Process for preparing aryloktahydropyridines

The invention relates to a process for the preparation of arylooctahydropyridines.

Recently, efforts have been made to synthesize new analgesics, i.e., substances that alleviate feelings of pain. Indeed, some conventional analgesics are limited in their use to the undesirable side effects that commonly accompany their long-term administration. These effects are, for example, drug addiction and allergies. Examples of novel analgesics which have recently been discovered are the decahydroisoquinolines, in particular the 4α-aryl-trans-decahydroisoquinolines described in Belgian Patent No. 802,557.

The present invention provides a process for the preparation of compounds from the group of trans -4a-aryl-2-substituted octahydro-1H-2-pyrindines. These compounds are structurally somewhat related to the above isoquinoline derivatives. However, the compounds of formula I have not yet been synthesized. Simple unsubstituted pyrindines are known in the literature. Volodine et al. Prepared, for example, some octahydro-2-pyrindines, but none of them was substituted at the 4a position, as evidenced by Doc. Akad. Nauk USSR 173 (2), 342-345 (1967) cf. CA sv. 67, 6034 (1967). Similarly, Procházka et al. Prepared trans-octahydro-2-pyrindine without a substituent at the 4a position, as is evident from Coll. Czech. Chem. Commun., 31 (9), 3824-3828 (1966), Cf. CA sv. 65, 13, 651 (1966). Recently, Zimmerman has prepared cis-4α-aryl-2-substituted octahydro-1H-2-pyrindines which have analgesic activity and are described in Belgian Patent No. 860,314.

The present invention relates to trans -4a-phenyl- (optionally substituted) -2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindines, which have not been known hitherto, and to intermediates used for its production .

The invention therefore relates to a process for the preparation of novel dicyclic compounds which are called octahydro-1H-2-pyrindines or hexahydro-1H-cyclopenta [c] pyrindines.

The present invention therefore provides a process for the preparation of compounds of formula (I)

<img file="CS203940B2_D0001.tif" />

N-R'f (I) in the trans configuration where is

R 1 'alkyl of 1 to 8 carbon atoms,

R2 is hydrogen, hydroxy or (C1-C3) alkoxy, as well as pharmaceutically acceptable acid addition salts of said compounds, characterized in that the compound of formula (II) is reacted,

<img file="CS203940B2_D0002.tif" />

(.II) where is

R1 is hydrogen or alkyl of 1 to 8 carbon atoms,

R @ 2 is hydrogen, hydroxy or alkoxy of 1 to 3 carbon atoms, with hydrogen and oxide. platinum followed by alkylation when R 1 is hydrogen to give compounds of formula I wherein R 1 'is as defined above, optionally followed by deetherification when R 2 is an alkoxy group of 1 to 1. 3 carbon atoms to give a compound of formula (I) wherein R 2 is hydroxy, then optionally converting the resulting compound to a pharmaceutically acceptable acid addition salt thereof. .....

. The term ':' alkyl of 1 to 8 'carbon atoms' means throughout the description i. in the definition of the subject invention, the alkyl radicals having a straight or straight chain radical are used. .branched. string up. of 8 carbon atoms. . . Examples of typical alkyl radicals of 1 to 8 carbon atoms are methyl, ethyl, propyl, butyl, and the like. isopropyl,. isobutyl, pentyl, 3-methylpentyl, 1-, 2-dimethylpentyl, 2-methylbutyl, 3-ethylpentyl, n-octyl, 2-methylheptyl. isoheptyl, 3-ethylhexyl, .. '1,3,3-irimethylpenlyl' and related groups.

As it was already mentioned, very. . important compounds for the preparation of all pyrindine derivatives of formula (I) are those pyrindine derivatives which are not substituted in the position. 2 and thus containing a hydrogen atom. ve. the meaning of R 1 in formula II. These compounds are. at position 2, it can be easily alkylated. to produce pharmacologically active substances. octahydropyrindines of formula I.

Suitable alkylating agents are, for example, compounds of formula

R1'-Z where

R1 'is as defined above and

Z is one of the common easily cleavable groups.

