DE1695740A1 - New indenopyridine derivatives - Google Patents

Description

Pafenfanwäffe

Dr. W. ScMt. ^ i-! ν, 'P W-rfh

Dtp ¹ ·. Λ r ■■■ fry ■■ "■

Or. '- · _ ■■ {i' -. O ■■ ■■!? (._ &

6 Ffonkiun, ' , ν, or. uu '] !. fi, * ,. _Jlt ;] arS> r.39

SANDOZ AG.

Basel Case 100-2442

New indenopyridine derivatives

The invention relates to .Acid addition salts of new indenopyridine derivatives of the formula I (see formula sheet), in which R _{1 is} hydrogen, a lower alkyl, alkenyl or alkynyl group; the benzyl or phenylethyl group and R ₂ denote hydrogen, chlorine, bromine or a lower alkyl group, and a process for their preparation and pharmaceutical preparations thereof. The compounds of the formula I have at least one asymmetric carbon atom and can therefore occur in an optically uniform or in spatial form.

The method according to the invention is characterized in that that from hydroxy compounds of the formula II, in which R, and Rp have the above meaning, by treatment with strong Acids split off water.

The end products of the formula I are stable in the form of their acid addition salts, but if they are present as free bases, rearrangement occurs with migration of the double bond from the 4a, 5 to the 4a, 9b position. Therefore are used for dehydration, preferably strong acids, which crystallized with the compounds of formula I form salts} Examples of suitable acids are hydrogen chloride or bromide, sulfuric acid, nitric acid, phosphoric acid or methanesulfonic acid, benzenesulfonic acid, naphthalene-l, 5-disulfonic acid, etc. Using as starting products optically active connec-.

. 009829/1844

New documents (atlj ι ι ad ·, 2 No. 1 sentence 3 * · And * run # ^ «, v. 4.9. Imti

fertilizing of the formula II, optically active end products are obtained of formula I.

The method according to the invention can be, for example, as follows be carried out: A hydroxy compound of the formula II is heated - as a free base or in the form of an acid addition salt - in aqueous mineral acid, such as 2N hydrochloric acid, mixtures of conc. Hydrochloric acid and water, etc., for approx. £ 3 hour at reflux to the boil. The resulting acid addition salt, e.g. the hydrochloride, the compound of the formula I, usually falls during heating or during Cooling the reaction mixture in the form of a crystalline Precipitate, which is filtered off; Otherwise, the reaction solution is used until the start of crystallization or evaporated to dryness. The crude product filtered off or remaining as a residue can be purified by known methods be, for example by crystallization from a solvent such as methanol, ethanol, isopropanol, ethanol / Ether, water, dilute aqueous hydrochloric acid, etc.

Instead of using mineral acids, dehydration can also be carried out in an analogous manner using organic sulfonic acids, ζ .B. with naphthalene-l, 5-disulfonic acid, be performed.

The acid addition salts of the indenopyridine derivatives of the formula I. have not yet been described in the literature; they are characterized by valuable pharmacodynamic properties with low toxicity Properties. In this way, they develop pronounced analgesic effects that manifest themselves in mice and monkeys and also have certain psychotropic properties. The acid addition salts of the compounds of the formula I also develop a pronounced effect in hypertensive animals (Grollmann rats) antihypertensive effect without significantly affecting the blood pressure of normotensive animals. They also have anti inflammatory properties Properties that are particularly pronounced in the alkenyl and alkynyl derivatives.

009829/1144

■% &? -: .. ν »- - 3 - ~ -;,: 100-2442

Π XTIi OCr

The acid compounds of formula I can therefore be used in therapy as anaesthetics for pain of various origins and in psychiatry for the treatment of neurotic and psychotic disorders. They can also be used in internal medicine to treat hypertension. The average daily dose is 1 - 100 mg and can be administered in 1 - 4 servings v / erdenk """'- ¹

The new compounds of the form oil I can be used as medicaments in the form of their water-soluble, physiologically compatible ¹ acid addition salts, alone or together with init-pharmalcolo-. giseh indifferent auxiliary sticks in suitable dosage forms are administered r. · -, - · '· .- "- -

Also included for the production of hydroxy DER formula II WEL ■ before also voti the "invention, one following procedure may ^apply: · '-

a) | 4an; 'deduces ketones, of the formula III, in which R, and R ^ above Have meaning * with complex hydrides of alkali metals in a solvent.

b) For compounds of the formula Ha, in which R ^ "" represents hydrogen, a lower alkyl or phenylethyl group and Rp has the above meaning ^^ n ^ Lftnst.naii .. durph catalytisehe Hydrogenation of ketones of formula III; be there

, any alkenyl or alkynyl groups reduced to the corresponding alkyl groups or any senzyl group cleaved.. ,

c) Compounds of the formula Ilbj, in which Rp has the above meaning and Ry stands for a lower alkyl, alkenyl or alkynyl; .. group 3enzyli- or, - the Pherepiathylgruppe, are obtained "one of compounds ¹ * iei3 orrH ^ ^ l JiIc ;; wherein R ₀ is as defined above besitsti by: ^ UiKSoUzungo it .ye ^ compounds of the formula IV, wherein R ^ " , above 3gd-eutuug> .besi ^ t _; uad X for the acid residue of a reactive ligest:.? -. especially for

2 9/1 * 044 ^ ^ -

- 4 - '' 100-2442

Chlorine, bromine, iodine or a methane, benzene or p-toluenesulphonic acid group - stands in the presence of an acid-binding agent.

d) Compounds of the formula 1Id, in which R _{0 has the} above meaning belli

and R _{1 is} a lower alkyl group bearing at least two hydrogen atoms on the carbon atom connected to the nitrogen atom, which is benzyl or phenylethyl, can be prepared by adding compounds of the formula V, in which R _{2 has the} above meaning and R stands for lower. Alkyl or alkoxy, phenyl or benzyl, or compounds of the formula VI in which R _p and R have the above meaning and R _{1 is} hydrogen or a

Radical of the formula -CO-R, in which R, has the above meaning ■ reduced in an inert organic solvent under the reaction conditions by means Lithiümaluminiumhydrid. Babel reduces an N-alkoxycarbonyl group to the methyl group or an N-acyl group to the corresponding alkyl or aralkyl group and - in the same operation - reduction of the keto group (formula V) or reductive cleavage of any O-acyl or 0-A1- • koxycarbonyl group (formula VI).

e) Compounds of the formula lie in which R _{0 has the} above meaning

IV '

and KZ stands for hydrogen or a lower alkyl group comprising at least two carbon atoms, is obtained by catalytic hydrogenation of compounds

V of the formula Hf, in which R ^ has the above meaning and R ^ represents the benzyl group or a lower alkenyl or alkynyl group; the benzyl group is split off in the process

or a lower alkenyl or alkynyl group for the corresponding

corresponding alky! group reduced.

O09829 / 1SU

> 5 - 100-2442

If, for example, lithium aluminum hydride is used as the reducing agent in process a), a cyclic ether, such as tetrahydrofuran or dioxane, for example, can be used as a solvent which is inert under the reaction conditions. Used, for example sodium borohydride _$ man is as a solvent for example a lower alcohol optionally mixed with water, for example ethanol or ethanol / water '' geeigne t.

In process b), e.g. platinum, Palladium, Raney nickel and than under the reaction conditions inert solvent preferably a lower alcohol such as ethanol are used,

"The reaction according to process c) takes place in the presence of an acid-binding agent, for example an alkali metal carbonate such as potassium carbonate, or a tertiary organic base such as triethylamine and in a solvent which is inert under the reaction conditions, for example in a lower alcohol such as ethanol, in a chlorinated hydrocarbon such as chloroform or in an aromatic hydrocarbon such as xylene. The reduction preferably takes place at elevated temperature, for example at the boiling point of the reaction mixture, and lasts between 15-25 hours.

