ -2-methylpropyl / -benzaniid.

A solution of 0.31 g of oxalic acid in ethyl acetate is added dropwise added to a solution of 0.9 g of the base in ethyl acetate. A sticky precipitate is obtained. That A few drops of methanol are added to the hot mixture to dissolve the precipitate. Crystals are obtained on cooling of N - /? - / "(cyclopropylmethyl) methylamino ^ 2-methylpropyl / benzamide oxalate of m.p. 142-144 ° C.

Example 8j5

Preparation of N- / 2- (Ally] .methyla jn ino) -2-methyl p-ropy3.7 ben7.aiTiJd- oxalate

A solution of 0.58 g of allyl bromide in 25 ml of methylethyiketane, .the Contains 0.55 g sodium carbonate and some sodium iodide crystals, is with a solution of 1.0 g of N- / 2-methylamino-2-methylpropyl7-benzamide added in 25 ml of methyl ethyl ketone. The mixture is refluxed for 24 hours. After that the inorganic solid constituents filtered off and the piltrate evaporated under reduced pressure. The liquid residue is on an AlumMumox liquid chromatography column using ethyl acetate Purified as the eluent, and 1.1 g of N- / 2- (allylmethylamino) -2-methylpropyl7-benzamide are obtained.

The oxalate is made as follows:

A solution of 0.4 g (0.045 mol) of oxalic acid in 20 ml of ethyl acetate is added dropwise to a solution of 1.0 g (0.0045 mol)

309818/1212

BATHROOM 0RK3INAL

^Λ V ■■ '"" - ■' ■ ■■. - "- 69 - ^; "

■ ^; ; the base iü 20 ml of thylaeetat Gögeberiv 'fen receives

elneh sticky Niedersehläg. The hot Gemisöh will agree Drops of methanol were added to dissolve the lower floor. On cooling, one obtains: Crystals of N- / 2- (Allyllηethylamino) -2 ^ methylpropyl / benzamicl oxalate van Fp.

Example $ 4 / ν '...'

Production of N- / 2-Methy1-2- (never thy lphenä thy 1 amino) -propylZ-benzamide . . ,

A mixture of Q ^ 97 g of 3-phenylethyl bromide in 25 ml of methyl ethyl ketone, 0.55 g of tiatrium carbonate and a few crystals of sodium iodide is with -a mixture of 1.0 g of N-i ^ -Methyiamino-2-methylprcpyl? · benzamide in 25 ml of methyl ethyl ketone dropwise yer * sets. The mixture wlrd ^ "JO; Stand heated under reverse flow. Then the änqrganiaeheri solid components are filtered off and the " Piltrate evaporated under reduced pressure. You get one oily residue. This "residue" is placed on an alumina chromatography column given and eluted with ethyl acetate »Fractions of 15 ml are removed and the first 7 fractions combined, itabersehüssiges ethyl acetate is reduced under © jerk atgedampf t. i4an receives 0.5 g; N- / 2-methyl-2- (methylphene;. ._; Ethylamino) propyl / benzamld. .

The Qxeilat will; manufactured as follows:. ; ■ -: · ■ :, ■ · -.- ·: ■ .- <■ '[O ₃ H g of the base: \: are dissolved in 20 ml of ethyl acetate and added dropwise with a solution of 0.12 g of oxalic acid , in; 1O ml .: ethyl acetate added. It falls; · a sticky precipitate .aus ... ■ -, · "■

. der., äue /M.nem ^; Gemise ^
is crystallized »0.25 g of N- / 2-methyl-2-i [inethyl-

phcnäth, yl £.!: iino) -propyl / -benzarnM-oxalate of m.p. 150-1'3 ^ C

Example 85 Production of 2-methyl-2-dimethylaminohexylamine

a) Preparation of 2-methyl'-2-diniethylaminohGxanenitril A stirred solution of 40.8 g of dimethylamine hydrochloride and 50.0 g (0.5 mol) of hexan-2-one in 60 ml of water, which is cooled in an ice bath, a solution of ^ 4.2 g of potassium cyanide in 75 nil V / water is added dropwise. The mixture is stirred vigorously for 24 hours, diluted with 200 ml of water and extracted four times with 200 ml of ether each time. The combined ether extracts are washed four times with 200 ml of water each time, dried over anhydrous NapSO ^ and evaporated. It behind-