Suitable cleavable groups include, for example, a halogen atom, in particular a chlorine, bromine and iodine atom, a paratoluenesulfonyl group (tosyl group), a sulfonyl group, a methanesulfonyl group (mesyl group), a p-bromophenyl sulfonyl group (brosyl groups) and azido groups. It will be appreciated that when the alkylating agent has the general formula R 1 -Z, the alkyl portion of the alkylating agent may be derived, for example, from unsaturated, aryl and cycloalkyl substituents. Thus, the term "alkylating agent of the formula R 1 -Z" includes the following compounds:

methyl chloride, ethyl bromide, 5-methenoxy-lysylate, allyl bromide,

4-hexenyl iodide, t-ethyl-5-pentenylbromolate, cyclo-propylmethylene celloride, cyclobutyl mercuryl iodide, cyclohexylmethyl methyl ester, 3-tetramethyl-4-methylmethylamide, 2-fluoromethalazide,

2- fennletenlcelorid,

3-Benzoylyropyl bromide

2- (3-chlorophenylthio) ethylazide, phenoxymethyl bromide,

3-Isoproyyl-phenylthiomethyl bromide and related compounds.

Thus, 4a-amino-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-yyrindine with an alkylating agent can be reacted to give the corresponding 4a-aryl-2-substituted-2,3 , 4,4a, 5,6,7,7a-octaeydro-1H-2-pyrrolidine · Alkylation reaction of this. of the type is &amp; quot; quite conventional &amp; quot; The reaction is carried out by reacting the corresponding 4α-arnloctahndro-1H-2-pyrindine with the appropriate alkylating agent, preferably in a non-reactive organic solvent. Alkylating agent. 'is usually used' in excess,. for example in a 0.5 to 2.0 molar excess in a ratio. k. the pyrindine derivative used. As the "non-reactive organic solvent", it can be used. ether, such as diethyl ether, dioxane, tetrahydrofuran, as well as other solvents such as benzene, dichloromethane, dimethylformamide, dimethylsulfoxide, nitromethane and hexamethylphosphoric triamide may be used during the reaction. The alkylation reaction is usually employed. alkali as an acid binding substance, because. reaction of ynrindineeo derivative. a. . The alkylating agent is usually accompanied by the formation of an acid, for example an acid. hydrochloride or paratoluenesulfonic acid, which could form a salt with the unreacted 2-pyridine derivative. Principles,. in this context. used as acid binding agents, for example, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, triethylamine and pyridine. . Typically. one equivalent of base is used, but is 'possible' in the case of. needs: use i. surplus mystery .. Usually. . se. The alkyl 203940 reaction is carried out at an elevated temperature in the range of 50 to 200 ° C, at which temperature the reaction is generally substantially complete within 1 to 10 hours. However, longer reaction times may be used, as prolonging this time does not reduce the yield or purity of the final product. The product is usually isolated by simply adding water to the reaction mixture followed by extraction of the resulting product into a water-immiscible organic solvent, such as extraction with, for example, benzene, ethyl acetate, dichloromethane, diethyl ether, chloroform and related solvents. The solvent is removed from the extracts thus obtained, for example, by evaporation under reduced pressure, whereby the title product is obtained.

4-aryl-2-substituted-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine; this material is in solid form or in oily form at room temperature. The resulting product can be subjected to further purification, for example, by chromatography, crystallization, distillation, or the resulting pyrindine can also be converted to the acid addition salt by reaction with an inorganic or organic acid. The salts obtained are usually highly crystalline and can be easily recrystallized to a solid salt with a high degree of purity. If desired, the salt thus obtained can be treated with a base, for example sodium hydroxide or potassium carbonate, to cleave the salt to give the purified 4α-aryl-2-substituted-2,3,4,4a, 5α-free. , 6,7,7a-octahydro-ΙΗ-2-pyrindine.

