DE1468813A1 - Process for the preparation of substituted bicyclo- [2.2.2] octanes - Google Patents

Description

Dr.kifl. mm Krebtw t> r.-h »e-Dr.-lna.TTi.M * yer Df. hm Br. E

KBi Dekfcraonnhout

; Ϊ1Α68813

19 »May 1965 · ΑνΚ / Λχ / Pa-

EI du Pont de Nemours & Company,
Wilmington. 98i Delaware (V.St.A. ^ I-

Process for the production of substituted bicyclo / ~ 2.2.2 Jo ct ane η.

The invention relates to a process for the preparation of novel bicyclo ^ / l ^ S ^^ / bctanen in which a substituted or Amlnogruppe 'Amihogruppe over a methylene group s is a tertiary ring carbon atom or bridgehead Ringkohlenstoffatpm is bound,

As part of the development of more effective means of Fighting viral infections introduced a new class of l-Ainirobicyclcootanen and Bicyclcoctan-1-ir.ethylaminen found, which are extremely effective. the leanness of the different most harmful viruses hemir.en and the Eefall with them prevent. · ■

The compounds of this class have a remarkable range of activity in tissue cultures and in animal experiments. For example, it has been used in tissue cultures. Efficacy against Inf luenza ■ "- & ^; f Stärt'ir.e WSlI and swine influenza), Influenza A-2 ( ¹ StWnIe``Hlch'fgan Α / ΛΑ, 'JFC and JaP> 05) and Influenza D (Sendai strain ) observed "Tests with living mice showed effectiveness against swine influenza viruses, Michigan A / AA, JFC and Sendai as well as against the herpes virus and Semliki forest virus". The compounds prepared according to the invention were found to be prophylactic and also therapeutically effective .

BATH ORIGINAL

; -; -o, sicf «809902 /

Have the compounds prepared according to the invention the formula ;

CH.

R is hydrogen or alkyl with 1 to 6 carbon atoms :,

X and Y can be identical or different and stand for hydrogen., Methyl or ethyl.;. . . ....- _: - .. / .; · ... '.

R ₁ *

fCH

-NR ₂ R,
-N = CHR ₂ ^

dn ^; or

where η = 2, 3,

5 or .6 -. ;;

wherein R _{2 is} hydrogen, alkyl having 1 to 6 carbon atoms. monosubstituted alkyl with 1- to -6. C-Atorr.en ^ in which the substituent Hydroxy., Alkoxy with 1 to 2 C-Aton.en.,

-NHR ₅ or -

is where -R ₁ - ■■ u'nd;

or are different and represent alkyl radicals with 1 to h C atoms; Alkenyl with 2 to 6 carbon atoms ,, ¹ : "~ alkynyl with 2 to 6 carbon atoms, cyclopropyl, CycLa-: ¹ : .... butyl, cyclopropylnr.ethyl or cyclobutylrrethyl .is ^:" ^v <

R, = R ₂ , chlorine, bromine, formyl, -CH ₂ CCOH ,,. or -CHgCOOCgHj- with the proviso that -R ^ in-. Cases in which R _{2 is} alkenyl or alkynyl with an unsaturated bond in the 1-position i · «ty« in-flaky 1 radical of the type mentioned above or a substituted alkyl radical of the type mentioned above.

ORIGINAL BATHROOM -

R ₂ . = an aliphatic monosubstituted aliphatic hydrocarbon radical in which the substituent is aromatic or heterocyclic, an aromatic or heterocyclic hydrocarbon

rest with a maximum of 12 carbon atoms.

Connections related to the connections of the formula (1) hydrolyzable are for most purposes those above compounds mentioned are equivalent, and their production naturally falls within the scope of the invention.

The compounds falling under the formula (1), the one contain basic amino groups, easily form salts « These salts, which contain a non-toxic anion, also fall within the scope of the invention, examples such salts are the ■ hydrochlorides, hydrobromides, sulfates, Phosphates, acetates, succinates, adipates, propionates, tartrates, citrates, bicarbonates, pamoate, cyclohe; <ylsujfamate and acetylsallcylates. Of these, the hydrochlorides, Acetate and Cyelohexylsulffr.ate preferred »The Cyclohexyl sulfate has a pleasant taste and is therefore

particularly advantageous for the production of syrups for oral application, they are also suitable for production of non-coated tablets that are not unpleasant have a bitter taste, for oral application, as further salts come those with caprochloron and with Penicillin in question.

The salts mentioned above increase the value proportionally insoluble amines in pharmaceutical applications.

Of the compounds of the formula (I), preference is given to those in which R is alkyl, in particular alkyl with 1-4 carbon atoms, is especially methyl and ethyl. A big Effectiveness against viruses can be determined with this class of compounds «

Particularly unique in terms of the combination of 8flS5D2 / 09U BAOORfGfNAL

Antiviral effectiveness and other properties are dialkylamine-substituted compounds. Although unsubstituted dialkyl is particularly preferred, however, when using special substituted products , for example. Hydroxyl- or alkoxy-substituted compounds., Certain advantages can be achieved in the preparation of the preparations. "The most advantageous are lower dialkyl substituents, ζ.Β" Dimethyl and diethyl ₀ However, the monomethyl and conoethy! derivatives and the unsubstituted amino compounds are most substituted alkylamino -, derivatives preferred. . ^: , ■ -'.->

Particularly preferred are the hydrochlorides of the following Links: : ·.