> under reduced pressure , a colorless oil remains. After distillation / obtained 51.547 g (67 $> of theory) of 2-methyl-2-dimethylaminohexannitril, bp. 92 ⁰ C at 12 mm Hg.

b) A stirred solution of 43.5 g of sodium dibydro ~ bis (2-methoxy ~ ethoxy) -aluminate (70 percent solution in benzene, 25 percent excess) in 100 ml of dry ether, which when cooled with ice water is kept under nitrogen atmosphere, wird.mit a solution 7.7 g of 2-methyl-2-dimethylaminohexanenitrile in 100 ml of dry ether are added dropwise. The solution will be over Heated under reflux in a nitrogen atmosphere overnight and then cooled. Then 200 ml of ether are added and then, while cooling with ice water, excess water is added dropwise to remove excess reducing agent to decompose. The mixture is c ° - with a filter aid

309818/1212

■■■■■: - ', 224 & 72Β

filters and the- Fiiträte. four times init..each 100 ml. ". Jifchpr ex-. '_. trc ^v hlei \ t. The combined ether extracts are mixed four times;' with. j, & ~ because s-200 ml of water // ai> EHCN) over wasserfreiem.'HaJ ₅ SOjV. dried and evaporated. Ea verbleitat a colorless. oil. ''N'ich Dostillatlqn the oil gets .- "aft Λ, 80S g- J6l · ^ theory ) 2-Ifethyl-2-dimethylaminohej; ylamine of b.p. 86-88 ⁰ G at. 12 'mn Hg as a colorless. Liquid. ■ "■ / -; '·. '.- ■.' ■■ .. "■

Belspj el 8.6 . '■; ·, '■ "". . "■"; . _ ^: _. ··; . ^!

Horst stellung von J>', h ~ ^ o hl or-N-' / 2-methyl-2-dirn, e ^: th'y lamin.ohsxyjj ⁷ ".

A .LO ^ ¹ Un ^- S from. 1.58 g of 2-r4ethyl ~ 2-dimethylaminohexylaiHin. in 25 ml _Λ TROCK-cneiri benzene is treated with a solution of 2 _y ^ lg, 4 · -PI chi orbenzoylchlorid in 25 ml of dry benzene versetzt'und the mixture for 1.5 hours, heated to reflux. The mixture is then diluted with water, made alkaline with 2% sodium hydroxide solution and extracted four times with 100 ml of benzene each time. The 'ver ~ \ agreed Benzöl.extrakte v.'erden vieijnal with jevreils \ 50 ml of water, dried over v: a "serfreiem Natriuiris.ulfat dried and evaporated. One obtains; 5> β g (about 100 ^ of theory) ^^ - dichloro-r. '". · ■ N ~ / 2-methyl-2-aimethylainino-hexyl / ~ benzamide as a colorless oil which slowly crystallizes.. ■ -." . / - - ■ "'; .- ■ -

309818/4212

Example 87 ■: ' ^:

Production of NZ ^ -Methyl ^ -dimethylaminohexyl / formamide 2.04 ml of acetic anhydride and 0.86 ml of formic acid are mixed on a water bath at 50 to 60 ° C for 2 hours with stirring and then cooled. A solution of 2.9 ml (0.02 mol) <

2.37 g of 2-methyl-2-dimethylaminohexylamine are added dropwise to this mixed anhydride with stirring in such a way that the temperature does not rise above 40.degree. The solution is then stirred for 30 minutes, then 6 ml of ether are added and the mixture is stirred at room temperature overnight. The mixture is diluted with 50 ml of ether, made alkaline with 2N sodium hydroxide solution and extracted four times with 100 ml of ether each time. The combined ether extracts are washed twice with 100 ml of water each time, _{dried over anhydrous Na 3} SO and evaporated. 2.2 g of a colorless oil are obtained. By thin layer chromatography (silica, methanol as eluent) to 2 Ver _T "connections with stain at Rf values of 0.5 and 0.0 fixed set {The oil is then applied to a chromatography column. (Χ 20; 3.0 cm) abandoned with silica filling and methanol as eluent, and 6 fractions of 100 ml each are withdrawn. '

Fractions 2 to 5 are combined and evaporated. 1.427 g (51 % of theory) of N- / 2-methyl-2-dimethylaminohexy] / / -formamide are obtained as a colorless oil.