As mentioned above, the 4α-aryl-2-substituted-octahydro-1H-2-pyrindine derivatives of formula (I) can be reacted with an organic or inorganic acid to form a crystalline salt which can be purified by crystallization and can be converted back to the free pyrindine by treatment with a suitable base, for example sodium hydroxide. Some of the acid addition salts are included in Formula I. These are non-toxic, pharmaceutically acceptable acid addition salts, which will be described hereinafter. These non-toxic pharmaceutically acceptable acid addition salts are prepared by reacting 4α-aryl-2-substituted-octahydrol-2-pyrindine of formula I with an organic or inorganic acid. Acids commonly used in the preparation of pharmaceutically acceptable acid addition salts of compounds of formula I include hydrohalic acids such as hydrogen bromide, hydrogen chloride, hydroiodide, sulfuric, phosphoric, nitric, perchloric, phosphorous, nitrous and related acids. Among the organic acids, for example, acetic, propionic, paratoluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, citric, lactic, palmitic, stearic, benzoic acids, as well as acetic, propionic, paratoluenesulfonic, chloroacetic, maleic, tartaric, succinic, oxalic, and related acids. Pharmaceutically acceptable acid addition salts of the compounds of formula (I) are readily prepared by dissolving 4α-aryl-2-substituted-octahydro-1H-2-pyrindine in a suitable solvent such as diethyl ether, ethyl acetate, acetone or ethanol, and an equivalent amount or an excess of the appropriate acid is added to the resulting solution. The salt thus formed usually crystallizes from solution and can be separated by filtration and is already ready for use in pharmacology, or it can be further purified by recrystallization from conventional solvents such as acetone and methanol.

It will be appreciated that the compounds of Formula I have two centers of asymmetry at positions 4a and 7a. The process of the invention involves the production of both separate isomers and racemic mixtures of these isomers that are effective as analgesics. However, they are predominantly trans-isomers of formula I, which means that the 4α-aryl group is oriented to the opposite side of the plane of the molecule than the hydrogen atom at the 7a position. Thus, the process of the invention involves the production of pharmacologically active optically active trans isomers and, in addition, racemic mixtures containing trans isomers. Racemic pairs of trans-octahydropyrindine can be resolved into stereoisomers by known methods. When only one stereoisomer has pharmacological activity, the d, l-racemate is useful because it contains a pharmacologically active isomer as one of its components.

The process for the preparation of the 4a, 7a-trans-isomers of formula (I) consists in the catalytic hydrogenation of the 4a-arylhexahydropyrindine of formula (II), in particular those having a double bond at the 1,7a position. This hydrogenation is generally carried out by reacting 4α-aryl-2-alkyl-3,4,4a-5,6,7-hexahydro-2-pyrindine with hydrogen in the presence of a catalyst, such as platinum oxide. This hydrogenation is usually carried out in a solvent such as methanol or ethanol and is completed within 1 to 8 hours when carried out at 25 ° C under a hydrogen pressure of 2.74.10.² to 5,48.10² kPa. The hydrogenation usually results in a mixture of the 1,7α-trans-isomer and the 1,7α-cis-isomer. However, the trans-isomer is usually predominant in this mixture. Separation of these isomers is readily accomplished by salt formation and crystallization. For example, a racemic mixture of octahydropyrindines can be converted to a suitable salt, for example picrate or maleate, the cis racemate usually crystallizing first as a solvent such as diethyl ether and diisopropyl ether, and separated by subsequent filtration from the trans-isomer. The trans racemate can then be isolated from the filtrate and purified by recrystallization.

In the preparation of the 4α-aryloctahydropyrindines of formula (I), it is necessary to employ various starting materials, some of which are as yet unknown or have not been prepared. For example, in the preferred process described above for the production of trans-4α-aryl-2-substituted-octahydro-1H-2-pyrindines, the corresponding 4α-aryl-2-substituted-3,4,4α, 5α, 5α, 5α, 5α, 5α,_&gt;6,7-hexahydro-2-pyrindines, i^17a-hexahydropyrindines. These compounds can be prepared by condensing phenyllithium or 3-substituted phenylllithium with 1-alkyl-4-piperidone to give the corresponding 1-alkyl-4-phenyl- or substituted-phenyl-4-hydroxypiperidine. Dehydrogenation

4-Hydroxypiperidine yields 1-alkyl-4-aryl-1,2,3,6-tetrahydropyridine. This tetrahydropyridine derivative is reacted with propylene dihalide, for example 3-chloropropylbromide, to give 1-alkyl-4-aryl-4- (3-halopropyl) -1,2,3,4-tetrahydropyridine which can then be easily cyclized by reaction with sodium iodide in acetonitrile to give the corresponding 4α-aryl-2-alkyl-3,4,4α, 5,6, -

Of 7-hexahydro-2-pyrindine.