N, N-Dimethyl-4-ethyl-bicyelo / ~ 2,2,2 ^ yOCtBn-I-ITe thy 1-arnine N _J N _J 4-Trimethylbi'cyclo / ~ 2 _J 2 _J 2j7octan-l, -methylamine N _J 4-dimethylbicyclo / ~ 2.2 _J 2_7octan-l-ir.ethylamin N _J N-DimethylMcyclo / 2 ~ _J 2, 2 _i _7oetan-l-ir.ethylan] in 4-methylbicyclo / ~ l-2,2,2_7octan -jr.ethylamine N-meth.ylMcyclo / ~ 2 _i 2 _J , 2-7octane-.l-methylamine bicyclo / ~ 2 _J 2 _J 2-7octane-l ~ ir.ethylamine

N-Ethyl ^ -ir.ethylbicyclo / ^^^ J / octane-l-methylainin a _J 4-Dimethylbicyclo / ~ 2 _i 2 _J 2_7octan-l-methylamine hydrochloride _:) a particularly effective compound, .-Α, α, 4- Trime thylbicy ο1ο / ~ 2, 2, 2_J7octan-l -me thy laninhydroch] or 4-id I4thyl-a-methylbicyclo / ~ 2 _J 2.2__7octan-ln: ethylatninhydro-

chloride.

4 -] \ thyl-a, a-dimethylbicyclo / ~ 2 _J 2,2_yoctan-l-methyl-amine hydrochloride "

The above-mentioned compounds can be according to various Methods are produced »

Production of

I-Aminpfcicyelo / ~ 2., '2,2 _i _yootane and various derivatives "of this compound can be easily prepared according to the process, the subject of the German patent ...",.,

BAD ORJQlNAl,

(Patent application P Jk θ88 IVb / l2o),

As a suitable alternative to the procedure described there, can use alkyl esters of. optionally substituted

her »■ -" '-

oc-Pyro ^ jJ-earbonsäure with ethylene to 4-Alkylbieyclo_ / are reacted _i 2 2 _J 2_ / oct-2-en-.l-carboxylic acid alkyl esters, to the 4-Alkylbicyelo / ~ 2.2 _J 2_7octan-l-carbonsäurenlkylestern - - hydrogenated and then with alkali to ^ I-Alkylbicyclo- / ~ octane 2 _J 2 _J 2_7! hydrolyzed carboxylic acid "can" see connections This Zvi in the manner described in the earlier patent application Iv'eise in l-amino-4-alkylbicyclo - £ 2.2 ^^ ybctanes are converted,

Octane for the preparation of the new aminorr.ethylsubstituierten bicyclo can 4-alkylbicyclo / ~ 2_, 2 _J 2_7octan-l-carboxylic acids to the corresponding 4-alkylbicyclo / ~ _2,2-jr 2j7octan lcarbonsäureamide be converted to the latter with lithium aluminum hydride to give Wvlkylblcyclo / ~ 2 _J 2 _J 2_7octan-l-methylamines are reduced "

a-Allvylbicyclo / 2 ~ _J 2 _J are prepared by reduction of Bicycloy ^^^^ octyl-fl) alkylketonoxiir.en with lithium aluminum hydride ^{2_7Qctan-l-ir.ethylami>} ne can, The ketones, _of:.. which these derived oximes v; ground, by reacting the corresponding Cadmiumdialkyls with a Bicyelo / ~ 2 _i 2 _J are zweckirässig, 2_yoetan-l-carbqnsäurechlorid prepared »· ....'_. . · ■ -

α, α -Dia Iky Ixxsxfei cyclop2 , 2 j2 __ / octan-l -ir.e thy! amines can be obtained by reacting acetonitrile and sulfuric acid (Ritter reaction) with the corresponding α _J a-dialkylbicyclo / ~ "2 _J 2 _i 2_7 -octane-1-methanol are produced, - the H-acetyla _i a-dialcylbicyclo / f "2 _J 2 _J 2_yoctan-; l-ir.ethylamine is obtained. Since S ^ Ami η is obtained by alkaline hydrolysis. "The bicyclooctahfiethanols serving as starting materials for this reaction are converted into the corresponding bicycleso _< / *" 2 _i ; 2 _i 2V7octane-1-carboxylic acid chlorides with alky! -

produced *.

BATH

-D-

Manufacture of N-substituted bicyclooctane-l-methyl-. ami nen.