Example 88 j

Preparation of N-methyl-2-methyl-2-dimethylaminohexylamine \

"""^ ^- " ¹ "** ™" ^β "■ '' ..« I 'Ul ■''■■' Il. DMa ^ MI IJI II .III .III "I. . ,;

An ice-cooled suspension of 0.51 g Lithiumalurniniumhydrid in 25 ml of dry tetrahydrofuran is treated dropwise with a solution '

of 1.395 g (0.0075 mol) of N ^ / 2-methyl-2-dimethylaminohexyl / -formam3d | offset. After finishing ^ ER_ Ziigabe the mixture '

ORIGINAL INSPECTED

"irofeer Rt ^ fiuss heated ν, τίύ-

ng becomes tvpp £ §meS.§ & M & sbqv urn iibepsphÖBB.iiges. ', Reöwtefct & ßsmittel. to

Mixture with a filter aid becomes sviein ^; ni; i, t jew§il§ 50 ml 2 η four times with ^ each time. IQQ. ml- water .washed

OIL evaporated.

Dag oil Trtira dissolved in © ensol and ^ dejroal with in each case | o ml gn extracted. Pie sour 'extract are treated with 5n Na-

gtiögung allcalisoh jgemaeht and extracted ^ 4ernml with each ml of itther. The combined Ktherextret ^ te be getroqlontet k see each IQQ ml Vi ^ ter üeW ^ * ttber anhydrous and OnPD ^ mßft. One obtains Q ^ i. g (6§ % of

^ Wethyl ^ g-methyl-t ^ dimethyiaminohexyla ^ im as yellow oil * "- ■" ^r : -. , V- ^; ..;. / \

Production of 3,4-DiGhlor-N-methyl ~ N- / 2-methyl-2-dlmethylamino- hexyl7 ~ benzamld

A solution of 0.754 g (0.0044 mol) of N-methyl-g-methyl-S-dimethylaminohexylamine in 25 ml of dry benzene is mixed with a solution of 1.048 g (0.005 mol) of 3,4-dichlorobenzoyl chloride in 25 ml of dry benzene and Heated under reflux for 1 hour. The solution is then cooled, washed four times with 100 ml of 2N sodium hydroxide solution each time and four times with 100 ml of water each time _{, dried over anhydrous Na 2} SO ₂ and evaporated. One receives 1, j5l2.g of a colorless oil. The oil is dissolved in benzene, on a chromium & tQgra, phy column (25 χ 3.0 cm) with aluminum

.filling,
oxiq / and , ^v a mixture of benzene and ether in the ratio \> \ . . - .- ■ -. 30 9 818/1212. {,. ■ ■. . \.

.öls eluent added, and 9 fractions of 100 ml each are removed. Fractions 2 to 8 are combined and evaporated. 1.282 g (8k% of theory) are obtained

The oxalate is made as follows:

A solution of 0.18 g (0.002 mol) of oxalic acid in 5 nil ethyl acetate., Is mixed with a solution of 0.69 g (0.002 mol) of j5,4-Diehlor-N-methyl ~ N- / 2-methyl ~ 2- dimethylaminohexyl / benzamide in 5 ml ethyl acetate are added and the mixture is heated for 2 minutes. The solution is then cooled and concentrated to a volume of about 5 ml. Dabex separates a colorless oil. The oil is left to stand overnight and crystals form which are filtered off, washed with ethyl acetate and dried. Obtained 0,6kk g (76 fo of theory) of 3> 4 ~ Dlchlor-N-methyl-N- / 2 ~ methyl ~ 2 ~ diroethylarrtino hoxyl / -benzamick> xa! At of melting point, 130-135 C. ■

Example 90 Manufacture of l ^ Dirneth ^ larnlnocyoloheXylamici

4.0 g (9.26 mol) of 1-cyanocyelohexy id! Triethylamine are heated on the steam bath with 50 nil sulfuric acid for 10 minutes and then cooled. The reaction mixture is poured onto 150 g of decomposed ice, made alkaline with ammonia, and the alkaline material is extracted with chloroform. The chloroform extract is washed with water, _{dried over anhydrous Na 3} SO ^ and evaporated under reduced pressure. M.an receives 3 »? 6 (72 * 7 # of theory) of a colorless oil. After the circulating solution from PetroUither (60-80 ° C.), 1-dimethylaminocyolohexylamide with a melting point of 55-56 ° C. is obtained in the form of colorless prisms.