Some of the 4α-aryl-2-substituted octahydro-1H-2-pyrindines of formula (I) are useful in the treatment of pain disorders and thus to provide an analgesic effect in pain. In addition, the pyrindine derivatives of the formula I have effects which are common to analgesics and, on the other hand, effects which reduce some of the undesirable effects of analgesics, e.g. Indeed, the side effects of analgesic drugs are responsible for the development of addictions to these drugs, especially in the case of opiate-type effects. Thus, the compounds obtainable by the process of the invention are of particular value. Some of the compounds of the present invention can be used only to eliminate the addiction to certain drugs, such as opiates such as morphine.

The analgesic activity of the compounds of formula (I) can be determined by experiments commonly used for this purpose, for example, a mouse seizure test and a rat tail test.

The mouse cramp test is performed as follows:

Male white 20 to 22 g strain Shoi mice were used in the experiment and fasted overnight. Convulsions, which are characterized by contraction of the abdominal muscles, hind limb extension and torso rotation, are induced by intrapereritoneal administration of 0.55% acetic acid at a dose of 55 mg / kg. Each group consists of 5 mice. During the 10 minute observation, the total number of seizures was determined, starting 5 minutes after the acetic acid solution was administered. Control groups usually have 200 to 350 convulsions over this period. Control and test groups are compared and α / q inhibition is calculated as follows:

% inhibition -

<img file="CS203940B2_D0003.tif" />

[total convulsions in experimental animals] __ total convulsions in control animals x 100

Test substances are administered at a dose of 100 mg / kg orally 30, 90 and 180 minutes after acetic acid administration and 30 minutes before intraperitoneal administration of acetic acid subcutaneously.

The second standard test for analgesic efficacy is rat tail convulsions. This experiment is performed as follows:

Female Sprague-Dawley rats weighing 70-80 g are taken without food overnight. Subsequently, the test substance is administered in solution or only in the case of control animals, after which the animals are placed in a plexiglass holder. The rat's tail is placed on a resistance wire that is tensioned between two copper terminals. As the current passes, the wire is heated and heating the wire irritates the rat's tail for 6 and 7 seconds, causing a spasm to draw the tail away from the wire. The time elapsed since switching on the current to the rat tail spasm is recorded as the reaction time. The mean reaction time of the experimental group is compared to the mean reaction time of the control group, using Student's &amp; quot; t &amp; quot; as a method to evaluate statistical significance. Usually 5 animals are used per test group. The average response time ± standard error for a typical control group is 6.85 ± 0.3 s.

In the mouse cramp test, the ED 50 mg / kg dose is determined to reduce the number of cramps to 50% 30 minutes after administration, compared to the control group. These doses are shown in Table I for the compounds of Formula I. In the rat tail spasm test, the effective doses of ED 50 in mg / kg causing an increase in reaction time of 2 s after 30 minutes are also reported for the compound of Formula I in the following table. AND.

TABLE I

Example Convulsions (mg / kg) Rat tail convulsions (s)

<td>number</td><td>subcutaneously</td><td>orally</td><td>subcutaneously</td><td>orally</td>

<td> 1</td><td> 12,1</td><td> 25,5</td><td> 2,52*</td><td> 2,88*</td>

<td> 3</td><td> 2,32</td><td> 4,8</td><td> —</td><td> —</td>

<td> 4</td><td> 0,94</td><td> 4,8</td><td>2,8ΟΔ</td><td>2,20A</td>

* increase in reaction time 10 mg / kg (30 min) increase in reaction time 0.5 mg / kg (30 min) compared to control versus control

Thus, the 4α-Aryl-2-substituted-2,3,4,4α, 5,6,7,7α-octahydro-1H-2-pyrindines of formula (I) may be used to produce an analgesic effect in mammals, for example humans. The compounds are administered orally or parenterally. It is generally preferred to use a pharmaceutically acceptable acid addition salt when the compound is to be administered orally; these salts are better formulated into oral preparations. For example, one or more of the pharmacological compounds of formula (I) in free or pharmaceutically acceptable acid addition salt form can be formulated for oral administration by admixing these with conventional diluents or carriers. Examples of such diluents or carriers are starch, sucrose, cellulose, magnesium stearate, lactose, calcium sulfate, sodium benzoate, and related substances. The mixture can then be compressed into tablets or stored in telescopic gelatin capsules. If desired, the active compounds of the formula I can be mixed with other active compounds, such as caffeine, acetaminophen or propoxyphene.