One or both hydrogen atoms of the amino substance of BiOyelo / ~ 2.2., 2-7octane-l-! R.ethylamine. the 4-alkyl-bicycle- / ~ 2,2,2j7o.ctane-l ~ ir.ethylan! inen, a-4-dialkylfcicyclo / "2, -2,2_7-ootan-1-ir.ethy larainen or α , A , 4- _{Trialkylbicyclo / ~ 2 J} 2.2-7-ootan-1-ir.ethylarainen can be replaced by alkyl, most conveniently by acylation, e.g. with an acyl halide, whereby an acylamine compound is formed Which is then reduced to the N-alkylamino compound: Lithium aluminum hydride is excellently suited for this purpose , but a catalytic hydrogenation or any other type of reduction can also be carried out. The N-alkylamino compounds can be acylated and reduced again ., whereby the 1-N, N-dialkylamino compounds are obtained. Various alkyl radicals can be added to these elements = for example, by reducing the 1-acetapido compound with subsequent reaction of the product with butyryl chloride ■■ obtained the N-Bufc-yl-N-üthylarainove-Kbina-ung. With the following reduction,.

The N-alkylated bicyclo / ~ 2 _j , 2 _J 2_7 ° ctan-1; -ir.ethylamir.e .. ·: ■: and ⁱ l - alkylbicyclo / ~ 2.2 _i 2_7octan-l-ir.ethylamine can ·, _Ϊ́: · .... can be produced by acylation and reduction or by alkylation with alkyl & alogenides. However, be ~ ■ - ■ -_ is the best and easiest methods is ,, that corresponds <speaking Blcyclo / ~ 2 _J 2 _i 2_7 ° C fcaft-l-carboxylic acid amide from. . ■ the BioyGlo / ~ 2,2,2_yoctan-l ^ ca.Ffco.n'säureohlorid and the -. '. to prepare appropriately substituted amine and to reduce it to the desired N-alkylated or N., M-dialkylie.rten connection. The reaction of -beispielsweise ./ bicyclo / ~ 2.2 _J 2_7octan-l-carboxylic acid chloride with Kethylarain. gives N-Kethylbicyclo / 2 ~ _J 2 _J 2V7bctan-l-carboxamide _o The reduction of this compound with Lithiumalumlniumhy-. drid 'leads to N ^; -KethylbicycIo / ~ 2 .2 _J \, 2_7octann "The .ethylamln--: Reduction of N-Alkyi-4Hr.ethyrbicyclo / ~ 2 _i 2, 2_7octa-n-lcarbonsäureapii3; führfe / to N-alky 1-4- methylbicyclo / ~ 2 , 2,2_J ~

809902 / 09H; BATH

octane-l-xrethylair-in. The formula of N-IIethy 1-H- (J-ir.e thoxyjropy 1V- ² J -athylbi eye lo / ~ 2.2,2_7ceΐεηΐ -c ε rtcnel'vre ε iri d gives Ni: ethyl-H- (3 -retho; -yproiyl) - ⁱ l-ethylfcicyclo / ~ 2,2, .2_7-octane-1-methylamine »For the preparation of almost every N-alkyl or Ν-, Ν-dialkyl compound including the NjN-dialkyl compounds with various alkyl radicals, iran reacts the corresponding amine with the corresponding carboxylic acid chloride and subjects the amide obtained to reduction.

The formylation of the amino compound with anseMiessender Reduction is a viable method for the production of N-methylamino compounds, but these can also be used by using Ν-Γ / ethylacetamide in a modification " the Ritter reaction. As described in the earlier patent application mentioned above =

In the production of JNF-Λ lkenyl-., N ^ N-dialkenyl-, N-alkynyl- and N _r N-dialkynylbicyloyf2,2,2__7octan-imethylaiainen and 4-alkylbicyclQ / ~ 2 _J 2. _! 2_7oGtan-ln: ethyl amines is the use of the corresponding alkenyl or alkynyl halide with an acid acceptor such as sodium bicarbonate. in a solvent ₃ such as ethanol, because the process of choice «ES are formed by mono- and diallcenylated and alkynylated compounds, but the nature of the undesired component can be determined by Λ

change in the nature of the halide can be kept to a minimum. If the amounts of amine and halide are equal, they predominate the ironosubstituted compounds If there is an excess of the halide, the disubstituted ones predominate Compounds * In any case, the mono- and disubstituted compounds are relatively easy to separate ^ e.g. by distillation. If the halo geriid is very large There is an excess. naturally finds a certain Quaternization instead of *. .-,.,.:

The process of eylation and reduction is also, phns, further for the production of N-Cyclopropylir.ethyl- and ,. ,, N-CTelobutylmethyl compounds are applicable. For example,

BAD ORfGHNAi. ^

the acylation of 4-MethylMcyclo / ~ 2 _J 2 _J 2_7octan-Ircethylarain with cyclopropanecarboxylic acid chloride leads to (N-Cyclopropylcarbonyl) -4-! r.ethylbicyclo / ~ 2 _i 2,2j7octane-l-! r.ethylamine, the N- Cyclopropylrr.ethyl- ² t-ir.ethylbicyelo / ~ '2 / 2.2 _ / - octane-1-methylamine gives »In addition, the same method can be used for the preparation of substituted bicyclooctane-l -rr.ethylanines including their Schiff bases as they are described in the earlier patent application mentioned for the 1-amino compounds ο. · .- ■ -