309818/1212

BAD ORiGtNAL

: ν ** · ■ * ■ '- ■;:. ■ ■■ ..; ..: =; ■ ■■■■; 2246728

He r S ta 1 Ii 3 η fr - ν ' ο η ΐ - Py r ro 11 α In; / 1 cyc 1 ph esc y 1 am jd. ^v. - '_' - ■ * - ^";: 2.0- g of 1- (l-CyanöcyclOhexyl) -pyrrolidine 10 minutes 4Ό ml SChv / efelsayfc on the steam bath, orhitzt .and then geliühlt subsequently. the reaction mixture is poured onto 150 g of crushed ice, made alkaline with ammonia and extracted with "chloroform." The chloroform extract is washed with water, dried over anhydrous NapS (X and evaporated. 1.75 g (96.1 io of theory) 'of a colorless oil which crystallizes on cooling are obtained. (80-1QO ⁰ C) one obtains l-pyrr; olidinylcye ^; Qhexylamide of Pp. 106-10.7 ° C in the form of colorless platelets »'·. ,, -"..'.'■"-.■'"':■> .-- "."' -. _'I ''. ~: ^! : "- ■■ '

Example 92 . ■ ' : _ _r - . ";.'.;;;., ■ · '" ■.: ■. /; ■■ '..,.,, ■ _{;: ■ _:} - ■■ . - Ee rs division of 1- (4-MethVlpiper aziny l ^ -cyclohexy-lamiicl , '■;. 2.07 g (0.01 mol) l - »(r-Cyanocyclohexyl) -4-met: hylplperazi.n · .Vie-rden.. "" with 500 ml of sulfuric acid, heated for 25 hours on the steam bath and then cooled. Subsequently, the reaction mixture is broken down to 150 g of ice-cream and made alkaline with ammonia \ and ". the extracted chloroform ChiorDformextrakt wird'Mt" with, washed Viasser, ■ wasserireiem dried over magnesium sulfate, and evaporated under reduced pressure to give 3 / 5I 'g' - ^'(67.7% of theory) of . amber viscous oil obtained after Ümkristallisation from petroleum ether (8'Ö-iOO ^Q C) is, '■■ ..-' ■: 1- (4-methylpiperazinyl) -cyclohexylamid from Fpv Lof C ^ in 'the form of colorless. - laser plates.. ■ -..'- '"""■-""/.·":::; ^: _ / ^; '" , ', __' ■■ - ', "".-- . '■■ -.. - \ -

BATH

■,. ; ^: '■ 2141728

Example 93 '' - ■

ι.

Deduction of 1 - Piper idy Icy c I open ty lanii d ■. .

1ί? 8 S (OjI Mo]) l-Cyanocyelopentylpiperidin v / earth heated for 10 minutes with 40 ml of sulfuric acid on the steam bath and then cooled. The reaction mixture is then poured onto 150 g of crushed ice, made alkaline with ammonia and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous NapSOw and evaporated. 1.6 g (82 % of theory) of a colorless oil are obtained, which crystallizes on cooling for a day. After recrystallization. petroleum ether (100-120 ° C.) gives l-piperidylcyelopentylamide with a melting point of 112 ° -14 ° C. in the form of colorless platelets. ·

Example 94 Production of l-dimethylaminocyclohexanecarboxamide

20 ml of concentrated sulfuric acid are added in portions with 10.0 g

' Ella /

l-Cyano-NJN-dimethylcyclohexylamine was added and the Lögung _v / iS allowed to stand for minutes. The solution is then cooled, diluted with ice water and neutralized with barium hydroxide octahydrate. The mixture is filtered with a filter aid and the filtrate is evaporated to dryness. It is the same S ₁ I g (81% of theory) of an oil which crystallizes on standing. After recrystallization from petroleum ether (80-10O ⁰ C), rg l-dimethylaminocyclohexanecarboxamide of melting point 65-4'9 ° ^

3 Q 9 818/1212

Example 95.. ._ ^Λ ": ..", W - _; ^; :

"Production of 1-Dim ethylamino-N- (3, ^ -eiic hlortolyl) ^ c ^ carboxamld and its. Hydrochloride \. \. ' -.- V ",.::" ■■ - "- \ ^; :