The active compounds of the formula I can also be formulated as sterile aqueous or non-aqueous solutions, suspensions and emulsions for parenteral administration. Non-aqueous solvents commonly used in the formulation are propylene glycol, vegetable oils such as olive oil, and various organic esters such as ethyl oleate. Suitable aqueous solutions for oral and parenteral administration are also solutions in isotonic sodium chloride solution.

The amount of active ingredient per unit dose, i.e. the amount of pharmacologically active 4α-aryl-2-substituted-octahydro-1H-2-pyrindine of formula I when administered to mammals, for example humans, can be varied within a relatively wide range. The appropriate dose will depend upon the desired therapeutic effect, the route of administration, the duration of treatment and the disease being treated. The doses of the active compounds of the formula I are usually in the range of 1.0 to 25 mg / kg per day, which dose can be divided into 1 to 4 individual doses. For oral administration, a dose of 2 to 50 mg / kg is preferred.

The invention will be illustrated by the following examples.

Starting materials

Example A

A solution of 159 ml of n-butyllithium in 100 ml of hexane containing 47.7 g of 3-methoxybromobenzene was stirred at -25 ° C for 20 minutes and then allowed to warm to room temperature with stirring to give 3-methoxyphenyllithium. The reaction mixture was cooled to 10 ° C and stirred while a solution of 50 g of 1-methyl-4-piperidone in 100 ml of diethyl ether was added dropwise over 30 minutes. After the addition was complete, the reaction mixture was stirred for 2 hours and then diluted with 50 mL of saturated aqueous sodium chloride solution. The solution was extracted several times with diethyl ether and the ether extracts were combined and evaporated to dryness to give 38 g of 1-methyl-4-hydroxy-4- (3-methoxyphenyl) piperidine.

Example В

To a solution of 200 ml of phosphorus pentoxide in methanesulfonic acid containing 50 g of this oxide, 59 g of 1-methyl-4-hydroxy-4- (3-hydroxyphenyl) piperidine are added portionwise over 4 minutes with stirring. The reaction is exothermic and the temperature rises to 70 ° C. After complete addition of the plperidine derivative, the reaction mixture was poured into 200 g of ice and the aqueous mixture was basified by addition of ammonium hydroxide. The alkaline mixture is extracted several times with diethyl ether, the ether extracts are combined, washed with water, dried and the solvent is removed by evaporation under reduced pressure to give

44.7 g of oily product. The oily liquid was distilled to give 1-methyl-4- (3-methoxyphenyl) -1,2,3,6-tetrahydropyridine, bp 123-138 ° C at 13.3 Pa.

Analysis for C 13 H 17 NO calculated:

C 76.81, H 8.43, 6.89 ® / o;

found:

C 76.52, H 8.15, N 6.67%.