The following compounds and their salts are non-tbxiWhen as representative examples für'geWlfes d invention, products prepared ^mentioned:;

Ν, Ν-Diir.e thy lbicycio / ~ 2 _i 2 _S 2_7octan-l-methy larain

Ethyl ester

4-Isohexylbicyclo / ~ _2> 2 _i 2_7octan-l-ir.ethylamin 4- {l-Äthylbutyl) bicyclo / ~ 2 _J, 2,2_7octan-l.-irethylamin 4 '- (l / l-dimethylbutyl) bicyclo / ~ 2 _J 2 _i 2 -7octane-1-ir.ethyiamine N-allyl-4-sec-butylbicyclo / ~ 2 _J 2 _J 2 -7octane-1-rcethylamine

l- (Benzylidenaminoäthyl5bicyclo _(/ ~ 2 _i 2 _J 2_7octan l-Forinaniidomethylbicyclo / 2 ~ _J 2 ₃ 2_7octano

The compounds of the .Formel (l) may be in antiviral treatment (each I \ ^T else administered vjerden, wherein said active agent is delivered to the infected by the virus infection area in the body "A detailed description is to find- in said prior patent application

The compounds prepared according to the invention are particularly effective against "swine influenza. An important one." Use of the compounds prepared according to the invention is thus combating this infection by adding an active ingredient for the feed of the infected animals, wine presses Details about this can be found in the earlier patent application mentioned »■ '*.

BATH ORIGINAL

S09907 / 09U

Example 1

A solution of 2.5 S (0.0149 koi) 4-Methyl-1-bieyeIo- ^"/ ~ 2.2 _J 2_7octan-1-carboxylic acid in 10 cnr (1.6,55 g, Oj 139 mol) of thionyl chloride was 2 hours heated at reflux condenser, and then cooled to room temperature, "the excess thionyl chloride was stirred at yern. removes eindertem pressure to give the acid chloride as a brown oil ztirückbliebo in a cooled solution (-1O ⁰ Cj of the acid chloride in 100 cm of dry chloroform was ammonia .1.0 minutes The reaction mixture was then stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in Λ 100 cm ^ benzene, insoluble ammonium chloride was filtered off and the piltrate was evaporated to dryness, with 3.13 g ($ 100) ^ -Methylbieyclo- ^^^ / octan-] carboxamide vojn, melting point -190-192JS ⁰ C were obtained »

Analysis: for ' C. 10.2 '' •8th N Calculated No: ' 10.33 8th ^C 10 ^H 17 * 71.8 '' , 38 ■ found ' 71.83 Λ8

The following table shows the results of experiments in which other 4-alkylbicyclo / 2.2y2__7 ~ ' ^ octane-1-carbonamides were prepared.

BAD ORJGiNAU

Starting acid -

4-methylbicyclo- / ~ 2,2., 27 ^o-ctan lcarbonsäure

IQ

Amine

. Methylamine. N-Kethyl-4-ir.ethylbicyclo- / f ^^ jg / octane-l -carboxylic acid amide. . -

4-Me thy lbi eye 1ο / 2 _Λ 2 ^ 27- N., N-Diir.ethyl- ^J l-irethy: lbieyclo-

octane-1-carboxylic acid diirethylamine V2 ", 2,2 / octane-i-carbonic acid- i - amide.. .. _{,, .... ..;} ...

4-propylbicyclo-

1-carboxylic acid ammonia: ^ -propylbicyclo /, 2-.2.2 _ / -. . ocfcan-1 -carboxamide

4-Propylbicyclo - / ^ 2 , 2., 2-7octane-.1.-carboxylic acid

Methylamine N-methyl - ^ .- propylbicyclo .- / ~ 2,2,2_7octane-1 -cartonic acid amide. . .-..-.:.

4-Propylbicyclo- / ~ 2., 2 _r 2_7octan-! -Carbonsäure .D lire t hy 1 a in i η N , N-.D i rre t hy 1 - 4 - pr ο py 1 bi cyc Io - / ~ 2.2.2._7oc tan-J. -car -r bonsäure.amid ■ .. _: ■ -,

BATH

Example_2:

In a 2CO cn. Hundkolben, which was provided with a Co:>: hlet ~ extractor. 1.56 g of lithium aluminum hydride and 200 cnr of dietary ether were added. 2J g (0.0162 KoI) of 4-methylbicyclo- _ / ~ 2.2 _r 2_7octane-3-carboxamide were placed in the extractor sleeve. The reaction was carried out overnight, the contents of the flask being stirred with a magnetic stirrer = the reaction mixture was cooled to room temperature and the excess lithium aluminum hydride was destroyed by carefully adding 3.32 enr ^ (0.184 mol) of water with stirring Stirred for one hour, then the mixture was filtered and the solid was washed well with ether. The filtrate and the washing liquid were combined, dried with solid potassium hydroxide and then with anhydrous magnesium sulfate The product was filtered and dried .