Process d) can be used as under the reaction conditions inert solvent, for example a cyclic ether use like tetrahydrofuran.

For the catalytic hydrogenation according to process e) one shakes the starting product of the formula Hf in one under the reaction "conditions inert solvent, e.g. in a lower alcohol / mineral acid mixture like ethanol / hydrochloric acid in the presence a hydrogenation catalyst, e.g. palladium with gaseous hydrogen.

009829/1944

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The hydroxy compounds obtained by this process Formula II can be used as free bases or in the form of their salts Can be isolated in the usual way and purified by known methods. Optically active compounds of the formula II can be obtained by converting the corresponding racemic compounds into diastereoisomers by reaction with optically active acids Salts transferred, these separated by fractional crystallization and then the bases by means of alkali releases.

The for the preparation of the hydroxy compounds of the formula II be ™ required starting products are partly unknown; they can be produced as follows:

Lower alkyl esters of isonicotinic acid are used with connective fertilizers of the formula IVa, in which R _{1 has the} above meaning and

I.
X stands for bromine or iodine, to the corresponding 4-alkoxycarbonyl-1-ϊ ^ -pyridinium halides, for example by heating the components in ethariol for several hours. From this, by means of sodium borohydride, tetrahydroisonicotinic acid esters of the formula VII, in which R ^ has the above meaning and R _{1, are obtained} . represents lower alkyl; they are reacted with magnesium compounds of the formula VIII, where R _{2 has the} above meaning, and the resulting products are hydrolyzed to give compounds of the formula IX in which R,, Rp and R have the above meaning.

II • From this one obtains ketones of the formula IHa, in which R ₁ and R have the above meaning, either by heating with polyphosphoric acid or by hydrolysis to the free carboxylic acids, preparation of the acid chlorides, e.g. using thionyl chloride, and treatment of the latter with anhydrous aluminum chloride. Ketones of the formula IHb unsubstituted on the nitrogen, in which R _{p has the} above meaning, are obtained from compounds of the formula IIIc in which Rp has the above meaning

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sits, by heating with a lower alkyl ester of chloroformic acid and subsequent hydrolysis of the resulting urethanes (formula Va, where R _{0 has the} above meaning and R ^ stands for lower alkoxy), for example by means of hydrochloric acid.

Compounds of the formula lic are obtained by reducing ketones of the formula IHd, in which R _{0 has the} above meaning and

Vt
RI denotes hydrogen or benzyl, in which case catalytically excited hydrogen is preferably used; otherwise the benzyl group in the reduction product is subsequently split off by hydrogenolysis.

Compounds of the formulas V and VI are obtained by ' Settlement of compounds of the formula IIIb or Hc with acetic anhydr Id or with compounds of the formula Cl-CO-R ^, wherein R, has the above meaning, in the presence of an acid-binding agent By means of how pyridines can be made from the compounds of the formula lic mixtures of N-GÖ-R ^ derivatives and Ο, Ν-bis (-CO-R,) - derivatives arise. When reducing the Ver However, bonds of the formula VI by means of lithium aluminum hydride (see above under d) become a possible G-alkyl or 0-alkoxycarbonyl group split off reductively, so that a separation of such mixtures is not necessary} a possible one However, 0-acyl or 0-alkoxycarbonyl group can also be split off hydrolytically before the reduction, e.g. by 10-15 minutes heating with a solution of kai iuinhydr oxide in a lower alkanol.

Compounds of the formula Hf are obtained either by reduction of the corresponding ketones of the formula IHe, in which rY and Rp have the above meaning by means of sodium borohydride or Lithium aluminum hydride or by reacting compounds of the formula lic with compounds of the formula IVb, wherein

Rl and X have the above meaning in the presence of an acid-binding agent Means.

00982371044. ■ original bathroom

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If the preparation of the starting compounds is not described, these are known or by processes known per se or analogous to those described here or can be produced analogously to processes known per se »

In the following examples, which explain the invention in more detail, but are not intended to limit their scope in any way, all temperatures are given in degrees Celsius and are uncorrected. .

SAD

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Example 1: i * 3 _i 4

pyridine

20, O s!, ^^

pyridino! are heated with 200 ml of 2 Ii hydrochloric acid for 20 minutes at reflux zvm boiling. The reaction device is then cooled to 0 ° and the precipitated hydrochloride of the compound mentioned in the table is filtered off, which is dried in a desiccator and recrystallized from methanol; Sinp.

- 260 ° (decomp.).

The 1.3 »4.4a * 5.9b ~ hexahydro-2-methyl-5 (2H) -indenQ {1,2-aIpyridinol required as the starting product can be made by one of the methods described below

I »A solution of 20> 0 g

2R * -indeno [1,2 ^ cJpyridin-5-one in 150 ml of methanol is at 60 ° and 5 atmospheres shaken with hydrogen and 0.5 s platinum oxide, until the calculated henge hydrogen was added is. The catalyst is filtered off and the filtrate is evaporated and the residue crystallizes from isopropanol Srop · des 1,3,4,4a, 5,9b-hexahydro- * 5 {2H) -indenoil, 2-c} pyridinols 14;> - 145 °.

II · To a solution of 50.0 gl _jr 3.4, _i 4a, 5 _J , 9b-Hexahydro-2-ethyl- ^ -indenofljja-elpyridin-S-dn in 50 ml of ethanol is within 10 minutes with good drilling a solution of 19 g of sodium borohydride in 50 ml of water was added dropwise, keeping the temperature at about .40 ° rises · Mah stirred for 1 hour 4o ° j then Z hours under reflux, then added dropwise 60 mi of methanol and cooled to 'another hour ^afcj: then filtered to UEN precipitate and the filtrate is evaporated to dryness .. the filter residue is combined with the filtrate and Dej Eindarapfrückstand taken up in water and chloroform; wan shakes until complete solution occurs, separates the ChXorofor; nsGhicht and extra-

The aqueous phase hiert two more times with chloroform * Man

- 10 - 100-2442

the combined organic phases are dried over magnesium sulfate and evaporated, and the residue is crystallized several times from isopropanol. The same compound as under I with a melting point of 145 ° -145 ° is obtained. To obtain a further fraction of the mother liquor at ca, 1; 52 - melts I36 ⁰ and the above compound is an isomer mixture of a narrow Stereor, but which can be readily used for the elimination of water.

UX »A suspension of 1.9 g of lithium aluminum hydride is added. In 50 ml abs. Tetrahydrofuran * at 20 ° with stirring dropwise with a solution of 20.1 g, 5 »4,4a, 5,9b-hexahydro-2-methyl-2H-Indepo [1,2-cIpyridin-5-one in 100 ml of tetrahydro -

• furan, the mixture is heated to boiling for 2 hours under reflux, then 8 ml of saturated aqueous sodium sulfate solution are added dropwise after cooling to 10 ° and the precipitate is filtered off, which is extracted several times with boiling tetrahydrofuran . will. The combined filtrates are evaporated and the residue is crystallized from isopropanol, mp, des 1.3 * 4,4a, 5,9b-hexahydro-2-methyl-5 (2H) -indenoU, 2-cJpyrldinols 14} - 145 °.

JV, ¹ A solution of 20 g I,] 3,4,4a, 5,9b-Hexahydro-2-methyl-2H-Indenofl, 2-cJpyridin-5-one in 150 ml of ethanol is in a shaking autoclave at room temperature and a Print of ; 50 Attt hydrogenated for 18 hours in the presence of 2 ml of Raney nickel. The catalyst is then filtered off, the filtrate is evaporated in vacuo and the residue is crystallized twice from isopropanol; M.p. of 1,3 * 4,4a, 5,9b-hexahydro-2-methyl-5 (2Ii) -indenoil, 2-c] pyridinol 145-145 °. j

V · Han added a suspension of 5 S lithium aluminum hydride in 100 ml abs. Tetrahydrofuran within I5 minutes under stirring j dropwise with a solution of 10 g of 2-Aethoxycarbo- ^s nyl-l, 3,4,4a, 5,9b-hexahydro-5 (2H) indeno [l, 2-c] pyridinol in 50 ml of tetrahydrofuran, the mixture is for 2 hours at. Stirred boiling temperature at reflux, then cooled to room temperature and washed dropwise with saturated aqueous sodium.