A solution of 2.0 g of l-pimethylaminocyclohexäncarboxamid'in 40 ml of dimethylformamide is 0.8. g sodium hydride ^; (50 percent dispersion in oil) are added and the mixture is stirred for 2 hours. A solution of 2.4 g of dichlorobenzylchloride in 10 ml of dimethyl, formamide is added dropwise and the resulting mixture is stirred overnight. The mixture is then filtered and the piltrate is evaporated to dryness After adding petroleum ether (80-100 ° G) the mixture is heated and the solid is filtered off. The pil is kicked with. Activated alcohol is decolorized and evaporated to dryness. It remains a colorless ·. Oil - The oil ■ is dissolved in 2ii hydrochloric acid and washed four times with 200 ml of benzene each time. The aqueous phase is made with 2N NaOH alkaiisch "and extracted four times each with 200 ml of benzene. The benzene extracts are washed νjeriml with 200 ml of water, dried and evaporated water over 'anhydrous Na ₀ ,. SOJ. There remain behind 2.1 g of a colorless ¹ oil which, according to thin layer chromatography (silica, ether), has 3 components. The oil is dissolved in a small amount of ether and placed on a chromatography column (59 x * 2.0 cm) with Ifeelsaurefülung and 'ÄttsKäls eluent'. .; 11 fractions of 100 ml each are removed. Fractions 3 to 3 are combined and evaporated to dryness. and chromatographically as above. examined. After purification and evaporation of the appropriate fractions, 1.315 g (35% of theory) "white crystals" are obtained after recrystallization from petroleum ether i

309816/1212

C) one obtains 0.846 g of cyclohexane carboxamide with a melting point of 82-8.5 C in the form of: ner M'tdeln. A second crop of 0.091 g melting at 78-83 ⁰ C.

0.658 g of l-dimethylamino-N- (j5,4-dichlorotolyl) -cyclohexanearboxamide are dissolved in 5 ml of ethanol and mixed with 10 ml of ethereal HCl. The solution is evaporated and a colorless oil remains, which is dissolved in a small amount of acetic acid. After the dropwise addition of ether, grinding and cooling, the hydrochloride precipitates in the form of colorless prisms, which are dried over potassium hydroxide under reduced pressure. 0.688 g of the hydrochloride with a melting point of 160 ° -170 ° C. are obtained. After crystallization from ethanol with the addition of ether, 0.351 g (48 % of theory) of 1-dimethylamino-N- (3,4-dichlorotolyl) cyclohexanecarboxamide hydrochloride of melting point 162-166 C is obtained in the form of white prisms.

309818/1212

i.

_; : BATHROOM 0RK3INAL

Claims (1)