Analysis: for * ^C l ₀ H ₂₀ KCl: 63 C. H , 0 N Calculated 63 , 4 10 , 34 7.38 found , 08 10 7.35

In the following table the results are obtained, if the carboxamides prepared in the manner described were used in these processes.,

BAD ORiGtNAt

CO O

OO l -

VO VO

_{:; 3}

<M rf

ω αϊ β
G CU α »

ω rf P

Sh O <«- J

ο) qj

A-J hfl

rlri

«Μ

iVO

ι-)

ü t

α)

CVl

α) Κ

S%

O O

(U

α):

Λ1 <

icvi

O O

"I O

fr Λ O fi • Η Ή

^ q ε

rf CJ

■ Ρ Λ φ -P H (O

• Η ί3

Ih I

E-irf

C I

Ji- β

η CO SP

· * O S O

Jf LA

Jf LA

VO VO

Q)

Jl "Ö

CV! <11

O CVJ β

Q) rf ί3

^ O <Μ

(D Q)

CVi

OJ Xt

o a rf rf

ο -p

• H Q) .O B rf I

. . I Ή OfJSi Pi CS A + -P <-t OA Jf O

Ό β 3

{CTvJO ICJ rf

rfVO } Ό rf

rf O

• Ρ CVI

ο) ίυ

β Ι ⁰¹

Λ rf

O Q)

(ϋ: 2

ί = 1- CVl O

--rf νο

O rf

I ß O · Η

.η ε

O PJ

^ a-P

rf Q)

>> £ Ρ »ι

O rf

ii ι P * βΌ

ι α · Η Jf -P i «

I O HOH

5 cvila

0} CVl ic

t— VD IA IA

rf ··

J CJ>

Q) S ß β CO G) Ä CVf ¹ O OK β

Sh rf α) ο

O
rf
O

>> t

ο β • Η Ή

.α ε

t CJ rf rf

bO

O -P Sh O)

I 1 J * "ii

1 I rf β

4OO Jl ₁ OH

BTV ³

• r4CVilO Ö "O t CVl it S

• σ ι ή ο ε rf CS OQ)

λ1

O U U α P. ο [I

Ä-P 4J O O) ₁ O

BATH ORIGINAL

Example. Yes

A mixture of 3) 6 g Uagnesiunis shavings, a small iodine crystal, 11 cn anhydrous benzene and 1 an absolute Ethanol is heated until a reaction begins. Then the heating is stopped and a mixture of 24.0 g diethyl malonate, 7 »0 g of absolute ethanol and 30 cn of benzene drop by drop added at such a rate that reflux of the reaction mixture is effected In addition, the mixture is heated in a reflux condenser until the magnesium is dissolved. The excess becomes ethanol by azeotropc distillation with a rope of benzene (|

removed. To the obtained solution of Äthoxyrcagnesiundiüthylmalonat a solution of 18.6 g of 4-J-etbylbicyclo- / 2, 2, 2 / * o et given an-1 & -csrtons acid chloride dropwise in 30 cn anhydrous benzene within 50 LIinuten. The reactor is heated in a reflux condenser for a further hour and then cooled in an ice bath. To the cold mixture was added 50 g of ice and then 10% sulfuric acid in such an amount that two clear layers were formed. The layers are separated * The aqueous layer is extracted with two 25 cn portions of benzene. The extracts are vereinißt with the organic layer, washed with water and 30 cn with anhydrous Natriuir.su! Fat dried, the Bencol is removed by concentration unter.verhinderten pressure at 4O ⁰ G, Zun residue is added a solution of 64 cn ^ glacial acetic acid, 39 cm water and 7 cm concentrated sulfuric acid are added (weight of the residue 32 g). The mixture is heated to a reflux condenser for 7 hours. It is then cooled and poured into 350 cn of water. Dan Genisch is extracted twice with ^ e 50 cn ^ ether. The ether extracts are combined, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 4-meth3? Lbicyclo / 2,2,27octyl- (i) -K: ethyl ketone being obtained.

A Gemisoh of 14 g of hydroxoxylamine hydrochloride, 65 cm ^ anhydrous Pyridine and 65% water-free ethanol are made up

β am '? / 0 9 u ^BAD0RIGIN «-

heat the steam bath until a clear solution has formed. To this solution, 12.5 g of ^ -Ilethylbicyclo / i ?, 2.2 / - octyl- (1) methyl ketone are added. The Genisch is heated for 2 hours at reflux and then cooled ο It is evaporated under reduced pressure at 7O ⁰ C to dryness. The residue is suspended in 150 cn water and stirred well. The pest substances are filtered off and dried, whereby.; 4-IIethylbicyclo / 2,2, g7-octyl- (1) r; .ethylketonoxia is obtained "