A. -r

003829/1144

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sulfate solution is added until a precipitate forms. It is filtered, the filter residue is extracted three times with boiling tetrahydrofuran and the combined ones are evaporated Filtrates in a vacuum. The residue is made from isopropanol, then recrystallized from acetone} the 1,3,4,4a, 5,9b-Hsxahydro-2-methyl-5C2H) -indenol 1,2-c] pyridinol melts at 14 ^ - 1 * 5 °.

The 2-ethoxycarbonyl-l, 3,4,4a, 5 _Jr 9b-hexahyäro-5 (2K) -inderio [l, 2-c] pyridineQl required as the starting product for variant V can be obtained, for example, as follows:

A solution of 20 gl, 3,4,4a, 5,9b-hexahydro-2-methyl-5 (2H) ~ indeno (l ₁ 2-c} pyrldinol in 100 ml pyrldine is mixed with 13/8 ml acetic anhydride at room temperature and left to stand for 24 hours. Then it is evaporated in a vacuum at 40 °, the remaining oil is poured into 20Q ml of water and made alkaline with aqueous sodium carbonate solution while cooling with ice and stirring well washed with water and dried in a desiccator. After recrystallization from isopropanol, the S ^ acetoxy-1 ^^, 4a, 3> 9b "hex &! hydi'o-2-methyl-2H-indeno [1,2-cJpyridine melts at. 98 - 100 °.

To a solution of 21.6 g of the above 5-Acetöxy ~ l, 3,4,4a, 5,9b-hexahydro-2-inethyl-2H-indeno (l, 2-c] pyr ⁱ IäIns in 200 ml abs. benzene is added dropwise within 30 minutes a solution of 40.7 g of ethyl chloroformate in 50 ml of benzene, whereupon the temperature rises to about 3O ^0th then heated> hours under reflux, wherein the first precipitate dissolved again to a large extent. It is then cooled, shaken first with 150 ml of water, then twice with 150 ml of 1N hydrochloric acid each time and again twice with 3e 100 ml of water, the benzene layer is dried over magnesium sulfate and evaporated

0GS823 / 184A

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Remaining, crude 2-ethoxycarbonyl-5-acetoxy-l, 3,4,4a, 5,9b-hexahydro-2H-indenoil, 2-eJpyridin is refluxed with a solution of 25 g of potassium hydroxide in 250 ml of butanol for 15 minutes. It is cooled in it, diluted with 400 ml of ether and shaken out several times with water until the washing water reacts neutrally. After drying over magnesium sulfate, the organic phase is evaporated and the residue is distilled in a high vacuum, the 2-ethoxycarbonyl-1, 3, 4,4a, 5,9b-hexahydro-5 {2H) -indeno [1,2-c] pyridinol at 190 - 200 ° / ° * 3. Torr passes over as a pale yellow viscous oil (temperature measured in an air bath).

Example 2; l _J 3,4,9b-tetrahydro-2-risthyl-2H-- | ndenc £ l _i 2-c] pyridine

A solution of 5 g i, 3,4,4a, 5,9b-hexahydro-2 ~ ffl € ithyl-5 (2H) indeno [l _i 2-c] pyr ⁱ idinol and 15 g Maphtha, lin-LV5-disulfonic acid in 50 ml of water is refluxed for 1 J £ hours. The reaction mixture is then evaporated to dryness in vacuo and the residue is crystallized twice from ethanoi; the bis-4,3,4,9b-tetrahydr-o-2-methyl- ^ -indenoil ^ -clpyridinjnaphthalin-l ^ -disulfonate melts with decomposition at 275-280 °.

Example 3: 223enzyl »1 _, 3,4,9b» tetrahydro-2H-indeno £ 1,2-c2 pyridine

10 g of 2-benzyl-1,2,4,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-cl pyridinol are in a mixture of 15 ml conc · hydrochloric acid and 35 ml of water at reflux for 20 minutes Boiling heated * When the reaction mixture cools, the hydrochloride of the compound named in the title crystallizes from which filtered off and first from water, then is recrystallized from ethanol. It changes color when heated from 165 ° slowly green and melts with decomposition

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at 215 - 225 °.

The compound eliminated as the starting material becomes like follows produced?

a) 4-Aethoxyearbonyl-1-benzyl-pyridiniiim-broinid

226 g of isonicotinic acid ethyl ester and ^ Q g of benzyl bromide in 375 ml of ethanol are refluxed for 18 hours heated to boiling - The cooled reaction mixture is added until the beginning of crystallization ether is raised The precipitate is titrated off after several hours and thoroughly washed with ether. You get the im Title compound in the form of hygroscopic crystals, which melt at 168 ° with decomposition.

A solution of 3 ^ 6 S ^ benzylpyridinium bromide in XHO0 ml ^^ methanol at> 5 - 0 ° is added in portions within 2 hours with # & g: sodium borohydride and the mixture is stirred for 3 % hours at room temperature. The methanol is then distilled completely in vacuo, the residue is taken in 1000 ml of Ben-,

zol, filtered from the precipitate and from "™ evaporate the Piltrat in vacuo The residue is distilled under high vacuum to yield l-benzyl ~ l _# 2,5,6-tetraliy4rQ-isonicotinsäureäthylester at II5 -. IL-8 ^p / O, Q3 Torr over-

goes i n ^ = 1.5337.

mixture)

Overlay 30 # 9 g of magnesium shavings with 120 ml of abs # Tetrahydrofuran, add a spatula tip of iodine and approx. 30 aa of a solution of 2C9 g of bromobenzene in 3OO ml of abs, Add toluene and heat until the * reaction starts., • dripping onto it; one de »remainder of the above bromobenzene solution

- l4 ·. ■ 100 * 2442

so quickly that the solution is constantly boiling (about X hours) and then refluxed for a further 2 hours. At this phenylmagnesium bromide was added dropwise at -15 now ^east with good stirring over 1 hour, a solution of l49 gl-benzyl-1,2,5,6-tetrahydroisonicsotinsaureathylester in 150 ml abs. Benzene, then stir for a further hour at -15 ° and then pour the reaction mixture into 2000 ml of ice-cold 20 % aqueous ammonium chloride solution while stirring. Filter through diatomaceous earth, separate the organic phase and extract the aqueous bubble twice with ether; the combined organic phases are extracted three times with a total of 1000 ml of 10 % aqueous acetic acid dried and evaporated. »The residue is triturated with 250 ml of hexane, whereupon small amounts of 1-benzyl-4-benzoyl-; 5-p | ienylpiperidine (melting point 162 °) crystallize out ♦

The precipitate is filtered off and the piltrate is evaporated and the residue is distilled in a high vacuum, the im Connection mentioned in the title at 17Ö - 18q? / Ö # 2. Torr passes.

d) 2-Benzyl-1,3,4,4a, |, 9b-hexahydro _: 2H-indenoll

To 700 g of polyphosphoric acid are added at about 100 ° 68 g l-benzyl-35-phenyl-isonipecotinsäureäthylester (isomer mixture), heated in a nitrogen atmosphere and with vigorous stirring within 1 hour of ^l to l80 ° and slowly keeping for 3 hours at this Temperature * The dark brown reaction solution is ί cooled to 100 ° and poured into 1000 ml of water; the solution is in a nitrogen atmosphere and good cooling with 50 % aqueous potassium hydroxide solution (approx * l400 ml)