■ pa I; e η ΐ an ip r ü C ίί e , j Silo st ituierte "-iithyl eiio Iaaine; deir 'iiäcli ^ teh en the ■ = Ίί : .v · -J 4 in welcttjer 4ie group av'E: ΐι ± & .: R "■ ■ glBiLch, or ^ er are- taii .: jov / eil.s 33.-e» ' Alkenyl, or: "Aikiiiylgfü.pp'e-23> - , -jr'Aniyl-i, -Äralülyl -; = tidisr ¹ Acylgruppeny borrowed arylsulfonyl groups, where the alkyl radical of the - AralfcyT- 'groups by one or more optionally esterified * hydroxyl groups and the aryl groups or the aryl radical of the acyl odea ? Aralkyl groups "by edn"or; halogenate several ^one: alkyl groups. Hydroxyl groups, allrocy groups ,; Tri-r, f luOi ^ methyl groups, nitro groups, amino groups and / or: dialkylaraino groups, subötituiearu- be liöimen, in which the groups R to R are equal to the boiling points and in each case VJässer st off atoms, or alkyl groups b.edeuji with dei ·. Hassgäbe _; that "not all groups R ^ to" -R at the same time Viasserst off atoms.- are, or in which ·, 5 6 ■■ - ■ Q - .t - ■ "- - Bl and % / 'or Jl' -imd. R together mean an Oar-bönyi; sax; .ar ^ toff (= 0) and in each pair of groups R / ll ■ _% R ^ / M - 8ο - R / R and R / R are carbocyclic or heterocyclic a can represent saturated or unsaturated ring system, which is optionally by lower alkyl or aryl groups is substituted. - 2. Compounds according to claim 1, formula (I), in which R and R together with the adjacent carbon atom is a carbocyclic ring system having 4 to 7 carbon atoms form. 3 · Compounds according to claim 2, in which the groups R and / R in each case with alkyl, alkenyl or alkynyl groups 1 to 6 carbon atoms. 4. Compounds according to claim 1, formula (I), in which R and R each -hydrogen atoms, alkyl groups of 1 to 4 carbon atoms, acyl or aralkyl groups. · ': ■ ■, _■': ι ■ '% i, ·> ■.' ■ ι ■.; ■■. 5. Compounds according to claim 1, formula (I), in which Ri and R as well as R and R are hydrogen atoms or alkyl groups with 1 to 4 carbon atoms. 6. Compounds according to claim 1 with the following general formula 309818/1212 ; '■ - "■". "'"■' ■■■ · 22ΆΒ77Β ■ '\; ■■■ :. . . , ■; - ■. - egg -. ■■ '■: ■ ■ ■ ^■: . 1 ■■ - '■■ "-""■■■-" -. ^"■: in which R the B ens ο yl group ·, a clilQrsubs'bituier'fce Benzoyl group or the group ■ C OOÄlk. with "-AXk .-- a ©: Gi * -. ■ ^: "- ■ ρ '' ■ ■"'■' ■ · "'- ■ :. Alkyl group means, E is hydrogen or the -.,., S ■ '- ■ ■ R ■ "■" ·· - -''β-' ^: - group, R is the methyl group and R is hydrogen. ; ..- .- 7. Compounds according to claim 1, formula (I), in _; which R; - ■ - has the following meaning: .. - · - "■■ -. ■ .3,4-dichlorobenzoyl, .formyl, benzoyl ,, 4-fluorobenzoyl,; · ■ 4-oleobenzoyl, 3» 4- Dimethoxy "benzoyl ;,. 4-MOtIiJfIbBnZOyI, 2-chlorobenzoyl, acetyl, p-toluylsulfonyi, 2,3,4 - ^^ 0.6 · ^ - - oxybenzoyl, .3,4-dichlorobenzoyl sulfonyl ^ ... 2 ^ _? 4-I) i; chXor- -.._. benzoyl ,. Hydrogen>. .the methyl or ethyl group :, \; . -.-. ' ■ 2 ■ ".. ■ -: .'--: ■■■■■ 3 while R is hydrogen or the methyl group, Rf _.: Ä ± e ;. \. Methyl group, R the methyl or benzyl group, - ■ "- 'or hydrogen ·, R and R are hydrogen uiid / pder are the methyl group and R and R together form the cyclohexyl group. *.' * ■ '"': '■ " - "■ '■:., - ^: -. · ■ ■ '''-.' _; : ^; : ^'■: .- "' ·. '' / '' .: 8. Compounds according to claim 1, formula (I), in which R has the following meaning: hydrogen, Formyl, acetyl, 4-fluorobenzoyl, 2-chlorobenzene, oyl, > 3,4-Dl chlorobenzoyl, 2,3,4-trimethoxybenzoyl, 4-nitro- ; benzoyl, '4-aminobenzoyl, the ethoxycarbonyl, methyl ■■■ - "- .." ■■■ ρ or ethyl group, while R is hydrogen or the methyl group is, R and R are hydrogen, R 'and R together. the cyclohexyl group "form and R and R ^ together with the adjacent nitrogen atom form the piperidyl group. ■. * ^Λ ι ■ "- s 309818/1212 S). Compounds according to claim 1, formula (I), in different R has the following meaning: hydrogen, Formyl, acetyl, 3,4-dichlorobenzoyl, 2,3,4-trimehoxy- bensoyl, ρ-ϊοluylsulfonyl, 2,4-Dichlorbcnzoyl, the methyl , W ater rstof f ,, " or iithyl group, while Il / ciie Forrnyi or Hotbylgruppe, 5 6 Ir is hydrogen or the phenyl group, R is hydrogen, 3 4 R and R coincide with the "adjacent nitrogen atom." the 4-Metnylpiperazinylgruppe and R and R together the Form cyclohexyl group. 