This compound is added in an amount of 1.8 g to a mixture of 3 »3 g of lithium aluminum hydride in 150 ca anhydrous tetrahydrofuran. The mixture is heated for 3 hours with stirring on a reflux condenser. It is""cooled in an ice bath" The excess Lithium aluminum hydride is not destroyed with a water-2-tetrahydrofuran-genetically. High 10 cm sodium hydroxide solution is added to accelerate the co-acylation of the solids. The pests are filtered off, washed with 50 cn of chloroform and discarded. The piltrate, consisting of the dead rahydrofuran solution and the chloroform solution is saturated with dry hydrogen chloride and then ^{concentrated to dryness under reduced pressure at 50 0} C = the residue is placed in a separating funnel and mixed with a mixture of "1CO cn.""iO ^ igej.1 Ifatriumhydroxyd and 3.00 cu ether shaken- The aqueous layer is discarded and the ether-Ib * some dried over Ealiumhvdroxyd, rrrnuiat, In the, Ether solution, dry hydrogen chloride is passed through until it is completely precipitated. The amine hydrochloride obtained is filtered off and dried. This crude salt '· lived in water with an excess of 50 ^' strength ITatriun- • hyöro: cydlösung treated and the free Ariln with .Äther extracted _o The ütherextrakt v; ill and decanted dried over Kaliuchydroxydgranulat. Then wird.Chlorwasserstoff initiated to complete zuv _v precipitation .. The ... Pällung is filtered and dried to wobei.-jaj obtain ^ -Dir-e-thylbicyclo- $ & i ·

BAD OHfGJNAi 80 9902/0 9U

Example. 3.b

4-l! Ethylbieyclo ^, 2,27octane-1-carboxylic acid (4 »95 0.0295 KoI) was dissolved in 100 cn dry tetrahydrofuran

solved,. With stirring, 31 cn ³ (0.062 Hol) 2N-IIethyllithiun in ether under nitrogen were added within 3-4 minutes. The mixture was heated to the reflux condenser and cooled to room temperature, the product was extracted with ether by adding 25 cn of water, and the ether was extracted after drying over magnesium sulfate, whereby 5.60 g (100%) of 4-nethylbicyclo / 2, 2, _27octjl- (Dnethylkcton were obtained as an oil Λ ^{π 1} JJ ^ ⁰¹ = 1700 cn " ^1. - i

/ I

3 cn t / water and 5? 9 g (0.147 Hol) of powdered sodium hydroxide were added, the reactor.sesseinisch was heated for 5 minutes with stirring in an Rüekiluss cooler and then poured into an ice-cold solution of 20 cn (0.240 Hol) of concentrated hydrochloric acid in 110 cn of water. The colorless solid was filtered off and washed with water. Drying over phosphorus pentoxide was 3? 84 g (72 $ j) ^ Hethylbicyclo / ?, 2.2 / octyl-! (L) r: ethslketor.oxin obtained, ¹ ^ ⁰¹ = 3200 cn ' ¹ .

A solution of 3? 84 q of 0: .in in 50 cn tetrahydrofuran was added with stirring to a suspension of 2.93 g (0.077 LIoIy lithium aluminum chloride in 75 cn iither. The mixture was heated over eight with stirring in a reflux condenser. After cooling to room temperature 7 cn (7 g, 0.0389 hol) of water are added dropwise. The mixture was stirred for one hour at room temperature. The solid was filtered off and washed thoroughly with ether. The product was topped up with gaseous chlorine hydrogen; the aryne hydrochloride would be filtered off - wild nither gevmechen, whereby 1.7 g (19f>) a, 4-dimethyl-

ö / f ^ 2,27octan-1 -lr.ethylaminhydxocftlorid obtained wufdeji:

BAD ORIGlNAU

1488813

Analyze e ^

Calculated for "O _1. , H ₂ HfHOl found:

-JL 8th 1 I. ,8th _ IL . 1 egg 45 64, 92 1 O , 93 , 88 1 7, 97 64, Q 7th , 65 6,

! game 4

To §in # r solution "of 27.4 _g.? Acid chloride in 500 ccr anhydrous ether are ERA 150 was added dropwise under nitrogen. Technical 3"] r.olares meth ^ sagnesiunbromid added at a rate such that slight reflux is maintained * After the addition, the reaction mixture is heated for one hour ρ and then cooled * "The metal complex is through. Additional "300 saturated Ameoniunichlorict cn disintegrated Ätherschicht.wird separated and the aqueous layer with 100 cm of chloroform" This extract v / ill ^with;. The combined itherschicht, The mixture \ 7ird n-it v asserfreiem magnesium sulfate and dried under verninderteri? Pressure at 35 ⁰ G concentrated to dryness »The residue is distilled with steam until the distillate is no longer milky · About 3 liters of distillate are collected.» After cooling, the steam distillate is extracted twice with 250 cn ether each time. The ether extracts are combined with anhydrous I.Iagnesiur.iGulfat, dried and concentrated under reduced pressure
£ 2, 2,27'-oetane.c: etliaiiol obtained

35 cm of concentrated sulfuric acid are added dropwise to 160 cm of acetonitrile while cooling, by means of which the temperature is kept below 10.degree. Then, 18.2 g AJA-dimethyl-i-bicyclo / f ^ j ^ gJ-octannethanol added "The temperature is increased to 48 ⁰ C and 45 minutes" maintained at this value The Reaktionsgenisch is cooling to. Leave room temperature and then slowly pour it into 1000 en ^ h'-is water . The separating Peststoffe be filtered off and taken and then dried at 500 cnr ether "dry .Chlorwasserstoff is passed into the ether solution until no further filling mehr.statt-

ORIGINAL BATHROOM.