- 15 - 100-2442

Made alkaline "Then 1500 ml of ether are added, stirred well through", filtered through diatomaceous earth, the ether is separated off and the aqueous phase is extracted twice more with ether. The Aetherschiehten are combined, dried over potassium carbonate and eingedampftj the residue under high vacuum distilled to give the title compound in I80 - 200 ^o / 0 (measured in an air bath temperature) * ° 2 torr as a yellow, viscous oil passes over. It is very sensitive to oxygen and is therefore processed further immediately. Mp. Of the hydrochloride 210 ° (decomp.), After crystallization from isopropanol.

dinol

To a suspension of 3 g of lithium aluminum hydride in 25 ml of abs. Tetrahydrofuran is added dropwise at 10 ° a solution of 29 g of 2-benzyl-l _i 3 * 4 * 4a, 5,9b-hexahyäro-2H-indeno [l, 2-c3 pyridin-5-one in ml of abs 75 miles. Tetrahydrofuran. The mixture is heated to boiling under reflux for 1 hour, cooled to 0 ° and 15 ml of saturated aqueous sodium sulfate solution are added dropwise with good cooling. The precipitate is filtered off and then extracted twice, each time with 100 ml of boiling tetrahydrofuran. Evaporate the combined filtrates and the residue is distilled under high vacuum ,, wherein the compound named in the title as a yellow, viscous oil in I80 - 190 ° / 0.02 <r _orr passes (temperature measured in the air bath) "is dissolved in the distillate 50 ml of ethanol and a solution of 15.1 g of naphthalene-1,5-eisulfonic acid in 50 ml of ethanol. The salt which crystallizes immediately is filtered off after some time and washed with ethanol; the base is released again by stirring with 1N sodium hydroxide solution and methylene chloride. This is a colorless, tough resin at room temperature. M.p. of the hydrogen ^{maleate 167-169 0} (decomp.), After crystallization from ethanol.

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Example 4: ii3 £ i £ 9b-Tetrahydro-2H-indenoU _£ 2-c] pyridine

10.0 g of 1,3,4,4a, 5,9b-hexahydro-5 (2H) ~ indeno [1,2 ~ eJpyridihol hydrochloride are refluxed with 40 ml of 2N hydrochloric acid for 20 minutes. The reaction mixture is then cooled to 0 ° and the precipitated hydrochloride of the compound mentioned in the title is filtered off, which is dried in vacuo and is recrystallized from methanol. M.p. 302-308 ° (Decomposition).

The as needed Ausgangsprodükt i, 3,4 _J 4a, 5,9b-Hezahydro-5 (2H) indeno [l, 2-cJpyridinol can the methods described below are prepared according to a =:

I. To a solution of 20.9 g, 3 »4j4a, 5 * 9b ~ hexahydro-2-methyl-2H-indeno [1,2-cJpyridin-5-one in 200 ml of abs. Benzene is added dropwise to a solution of 36.0 g of ethyl chloroformate in 50 ml of benzene over a period of 20 minutes with thorough stirring. The mixture is heated to boiling under reflux for 3 hours, then cooled and shaken first with 200 ml of water, then twice with 100 ml of 1N hydrochloric acid each time and finally again with water. the organic phase is dried over magnesium sulfate and evaporated. The crude, viscous oil that remains is refluxed under nitrogen with 450 ml of 5N hydrochloric acid for 17 hours. Then it is evaporated to dryness in vacuo and the residue is crystallized from ethanol; Mp of l, 3,4,4a, 5,9b-hexahydro-2H-indeno [l, 2-c] pyridine-5-onhydrochloriäs 235 -. 238 ⁰ (dec.).

A solution of 20.0 g of the above 1,3,4,4a, 5,9b-hexahydro-2H-indeno [1,2-c] pyridin-5-one hydrochloride in 250 ml of methanol is mixed with 0.4 g of platinum oxide and hydrogen shaken until no more hydrogen is absorbed.

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The catalyst is then filtered off _# the filtrate is evaporated in vacuo and the office liquor is crystallized from isopropanol; Βπφ * des l, 2,4 _# 4a, 5 ^
noCl ^ -eJpyridinol-hydroahlQrids 200 - 202 ° (dec.)

II. A solution of 20 g of 1,3,4,4 ^ 5 * 9b ^ Be3Eahydro-2H-indenofljrS-clpyridin-S-one hydrochloride ^ (preparation see above under I) in 300 ml of methanol is added to a solution From 4 g of sodium hyäroxio; in 10 ml of water and 4 ml of flaney-Ni & fcel and shake with hydrogen for 18 hours at 20 atmospheres and 0 °. The catalyst is then filtered off * the filtrate is evaporated * the solid residue is triturated with water and filtered! The filter leakage becomes good. ™ washed with water, dried and recrystallized from isopropanol. Mp. _{Des l J} , 3 _i 4,4a * 5 # 9 ^ - ^ ^{e :;} ^ ^h y ^ ^o '"5 ^ ² ^ 5" * indenone, 2-elpyridinols 182 - 184 °. -

III, Bine solution of 2 g of 2 * Ben0yl-l * 3 # 4,4a ^ i $ _Jr 9b-he3CEiihydro-5 (2H) -indeno [1,2-c] pyi'idinol (Example 3e) $ m- 30 ml of ethanol are mixed with 3.4 ml of 2 liters of hydrochloric acid and then saturated with hydrogen in the presence of 200 mg of a palladium catalyst (10 ^ on carbon). After the calculated amount of hydrogen has been taken up, the hydrogenation comes to a standstill. The catalyst is filtered off, the filtrate is evaporated, the residue is taken up in water and the solution is prepared the solution is alkaline. It is extracted with Methylenehlorid, the dried over potassium carbonate organic phase is evaporated and the residue crystallized from a little isopropanol, the 1,3,4, 4a _# 5 _J »9b-hexahydro-5 (2H) indeno {l, 2-c] pyridino! is obtained in the form of an isomer mixture from Sop, 152-176 *, which can, however, easily be used for the elimination of water.

Example ei

B T-chlorine-li ^^^ a ^ Sb ^ iexahy ^ ro-a ^ e ^^ - SC ^

ORfGfMALJNSFSOTED

- * 16Ö5740

- 18 - 100 ^ 2442

il, 2-c] pyridinol are concentrated with a mixture of 20 ml. Hydrochloric acid and 40 ml of water under reflux for 20 minutes Boiling heated. It is then cooled and evaporated in vacuo and absorbs the remaining foam in acetone, whereupon the hydrochloride of the compound mentioned in the title crystallized Srap * 256-258 ° (decomp.} # after crystallization from isopropanol.

The hexahydro-2-methyl-5 {2H) -indenot1, 2-cJpyridinol required as starting material can trie can be produced as follows:

A solution of 14.5 g of T-

generally 150 ml of ethanol

within 5 minutes with a solution of 4.7 g Sätrium « borohydride added in 15 ml of water. First stir for 1 hour * de at 35 °, then under reflux for 4 hours, there thenorl5 mt ^ Methanol and refluxed for another hour} the deposited precipitate is filtered off and evaporated the FiItrat entered. The filter residue and the evaporation fruit * stand are combined and dissolved in water and methylene chloride recorded. The methylene chloride layer is separated off and the aqueous phase is shaken twice with methylene chloride out, the combined organic phases are dried over potassium carbonate and crystallizes the at »evaporation of the solution baker remaining residue twice from isopropanol; Sjrap * des 7 ^ hlor «l, 3,4,4a, 5, c ^^ exahydro ^ - ^ Ci, 2-clpyridine oil 169-170 °.