10. Compounds according to claim 1, formula (i), in which R Hydrogen, the 3,4 dichlorobenzoyl, 2-chlorobensoyl, · ■ 2 Benzoyl or ethoxycarbonyl group, while R is hydrogen or the methyl group, R the methyl group, R ^ hydrogen, the methyl, benzyl, allyl, propynyl, dirnethylallyl, cyolopropylmethyl or phenethyl group, 5 6 R is hydrogen or the methyl group, R is hydrogen, 7 ft R is the methyl group and R is the methyl or butyl group. 11. A method for the preparation of compounds according to claim 1 ', Formula (I), characterized in that an aminonitrile of the following general formula CN N ■■■■■. '(II) in v / elcher the group R, R, Ir and R which claim have given meaning, by direct reduction into a 309818/1212 Amine according to the general formula ■ - ifc:,> \: i Cilia or that one is used to. · Establish connections in which E- and Rm together mean a CarlDonylgruppe "., _ The arflinqnitril the formula (II), liydrolysiert to the corresponding Aiiid, or that one goes to. Herst RECOVERY of compounds ■■ ·. in we.lclien R and R .. each mean hydrogen, the amide for. itmin reduced, - "■ or that one. for the production of yer "b in fertilize,:" both • ■ R is an "acyl group, the '■' .- Amiir of the formeit (III.); With a corresponding .'- Ύβτίο in the dung .aeylated ,,.. .." ^: or that for the "production of" compounds, when R is an alkyl group, this acvl group. ansehliessenti reduced to an alkyl group ^: ·. , '-. Or that yerb'indunrgeni are used for the production of: which R a: Äcylgruppe ^ means e ^, the-formed "MJonoalfcylami, !!: with, a corresponding compound: acylated ^ ^: ;: - / ^x " or that for the production of Vqrpinduiigen, at v / elcheii both Ε? as well as R.,: AlkylgrupppeiribedButene, das _; lupnoacylated monoalkylamine formed reduced, -i; - or, dO; Esa jiian sur .production. of Verbiriduiigen, ·. be; i 'which 5
with an alkyllithium compound R Li umcetat and the imine thus formed is then reduced to a primary amine, or that one for the production of connections in which 5 1 R denotes an alkyl group, R an acyl or alkyl group and / or R is hydrogen, an acyl or alkyl group, acylates the primary amine (R = alkyl) formed and if necessary, subsequently reducing the acyl group, or that one for the production of connections in which 12th
R or R denote an aralkyl group whose alkyl radical is substituted by a hydroxyl group based on ^: lying amide reduced (conversion of the group -O = O in the group CHOH), or that one has to make connections, "at which 12th
R or R denotes an aralkyl group whose alkyl radical is substituted by an esterified hydroxyl group, the compound formed above with free hydroxyl groups is esterified with an acylating agent, or that one has to make connections in which "5 4 R or R denotes hydrogen, from the corresponding Compounds with benzyl groups split off the latter, or that for the preparation of compounds in which R and / or R are not hydrogen, a compound 1 2 der Porno] ' ^T ), in which the group NR R cannot be aylated or alkylated, acylated or alkylated, 309818/1212 άäβs ^ lQan ^ - ^ g.äelD0.ae ■ r ^ f ■ έϊ ■ L ■ l · Θ- "äIlsö] ilie $: seIld ^; each dex Prrupi I '8
1 TaIs R within the given command ± & el "ne - aiid§- re G-rlippe converts * waä that mail ge ^; ge "in the event; the band product in ä ^^ • · - ■■ - · "- , yer trä g Ii ohei ^ 12 «itezneipräparaiie û the base-egg. pliarmäköiogisGli / zül'äs'-öigöft Tmg'erstoifes ^ 'gekennzeielMet diircli eiiie? e2? bindimg Näöl Äns ^ tfeh 1 _f ' Formula (I) as active ingredient * ' ^{: Γ} ~'"^ V Msführungmgsförfli iiaöli Mspriiteil i.2j dadureH; that the preparation iii fMssigei * öder'foster form tüld iür diBör & le or parent oral distribution adapted -14 ». Äu & fÜtemg & förfi * nahöh: ■ U 3S the preparation as a capsule * ^ gegei ieiifails with ■ an OB CFI versöneiie iCablettöj as liläektiönsfliisölgköit iöder as "■ '■. ·. FTIR' -äX® Oraleι V" De vice "breiGhiing ^ geöigÄete liquid Bäöis ^ or-, ■ 1 3 * external iriäeil · iäisprmeh: % 4 »- marked with it, äasö Jö ^ ö 'Itäsiseiniieit Ö to SöÖ fflg ftekstiäff: qdeS? a ORIGINAL (MSPEOTED