The solids are filtered off, dried, and placed in a separating funnel containing 200 cubic centimeters of vaccer and 500 cubic centimeters of ether. Ico Cciricch is shaken until the solids are dissolved. The aqueous layer is separated off and discarded, the solution is dried with non-ferrous iron sulfate, and cured to dryness. This gives E-acetyl-a, cc-dimethjlticyclo / ?, 2, Zfcctcn-I -r.etrylrmin /

A mixture of 2.0 g of I-acetyl-a, o; -dimethylbicyclo / 2% 2, I / -octane. ~ 1-methylamine, 10 g of potassium hydroxide and <0 cm of ethanol is placed in a closed ear Maintained at 225 ° C for 18 hours and then chilled. The contents of the ear are added to 100 cn drums. Bas mixture is introduced whereupon dry hydrogen chloride twice with 50 cn ether extracts "The extracts are combined, dried with Kaliuishydroxydgranulat, until precipitation completely The filling is _o v / ill be filtered off and dried to give a crude salt is obtained. This salt is dissolved in 80 cm v / water and treated with excess sodium hydroxide and then extracted twice with 50 cn ether each time. The ether extracts are combined and dried with potassium hydroxide granules. Then hydrogen chloride is passed in, λ until * the precipitation is complete "The hydrochloride is filtered off and dried, whereby a, cc-Dii .: ethylbicyclo- / 2,2 _}> g7octan-1-nethylaiainhydrochlorid is obtained"

To a weight of 1.5 g of lithium aluminum hydride 100 cm- * anhydrous diethylene glycol dir-ethyl ether 4.0 g of the H-acetyl-cc, o; -Dinethylbicyclo / 2,2,27octane-1-methylamine prepared according to Example 14 given ,, The reaction mixture is heated for 3 hours with stirring on the reflux condenser - and then cooled in an ice bath »The over Schüssige Lithiurialuminiunhydrid is by the addition of Damp diethylene glycol diethyl ether decomposes. Some cn lO ^ iges Hatr.iurahydroxyd are used for the coagulation of the

809 (902/0914

precipitation added, which is then filtered off and with 50 cn Ether is washed. The filtrate is treated with dry hydrogen chloride treated until there is no more filling forms. The precipitate is filtered off, in 100 cn water dissolved and mixed with SO ^ igen Hatriunhydroxyd in excess. The genic is extracted three times with 30 cn ether each. The ether extracts are combined with potassium hydroxide granules dried and until complete precipitation treated with hydrogen chloride. This precipitate is filtered off and dried, whereby F-ethyl- (i., A-dir_ethyl-1-bicyclo / 2,2,27 octane-1-cethylanine hydrochloride get v / ird,

Example 6 _r

A solution of diethyl cadmium in benzene is prepared by adding 19.6 g of powdered cadmium chloride to 0.2 parts of ethyl magnesium bronide in 100 cn of anhydrous ether within 5 minutes at an ice bath temperature heated. The ether is then removed by distillation on the steam bath, whereupon 65 cn benzene are added to the almost dry, brown, paste-like residue. The distillation is continued until the vapor temperature of the distillate reached 61 ⁰ C ο iTach addition of further 1CO cn benzene to Diätbylcadniunlösung this is heated again Eückflußkühler. The heating is interrupted, whereupon vigorous stirring is started and a solution of 17j2 g of Bieyclo / 2,2,27octcui-1-carboxylic acid chloride is added as quickly as the exothermic reaction allows. Then a further 45 liters are heated on a reflux condenser with stirring. The reaction mixture is cooled in an ice bath and 2CO g of water and ice and then 150 cn of 20% sulfuric acid are added. "The benzene layer is separated off and the aqueous layer is extracted with 75 cn of benzene dried with anhydrous sodium carbonate. The benzene v / ith by concentration under reduced pressure at 5O ⁰ C removed to give

... j. ■ BADOFUGINAL 809902709 1A-

itückgtand- Bicycle ^, 2,: | 7ooty: U (iHithylketon- received

Mixture γοη ^νί -ΐ ^ι 3Υ8 'g of this product, 75 em anhydrous ethanol, 75 em anhydrous pyridine and 16 g hydroxylanine hydrochloride ^: is heated in a reflux condenser for 2 hours and then ^{concentrated under pressure at 6O 0} C until e § is half-drunk. liaeli adding 200 cm / water will do that