Example 6: lj ^ * 4, §b- ^ trahy ^^

10 g of 1,>, 4,4a, 5,9h * hexahydro-2,6-diB! Ethyl-5C2H) -indenci [1,2 * cjpyridinol are refluxed for 20 minutes with 100 ml of 2 U hydrochloric acid, The reaction mixture is then evaporated in vacuo, and 25 ral of Äetäianol ν 00982S / tf «4 is added

ORIGINAL INSPECTED

- 19 - 100-2442

and evaporates again. The residual hydrochloride of the compound mentioned in the title is recrystallized from ethanol / ether and then from ethanol. It turns green slowly when heated from 195 ° and melts with decomposition at 250-255 ^0th

The raw material is produced as follows:

A suspension of 1.1 g of lithium aluminum hydride in 10 IüI abs. Tetrahydrofuran at 10 - 20 ° was added dropwise a solution of 12.7 gl, 3,4,4a _J 5,9b-hexahydro-2,7-dimethyl-2H-indeno [l, 2-c] pyridin-5-one i * ¹ 60 ml of tetrahydrofuran were added. The mixture is heated under reflux for 1 hour and then saturated aqueous sodium sulfate solution is carefully added dropwise at 20 ° with cooling until a precipitate that can be easily filtered is deposited; this is filtered off and extracted twice with boiling tetrahydrofuran. The combined filtrates are evaporated and the residue is crystallized from acetone. l, 3,4,4a, 5 * 9b-hexahydro-2,7-dimethyl-5 (2H) indeno [l, 2-cJpyridinol melting at 148 - I50 ^0th

Example 7t ι, 3 * 4 * 9te-; £ e ^^ y ^ Bz ^^ rPE ^ SÖr ??! ^^ ?! i * £ :: £ l

pyridine

8.0 g 1,3,4,4a, 5,9b-hexahydro-2-n-propyl-5 (2H) -indeno [1,2-c} pyridlnol are refluxed with 80 ml of 2N hydrochloric acid for 20 minutes heated to boiling. When the mixture cools, the hydrochloride of the compound mentioned in the title crystallizes from, which is filtered off and recrystallized from 2 N hydrochloric acid. M.p. 261-264 ° (dec.).

The starting product can be produced as follows:

A solution of 12 g of 1,5,4,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-c] pyridinol is added in 250 ml of chloroform with 15g of anhydrous sodium carbonate and 8.7 g of n-propyl bromide and

9829/1844

- 20 - 100-2442

reflux the mixture for 18 hours. After cooling, it is washed neutral with water, extracted three times with 10 % aqueous acetic acid, the extracts are made alkaline by adding sodium hydroxide solution and shaken out three times with ether. The organic phases are combined, dried over sodium sulfate and evaporated. The 1, J>, 4,4a, 5/9 ^ - hexahydro-2-n-propyl-5 (2H) -indeno [1,2-c] pyridinol remains as a residue and is recrystallized from hexane, m.p. 82-84 °. ^:

Example 8; 2-Allyr _r l _{t 1} 5.4 _2b; tetrahydr.o _r-2H-indeno [l, 2 _:: cl pyridine

10 g of 2-allyl-l, 5,4,4a, 5,9b-hexahydro-5 (2H:) - indeno ^[i:, 2-c] pyridinol with 100 ml of 2N hydrochloric acid '20 minutes under reflux to boiling -Heated ". After the mixture has cooled, the precipitated hydrochloride of the compound mentioned in the title is filtered off and recrystallized from 2N hydrochloric acid, melting point 260-265 ° (decomp.).

The raw material is produced as follows:

A solution of 8 g of 1,3,4,4a, 5,9o-hexahydro-5 (2H) -indeno [1,2-cJpyridinol in 200 ml of chloroform is mixed with 10 g of anhydrous sodium carbonate and 5.8 g of allyl bromide and 18 Heated to boiling under reflux for hours. After cooling, it is washed neutral with water, extracted three times with 10 % aqueous acetic acid, the extracts are rendered alkaline while cooling with sodium hydroxide solution and extracted three times with ether. The organic phases are combined, dried over magnesium sulfate and evaporated. The remaining 2-allyl-1,2,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-clpyridinol] is recrystallized from hexane. M.p. 77-78 °. . <-

009829 / 1-844

-21- 100-2442

Example ο, * li ^ iiiSk-Tjfcrakydr ^ - ^ gp ^

10 g, 5,4v4a, 5 _J 9b-hexahydro-2- (2-phenylethyl) -5 (2H5-indeno [1,2-c} pyridinol) are treated with a mixture of 1/2 ml of concentrated hydrochloric acid and 70 ml of water The hydrochloride of the compound mentioned in the title, which precipitates out during the heating process, is filtered off after the mixture has been cooled and recrystallized from methanol

The starting material is prepared as follows

20g l, 5.4

600 ml of xylene, 25 g of anhydrous sodium carbonate and 20 g of 2-phenylethyl bromide are refluxed for 20 hours. Then the cooled reaction mixture is shaken three times with water from the organic phase extracted three times _# mi.fc 10 M wlkseriger Essi ^ s ^ re, provides the extracts under cooling with sodium hydroxide solution were to admit of alkaline s, shaking three times with Äether. The ethereal layers are combined, dried and evaporated. remaining 1 _# 5 * ^^ Si ^ b-iiexahydro ^ a-phetfiai ^ I

nol is recrystallized from acetone. 112-114 °. t

Example 10: T ^ Brom-;!, HilsSb-tetr ^^ dro-l ^ methyl- ^ H-indeno ■

^ # 8 g 7 * Br0m-l _i 5,4,4a * 5 _# 9b-h ^ xahydr4-2-ynethyl-5 (2H> - ^ fl, 2-clpyridinol with a mixture of 14 ml of concentrated hydrochloric acid and 28 ml of water heated to boiling under reflux for 50 minutes. It is then cooled, evaporated in vacuo and the residue in ethanol, whereupon the hydrochloride

ira ^ ritel successful connection crystallized. Smp * - 255 ° (double,) »

-ORlGfNALlNSPSCTED

'4695740

The 7-bromo-1,3,4,4a, 5,9bhexahydro-2-methyl-5 (2H) -indeno [1,2-c! Pyridino! can be made as follows:.

(Mixture of isomers)

14.0 g of magnesium shavings are mixed with 50 ml of abs. A layer of ether and, after adding 0.2 g of iodine, 2O> P ~ -g ". $ H & i * bromobenzene was added, with a vigorous reaction ml of absolute ether are added dropwise in such a way that the mixture boils constantly 5,6-tetoahydro-isonicotdJl- * acid methyl ester in 45 ml of absolute toluene is added, the reaction mixture is stirred for 1 hour at -15 ° and then poured into a solution of 150 g of ammonium chloride in 600 ml of water It is extracted several times with ether, the organic phase is extracted with 1N hydrochloric acid and the aqueous acidic solution is made strongly alkaline with concentrated sodium hydroxide solution, then extracted with metal chloride and the organic extracts washed with water are dried over magnesium sulfate, after evaporation of the solvent we d; the residue under high vacuum distilled to give the l-methyl-JC ^ -bromphenylJ-isonipecotinsäuremethylester (isomer mixture) at l46 - l48 ^o / 0 * 06 Topr öbergehi; "

A mixture of 55.0 g of methyl icotinate and 550 g of polyphosphoric acid is stirred at 180 ° for 4 hours; 90 ⁰ cooled and then poured into I500 ml of water with vigorous stirring. At a

ORiGIHAL, JMSPSQTED

^; '7695740

- 25 - 100-2442

At a temperature of 10-20 °, the cloudy solution obtained is slowly mixed with 40% sodium hydroxide solution until a weakly alkaline reaction (pH = 8), the separated oil is extracted several times with methylene chloride, the combined organic extracts are dried over potassium carbonate and evaporated Solvent completely. The residue is distilled in a high vacuum, the 7-bromo-l,>, 4,4a _> 5,9b-hexahydro-2-methyl-2H-indeno [1,2-c] pyridine-5-oen at 170-185 ° / Q> 1 Torr passes,, ■ - -

7-Bromo-1,3,4, 4a, 5,9b-hexahydro-2-methyl-5 (2H) -indeno [1,2-c pyridine oil ' M

To a solution of 20.0 g of 7-bromo-1,3,4,4a _i 5,9b-hexahydrO'-2-methyl-2H-indenotl, 2-c] pyridin-5-one in 20 ml of ethanol is added within of 10 minutes with good stirring a solution of 5i ^ 5 ß sodium borohydride in a / mixture of 0.5 ml of 40 % sodium hydroxide solution and. 12 ml of water are added dropwise * whereby the temperature should not exceed 40 °. The mixture is stirred for a further 1 hour at 40 °, then for 2 hours under reflux, then 15 ml of methanol are added dropwise and the mixture is cooled after a further hour; the precipitate is then filtered off and the filtrate is evaporated to dryness. Of the. Filter residue is combined with the residue from evaporation of the filtrate and g taken up in water and chloroform; it is shaken until complete solution occurs, the organic phase is separated off and the aqueous phase is extracted twice more with chloroform. The combined organic phases are dried over magnesium sulfate and evaporated, and the residue is crystallized several times from isopropanol; M.p. of the compound I65-167 ⁰ mentioned in the title. One obtains a larger fraction from the mother liquor at about 142 - ⁰ I5I melts and consists of a stereoisomer mixture, but which can be readily used for the elimination of water.

009829/1844., Γ _{BAD 0R1} Q.NAU

- 24 - 100-2442 ■

Example 11; ^^^ i ^^^^] p ^ ridin ■

g of 2-ethyl-l, 5,4 / 4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-cJ

pyridinol with 100 ml of 2N hydrochloric acid for 20 minutes on the Rückr River heated to a boil. The hydrochloride of the named in the title which precipitates on cooling the reaction mixture The compound is filtered off and recrystallized from 2N hydrochloric acid; M.p. 275 ° (dec.).

The starting product can be according to one of the two following methods described are produced:

I »A solution of 8 gl,; 5,4,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-c] pyridinol in 200 ml of chloroform we, d with 10 g of anhydrous sodium carbonate and 7 * 25 g of ethyl iodide are added and the mixture is refluxed for 18 hours. The cooled reaction mixture is then washed neutral with water, extracted three times with 10 % aqueous acetic acid, the acidic aqueous extracts made alkaline with sodium hydroxide solution and extracted three times with ether. The ethereal phases are united. Dried over sodium sulfate and evaporated, the 2-ethyll * 3 * 4 _{/ t} 4a, 5,9b-hexahydro-5 (2H) -indenoil, 2-cJpyridinol remaining as a residue; M.p. 102-104 °, after crystallization from acetone.

II. A solution of 1.8 g of 1,2,4,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-c] pyridinol is added in 20 ml of pyridine with ice-cooling dropwise with 1.9 ml of acetic anhydride and leaves the Stand mixture for 12 hours at room temperature. It is then evaporated in vacuo, the residue is taken up in water, acidify the solution with dilute hydrochloric acid and extract several times with methylene chloride. The organic phases will combined, dried over magnesium sulfate and evaporated. The remaining 2-acetyl ~ 1,; 5,4,4a, 5,9b-hexahydro-5 (2H) -indeno [1,2-c] pyridinol becomes from

Q09829 / 18U

- 25-100-2442 ".

Isopropanol recrystallized and then damaged at 15 $ - 150 °. A suspension of \% j ^ lÜtüitanÄXü "rainiumhyärW in 2Φ 1 ^^^^ 20 ° _;

in portions with 4.6 g <Jes above 2 ^^ βί ^ -4.3 »4 _Λ ^ exany ^ o-5 (21i)" -ina ^ o (l> 2 »<i | p ^^ äas mixture ^ hours . on HUcfcflus & zwra Seven Then kUnlt to% Q <* from and drips slowly saturated - aqueous Natriumsulf'atlösung ztii "until a Nlederscnlag (approx fails J ralJi de ^ Hiederschlag is filtered and several times with sieäenäero ^ ^ tranydrofiü>

The combined rates are evaporated and the residue is distilled in a high vacuum with an oil of bp 140-150 ° at 0.0 $ (temperature measured in the air bath). Taking the Bestillat in a little acetone to j, filtered, small amounts of l, 3 ₄ 4,4a, 5,9b-He3saliydro- · 5 (2H) -indenötl # 2-c) pyrictinol off and the filtrate is acidified nachZusatz of ethanol mitätherischemGhlorwasserstoff at. The hydrochloride des2-ethyl-l, 5,4j4a, 5,9b-hexahydro-5 (2H) * indenori, 2-clpyridinol which precipitates out immediately is filtered off and recrystallized from ethanol, Bs turns ^{green when heated to over 20 p} and melts with decomposition at approx. 222 °.

Example 12; li ^ i ^^^ TSlS ^ yd ^ o- ^ isopropyl - ^ - indeno ^ l, ^ gyridine

gl, 3,4,4a, 5> 9b-hexahydro-2-isopropyl-5 (2H) -indeno {1,2-'cJ pyridinol are refluxed for 20 minutes in 100 ml of 2N hydrochloric acid Cooling the reac-; tion mixture precipitating hydrochloride of those mentioned in the title; ' The compound is filtered off and recrystallized from 2 N hydrochloric acid; sated; M.p. 260-26 "5 ^Q (dec,). I

The starting product could be made as follows:

009829/1144

- 2β - "100-2442

10 g of anhydrous sodium carbonate and 8 g of isopropyl iodide are added to a solution of 8 g of 1,3,4,4a, 5,9b-hexahydr6 »5 (2H> -indenpii, S-öJ pyridino! In 200 ml of chloroform, and the mixture is refluxed for 10 hours heated to boiling. the mixture is subsequently washed, the cooled reaction mixture with water to neutrality, extracted three times with 10 $> aqueous acetic acid, the acidic aqueous extracts with sodium hydroxide solution alkaline and extracted three times with ether from "the ethereal phases are combined, dried over sodium sulfate and evaporated to give the _{1,3 #} 4,4a, 5,9b-hexahydro-2-isopropyl-5i2li) indeno [1,2-cjpyridinol remains as a residue in Smp. 102 104 ^p , after crystallization from acetone.

Example 13t 1 * 3 ** »^ l-Tetrahydro-g - (^ -

10 gl, 3, ⁱ f, 4a, 5,9b-hexahydro-2- (2-propynyl) -5 (2H) -indeno [1,2-cjpyridinol are refluxed in 100 ml of 2N hydrochloric acid for 20 hours heated. The hydrochloride of the compound mentioned in the title which precipitates on cooling the reaction mixture is filtered off and recrystallized from water; M.p. 235-238 °

The starting product can be produced as follows:

A solution of 8 gl, 3,4,4a, 5,9b-hexahydro-5 (2H) -indeno (1,2-c] pyridino! In 200 ml of chloroform is mixed with 10 g of anhydrous sodium carbonate and 5.55 g of 2- Propynyl bromide is added and the mixture is refluxed for 18 hours. The cooled reaction mixture is then washed neutral with water, extracted three times with 10 % aqueous acetic acid, the acidic aqueous extracts made alkaline with sodium hydroxide solution and extracted three times with ether. The ethereal phases are combined, dried over sodium sulfate and

003829/1844

- 27 - 100-2442

evaporated, the 1,3,4,4a, 5,9t> -hexahydro-2- (2-propynyl) -5 (2H) -indeno [1,2-c] pyridinol remains as a residue; M.p. 148-150 °, after crystallization from acetone.