The booty is narrowed until it is semi-dry. Ter Küc3-; rd 'in 300 a what
are filtered a, ^ γQ bei

stmid becomes' in 300 a water, suspended- The Pegts'toffe

ketoüoxira is obtained, '".. ■ .. _ ^

This compound is in a Wenge of 6.7 g "^ u a Genisch, of 3.0 g Iiithiumaluminiunhydriä and 150 cn anhydrous Diäthylenglykoldicethylütlier. Gegeben- The mixture is heated for 3 hours with stirring Büekflußkühler, liacl 'cooling to 1O ⁰ C with a JZisbad the excess Iiithiuaaluriiniumhydrid with wet Dillthy ^ lenglykoläir.ethyläther sersfort. the solids are coagulated strength by the addition of 5 s lO ^ NatriumbydTosyd, abfiltrfert, _o washed with 50 cn Ätlier and discarded the Piltrat is gesjlttigt with dry hydrogen chloride and μ ^ 4ϋ * - ¥ «ϊ!" ^ 4τνν ~ -.νΐ'- ~~ · ^ ο-: until it is completely filled under prevented pressure ο the concentrated filtrate is cooled ο the solids are filtered off, see with ether and dried. The dried salt is dissolved in 150 cm of water. The solution is coated with excess 5% IFatriunhydröA-yd and extracted twice with 50 em of ether each time. The Itherextrakte are combined, dried with Kaliunhydroxydgranulat and until full /: usfällung with dry Ohiorwasserstoff treated, the: i ^r -ällung is filtered off and dried to give a-Zthylbicj / clo / s, 2,2,7octsn-1'-iuethylaniinhydrQchlQrid obtain

In. a 2 l-four-necked round-bottomed flask with! thermometer,?: ropftrichtey, Hi-flow cooler, paddle stirrer and ^ a connection

1488813

is fitted to a gas clock, 500 cm will be absolute Ethanol, 50.4 g (0.60 LIoI) hatriunbicartonate and 0.02 IToI

given ehlorid. Then, v / ground 24.2 g '(. 0.20 Hol) AllyXhxoraifl from the iropftrichter zugege / ben = The mixture v / irö allir.i'hlich to 65 ⁰ C erv / urmt. At this temperature the evolution of gas begins. The reaction is allowed to proceed until no more is developed. After the reaction has cooled down, the esters are filtered off. The filtrate is evaporated The ether layer is dried with anhydrous potassium carbonate and evaporated, vro'bei IT-Allyl-IT-nethyl- ^ r-ethylbicyclQ- «

received as a backlog. v: ird. _O

BADORiAAt.

Claims (1)

or 'from their salts or from compounds that are' to hydrolyze the compounds of general formula I, in this general formula R is hydrogen or alkyl with 1 to β carbon atoms. is and X and Y are hydrogen, methyl or ethyl, and . or where η = 2,3,4,5 or 6, -H = CHR ^ is
in which again has one of the following meanings: Hydrogen, alkyl with 1 to 6 carbon atoms, coro-substituted alkyl with 1 to 6 carbon atoms, the substituent being hydroxy, alkoxy with 1 to 2 carbon atoms _{, -NH 2} , -NHR, - or -NRj-Rβ , where Rp- and Rg are identical or different and represent alkyl radicals with 1 to 4 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cyclopropyl, cyclobutyl, cyclopropylmethyj. or cyclobutylmethyl, R, = R ₀ , chlorine, bromine, formyl, -CHoCOOH, -CH ₀ CQCCH, or -CHpCOOCgHj- is, with the proviso that R-, in the cases in which R _{2 is} alkenyl or alkynyl with the unsaturated bond in 1-position, is an alkyl radical with 1 to 6 carbon atoms or a monosubstituted alkyl radical with 1 to 6 carbon atoms, the substituent being hydroxy, alkoxy with 1 to 2 carbon atoms, or -NR ₁ -Rg and. ; R ₁ ^ is an aliphatic mono-substituted aliphatic hydrocarbon radical in which the substituent is aromatic or heterocyclic, is an aromatic or heterocyclic hydrocarbon with at most 12 carbon atoms, characterized by - that one a) a 4-alkyl'bLcyclo _< / "2,2,2 7octane-1-carboxylic acid into the corresponding 4-alkylbLcyc3o / ~ 2.2 / 'octane-i-carboxylic acid amide converts and this reduced to a 4 ~ alkylbicyclo / ~ 2,2,2_7octan-l-methyiamine or b) an "Eieyclo ₍ /" 2,2,2_7octyl- (i) alkylketcno: iAm reduced- or -Dialkyl c) an a, a / Ucyclo ^ ~ 2,2,2_ _i 7 ^o ctan - l-methanol of the ■ Ritter reaction subjects or d) a bicyclo / 2,2,2 ~ _m 7'octan-i-methylamine, 4-alkylbicyclo / ~ 2,2,2 7octan l _methylamine: α, Η -DialkylbLcyclo / ~ 2,2,27octan- l-methylamine or α, α, 4 ~ trialkylbicyclo / ~ 2,2,2 / octane-i-methylamine alkylated or e) a bicyclo / ~ 2,2,2 _r _ _i 7-octane-1-methylamine., ^ -Alkylbicyclo / "2,2,2_7octan-l-methylamine, α, ^ - dialkylbicyclo / ~ 2,2,2_7octane-l -methylamine or α, α, 4-trialkylbicyclo / ~ 2., 2, 2, 2-joo. tan-1 -methylamine with a corresponding aldehyde and BATH ORIGINAL 80 9902/09: 14 ..... f): "if one received according to ä) to _e) Combination with - an appropriate acid to ■ form salt. ■ · ■. ■ -... ■ "- · -..; - BADOBlGIi) Al.