Example 14 t &)

10 g (-) - l, 3, ⁱ t, 4a, 5,9b-hexahydro-2-ynethyl-5 (2H) -indeno [l, 2-c] pyridinol (mp, 135-136 ° * from acetone; M ^ hf = -98.5 Ic β 1; methanol]) are ^{refluxed for 15 minutes in 50 ffl} l 5 N hydrochloric acid. The reaction mixture is then cooled to 0 ° and the precipitate which has separated out is filtered off, which is recrystallized from 15 ml of 2N hydrochloric acid and dried at 80 ° in vacuo. (+) - 1 * 3 # 4,9b * "Tetrahydro-2-methyl-2H-indenot 1, 2-c pyridine hydrochloride melts with decomposition at 250-255 ⁰ ; la + 253 ° (c = 1.0; Methanol}. "

⁰ ; lal ^ Sg =

Proceed as above, but use as the starting product (+) -1,3,4, 4a, 5,9b-hexahydro-2-methyl-5 (2H) -indeno [1,2-c] pyridinol of m.p. 135-136 ° (from acetone); [alfS ^ = + 97 ° (c β 1.0; methanol). The (-) - l, 3,4,9b-tetrahydro-2-methyl-2H-indeno [1,2-cipyridine hydrochloride obtained melts with decomposition - at 250 - 255 °; tolfS ^ = -253 ° (c = 1.0; methanol).

The optically active starting products can be produced as follows:

To a solution of 40 g of l, 3,4,4a, 5,9b-hexahydro-2-methyl-5 (2H) -indenotl, 2-c! Pyridino! (Racemate with melting point 143-145 °, preparation see Example 1) in 100 ml of warm ethanol a solution of 76 g of di-p-tolyl-d-tartaric acid monohydrate is added in 200 ml of ethanol. The solution obtained is removed

009829/1844

- 28 - 100-2442

cools and left to stand for 30 minutes at 0 °; the deposited precipitate is filtered off and recrystallized from approx. 100 ml of 95% ethanol. The resulting di-ptolyi-d-tartrate crystallizes with one mole of crystal ethanol and melts at 144-145 ° with decomposition; iajj ^ g * »-247 ° (c = 1.0; methanol). The above salt is shaken with 250 ml of 10 % aqueous sodium carbonate solution and ether until complete dissolution occurs. The organic phase is then separated off, the aqueous phase is shaken out twice with ether, the combined ethereal layers are dried over sodium sulfate and evaporated, and the residue is crystallized from acetone. One obtains (-) - l, j5,4,4a, 5i9b-hexahydro-2-methyl-5 {2H) -indeno [l, 2-e) pyridinol from 'Snip. 136 °; ^ *

To produce the corresponding (+) - antipode, the ethanolic mother liquor obtained at the beginning is evaporated in vacuo. The residue is shaken with 250 ml of 10 % aqueous sodium carbonate solution and ether until complete dissolution occurs. The organic phase is then separated off, the aqueous phase is shaken out twice more with ether, the combined ethereal layers are dried over sodium sulfate and evaporated. The crude base which fades as a residue

20th
(faj »+ 70 °) is dissolved in 50 ml of ethanol and treated with a solution of 31 g of di-p-tolyl-1-tartaric acid monohydrate in 100 ml of ethanol, whereupon a precipitate separates out after a short time. Man. cool the mixture in an ice bath for 50 minutes, filter and crystallize the filter residue from 500 ml of 95 % ethanol. The di-p-tolyl-1-tartrate obtained crystallizes with one mole of crystal ethanol and melts with decomposition at 144-145 °; taj? 2β * - + 248 ° t (c = 1.0; methanol).

Ö0982S / 1S44

This salt becomes - in the same way as above for the Di-p-tolyl-d-tartrate described - the free base made. C +) -l, 3 # 4,4a, 5,9b-Hexahy ^ o «2-methyl ~ 5 (2K) -indeno [1,2-el pyridino! -melts at 135 - 136 ** fal ^^ «+ 97 ° (e = 1, Oj Methanol}.

Example 15: SC

10 g * 2 (2-butynyl) -l, 3, *, ^> 5 * 9b-nexahydro-5 (a ^ pyridinol be in 100 ml of 2 N hydrochloric acid for 20 minutes% aro refluxed to "boil. Then allowed it is cooled and filtered off. The residue is recrystallized from 2 K hydrochloric acid.

The 2- (2-butynyl) -1, 3, A, 4a used as starting material » 5,9b-hex € uiydro-5 (2H) -indenot l, 2-c] pyorid ± nol manufactured: ■;

A solution of 30 g of 1,3 * 4,4a, 5,9b-hexahydro-5 (2H) -. Indeno [1,2-elpyridinol in 750 ml of chloroform is mixed with 37 g of anhydrous sodium carbonate and 24 g of 1-chloro-2 -butyne added ^ and heated under reflux to the boil for 3 hours. The batch is then allowed to cool, the chloroform layer is washed neutral with water, then dried over sodium sulfate and evaporated. The residue is circulated twice from isopropanol ^; installed. The resulting 2 «(2-butynyl} -l, 3 _t 4,4a, 5,9bhexahydro-5 (2H) -indenoCl, 2-c] pyridinol melts at 170 °

Example 16: l * 5 £ 4,9b-Tetrahydro-2 ^ (2-methylallyl> -2H-

The procedure is as in Example 1, but different thereof from 1,3,4,4a, 5,9b-hexahydro-2- (2-methylallyl} -5 (2H) -indeno [1,2-cJpyridinol goes out. The hydro-

' 009829/1 ^ 44

1635740

-30- 100-24 * 2

Chloride of the compound named in the title melts about 210 ° (decomp.).

The 1,3,4,4a, 5,9b-hexahydro-2- (2-raethylallyl) -5 (2H) -indeno [1,2-c) pyridinol used as the starting material is made as follows:

12 g l, 3,4,4a, 5,9b-hexahydro-5 (2Ii) -indeiio [l, 2-c) pyridinol, 5 * 75 K methallyl chloride, 15 g sodium carbonate and 250 ml Chloroform is refluxed for 17 hours. The batch is allowed to cool and the chloroform layer is washed neutral with water, after which you put them over Magnesium sulfate dries and steams. The residue will dissolved in acetone and filtered through 50 g of silica gel. Man then elutes with acetone and evaporates the eluate. The raw 1,3,4,4a, which remains as an almost colorless resin, S ^ b-Hexahydro- ^ »(2-methylally2J-5 (2H) -indenote 1,2-c! Pyridino! Is used directly · Its neutral naphthalene! 5-disulfonate melts at 228-230 ° (decomp.

Example 17: ^^ j
indeno [1,2-c} pyridine

The procedure is as in Example 1, except that map deviates from 2- (trans-2-butenyl) -l, 3 # ^ * 4a, 5 _J [9b-hexahydro-5 (2H) -indenole, 2-c] pyridinol goes out. The resulting hydrochloride of the compound mentioned in the title melts 225-227 ° '(zero.) ..

The 2- (trans-2-butenyl) used as starting material l * 3 * 4,4a, 5,9b-hexahydro-5 (2H) -indenoil »2-c] pyridinol manufactured as follows:

The procedure is as in Example 16, but different of which from 12 g 1,3 »4,4a, 5>, 9b-hexahydro-5 (2H) -indeno [1,2-c] pyridinol goes out and this with 6.3 g of trans-

0098 29/1 * 44

- 31 - 100-2442

Crotyl chloride converts. The product obtained is recrystallized from acetone / pentane and melts at 110-112 °.

Example 18; 2 - (> butynyl) -1,3,4,9b-tetrahydro-gH-indenoil, 2-c] pyridine

10 g of 2- (3-butynyl) -1,3,4,4a, 5,9b-hexahydro-5 (2H) -indeno fl, 2-c] pyridinol are dissolved in 200 ml of 2N hydrochloric acid for 20 minutes heated to boiling under reflux. It is then allowed to cool and filtered off. The residue is from 2N Hydrochloric acid unicrystallized. The hydrochloride obtained in this way the compound mentioned in the title melts at 235 237 ° (decomp.).

The 2- (3-butynyl) -1, 3,4,4a »5i9b-hexahydro-5 (2H) -indenotl, 2-ejpyriainol used as starting material is like is made as follows:

A solution of I5 gl, 3 »4,4a, 5,9b-hexahydro-5 (2H) -indeno {1,2-elpyridinol in 360 ml of chloroform is mixed with 18 g of anhydrous sodium carbonate and 12.7 g of 1-bromo-3 -butyne is added and the mixture is refluxed for 3 hours. It is then allowed to cool, the chloroform layer is washed neutral with water, then dried over sodium sulphate and evaporated. The residue is dissolved in acetone and filtered through 100 g of silica gel. The filtrate is concentrated, whereupon 2- (3-butynyl) -1, 3,4,4a _J) 5 _Jf 9b-hexahydro-5 (2H) -indeno {1,2-clpyridinol crystallizes out. It is again recrystallized from acetone and then melts at 135-136 ^0th

Example 19 t

δ g (+) - 7-chloro-l, 3,4,4a, 5,9b-hexahydro-2-inethyl-5 (2H) -Sn "ieno [l" 2-e pyridinol (m.p. _a I58 - l € 0 ° _s from acetone}

- 32 - 100-2442

[α] ψ ° ₆ = + 144.9 ° [c β 1.0; Methanol]) are 40 ini. 5 N hydrochloric acid is heated to boiling under reflux for 40 minutes. Then it is evaporated in vacuo, re-evaporated with alcohol and the residue is crystallized twice from isopropanol, the 5- # conc. Contains hydrochloric acid to. (-) - 7-Chloro-1,3,4,9-tetrahydro-2-methyl-2H-indeno {1,2-c] pyridine'-hydrochloride melts at 255-260 ° (dec.); IaJ ^ = -173.0 ° (c 1.0; methanol).

The procedure is as above, but (-) - 7-chloro-l, 3,4,4a, 5,9ib-hexahydro-2-methyl-5 (2H) -indeno is used as the starting product

20 [1,2-c] pyridinol (m.p. 158-160 °, from acetone; ictj -144.9 ° ic «1.0; methanol]). The (+) - 7-chloro ^^^ b-tetrahydro ^ -methyl ^ H-indenoU ^ -cJpyridine hydrochloride melts at 255-260 ° (decomp.); [α + 173.0 ° (c * 1.0; methanol).

The optically active starting products can be as follows getting produced:

22.6 g of 7-chloro-l, 3,4,4a, 5,9b-hexahydro-2-methyl-5 (2H) -indeno [1,2-cjpyridinol (preparation see Example 5) and 23.8 g ( + J-Camphor-10-sulfonic acid monohydrate are dissolved in 120 ml of absolute ethanol. The salt which crystallizes out on standing at 0 ° is filtered off and recrystallized from 50 ml of absolute ethanol. The camphor sulfonate obtained melts at 205-207 ° (decomp.); IaIJj ^ ₆ »+ 108.0 °; (c = 1.0; methanol).

17 g of this Campf er sulfonate are mixed with 300 ml of 10 # Soda solution and 500 ml of methylene chloride shaken until everything is resolved. The organic phase is separated off and extracted twice more with methylene chloride, dry the combined

Ö09829 / .1ÖU

- 55 - 100-2442

Extracts over magnesium sulfate and evaporates. The residue is recrystallized from acetone. You get. (+ 1-7-ChIOr- * 1 * 2 # 4,4a, 5,9b-hexahydro-5 (2H} -indeno (1,2-elpyridinol of m.p. 158-160 ⁶ ,; ial | ^ ₆ = + 144.9 ° (c «1, O ₅ methanol).

Alis of the Ethanol mother liquor obtained at the beginning obtained the camphor sulfonate monohydrate of the other antipode by fractional crystallization from isopropanol

20th
will. Mp. I59 - l6l ° j folj ^ g = + 7.5 °} (c »1.0; methane

The camphor sulfonate obtained is after the first antipodes already described way further processed. This gives (-) - 7-chloro-1,3, * »* a, 5,915-hexahydro-2-methyl-5 (2H) -indeno [1,2-eJpyridinol of m.p. 158.160 ° j [a] JL- = -144.9 ° (c = 1.06 methanol).

009829 /

100-2 * 42

Man

Hc

-CIL

-X IV

—X ¹

IVb

R -.- OOC

VII

-CO-R,

.N-CO-R,

0-R »

Mg-Br

VIII

R _C -OOC 5

& 09829 / 1.844

Claims (2)

- 25 - 100-2442 claims: 1. Acid addition salts of indenopyridine derivatives of the formula I, where Ry is hydrogen, a lower alkyl * alkenyl or alkynyl, benzyl or phenylethyl and Κ «hydrogen, chlorine, bromine or a lower alkyl group mean. 2. Process for the preparation of acid addition salts of new indenopyridine derivatives of the formula I, wherein R, hydrogen, a lower alkyl, alkenyl or alkynyl group, the benzyl or phenylethyl group and R _{g is} hydrogen, chlorine, ~ bromine or a lower alkyl group , characterized in that hydroxy compounds of the formula 11, in which R _{1 and R 2 have the} above meaning, are split off by treatment with strong acids. 3 Remedies, wholly or partially consisting of acid addition salts of indenopyridine derivatives of the formula 1, in which R, hydrogen, a lower alkyl, alkenyl or alkynyl group, the benzyl or phenethyl group and R _{2 is} hydrogen, chlorine, bromine or a lower alkyl group . 4 * hydroxy compounds of formula II wherein R. is hydrogen, a lower alkyl, alkenyl or alkynyl group, the benzyl or phenethyl group d and R ₂ denote hydrogen, chlorine, bromine or a lower Alkyigruppe. 5 »Process for the production of new hydroxy compounds of the Formula II, wherein R- is hydrogen, a lower alkyl, alkenyl or Alkynyl group, benzyl or phenethyl group and Rg is hydrogen, chlorine, bromine or a lower alkyl group mean, characterized in that one a) Ketones of the formula III, in which R ₁ and R _{2 have the} above meaning. possess, with complex hydrides of the alkali metals in nterlagen | Art7 SlAiäs.2 Hr.l Satt 3 deaÄnd «uniieM.v. 4.3-1 * 521 TSoms / tsu 100-2442 a solvent or reduced b) for the preparation of compounds of formula Ha, wherein R ₁ stands for hydrogen, a lower alkyl or phenylethyl group, and Rp the above meaning, is hydrogenated catalytically or ketones of the formula III c) for the preparation of compounds of the formula Hb, wherein Rp has the above meaning and R. for a lower alkyl, Alkenyl or alkynyl, benzyl or phenethyl stands, compounds of the formula Hc, in which Rp has the above meaning, with compounds of the formula = IV, wherein R, has the above meaning and X stands for the acid radical of a reactive ester, in the presence of one acid-binding agent converts or d) for the preparation of compounds of the formula Hd, in which Rp has the above meaning and R _{1 is} a lower alkyl group bearing at least two hydrogen atoms on the carbon atom connected to the nitrogen atom, the benzyl or phenethyl group, compounds of the formula V in which R _{2 is the} above Has meaning and R "is lower alkyl or alkoxy, phenyl or benzyl, or compounds of the formula VI, in which Rp and R, have the above meaning and R ^, hydrogen or a radical of the formula -CO-R ^, where R- Has the above meaning, reduced by means of lithium aluminum hydride in an organic solvent which is inert under the reaction conditions or e) for the preparation of compounds of the formula He, in which R ₀ IV
has the above meaning and R _{1 is} hydrogen or a lower alkyl group comprising at least 2 carbon atoms, compounds of the formula Hf in which Rp is the above 009829/184 /. 16957A0 - 37 - 100-2442 Has meaning and R * for the benzyl group or is a lower alkenyl or alkynyl group, catalytically hydrogenated. 3700 / SR / HP Q09829 / 1844