Example С

To a solution of 25 g of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in 450 ml of tetrahydrofuran was added dropwise over 30 minutes at -5 to -10 ° C with stirring dropwise over 30 minutes. M solution of n-butyllithium in hexane. After the addition was complete, the solution was stirred at -10 ° C for 10 minutes and then cooled to -30 ° C. The cold solution was then added dropwise over 20 minutes to a stirred solution of 73.3 g of 3-chloropropyl bromide in 300 ml of diethyl ether cooled to -50 ° C. After the addition was complete, the reaction mixture was warmed to -20 ° C and diluted with 50 mL of saturated aqueous sodium chloride solution cooled to 0 ° C. The organic layer was separated, washed with water, and the product was extracted with 1200 ml of 1N hydrochloric acid. The aqueous acid layer was washed with diethyl ether and then basified by dropwise addition of concentrated aqueous sodium hydroxide solution. The alkaline solution was extracted several times with diethyl ether, the ether extracts were combined, washed with water and dried. Evaporation of the solvent at 10 ° C gave an oily liquid which was dissolved in 2500 ml of acetonitrile containing 52.5 g of sodium iodide. The reaction mixture was heated to reflux and stirred for 24 hours, then the solvent was evaporated under reduced pressure. The crude product thus obtained was dissolved in a mixture of 800 ml of 1 N sodium hydroxide and 1000 ml of diethyl ether and stirred vigorously for 45 minutes. The ether layer was separated, washed with a saturated aqueous sodium chloride solution and dried. The solvent was removed under reduced pressure to give an oil which, after distillation, gave 21.5 g of 4α-phenyl-2-methyl-3,4,4a, 5,6,7-hexahydro-2- pyrindine having a boiling point of 110 to 112 ° C at a pressure of 9.9 Pa.

Analysis for C15H19N calculated:

C 84.46, H 8.98, N 6.57%; found:

C 84.74, H 8.72, N 6.28 0 /₀.

Example D

Proceeding as in Example C, reacting 1-methyl-4- (3-methoxyphenyl) -1,2,3,6-tetrahydropyridine with 3-chloropropylbromide and sodium iodide to give 4α- (3- methoxyphenyl) -2-methyl-3,4,4a, 5,6,7-hexahydro-2-pyridine, bp 132-134 ° C at 13.3 Pa.

Analysis calculated for C16H22NO:

C 78.97, H 8.70, N 5.76%;

found:

C 76.58, H 8.28, N 5.36%.

m / e: calcd. 243, found 243.

Resulting products

Example 1

A solution of 5.0 g of 4α-phenyl-1-methyl-3,4,4a, 5,6&gt; 7-hexahydro-2-pyrindine in 50 ml of ethanol containing 500 mg of platinum oxide was stirred at room temperature for 4 hours under a hydrogen atmosphere. at a pressure of 4.13 10² kPa. The reaction mixture is then filtered and the solvent is evaporated to an oily liquid which is analyzed by NMR and high pressure liquid chromatography to show that it consists of approximately 40% cis-4a-phenyl-1-methyl-2,3,4, 4a, 5,6,7,7a-octahydro-1H-2-pyrindine and about 60% of the corresponding trans-isomer. The mixture was dissolved in 50 ml of diethyl ether and acidified by addition of a saturated solution of hydrogen bromide in diethyl ether. The ether solution was concentrated to crystallize. The mixture is filtered and the precipitate is recrystallized from a mixture of 30 ml of isopropanol and 70 ml of diisopropyl ether to give 2.6 g of cis-4a-phenyl-2-methyl-2,3,4,4a, 5,6,7,7a. -octahydro-1H-2-pyridinium bromide.

The filtrate was evaporated to dryness and the residue was dissolved in water. The aqueous solution was basified by addition of 1N sodium hydroxide and the aqueous alkaline solution was extracted with diethyl ether. The ether extracts are combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure gave 2.57 g of trans -4a-phenyl-2-methyl-2,3,4,4a, 5,6,7,7aoctahydro-1H-2-pyrindine.

The trans-pyrindine derivative is dissolved in 120 ml of ethanol and reacted with 2.76 g of picric acid to give 2.7 g of trans -4a-phenyl-2-methyl-2,3,4,4a, 5, 167 DEG-168 DEG C. 6,7,7a-octahydro-1H-2-pyrindinium picrate.

Analysis for C21H24N4O7 calculated:

C 56.75, H 5.44, N 12.61%, found:

C 56.99, H 5.65, N 12.46%.

Example 2

The procedure of Example 1 is repeated except that the trans-pyrindine derivative is reacted with maleic acid to give trans-4α-phenyl-2-methyl-2,3,4,4a, 5,6,7, 7α-octahydro-1H-2-pyrindinium maleate, m.p. 113-114 ° C.

Analysis for C19H25NO4 calculated:

C 68.86, H 7.60, N 4.23%, found:

C 68.66, H 7.82. N, 3.98%.

Example 1

By the method of Example 1, 4α- (3-methoxyphenyl) -2-methyl-3,4,4a, 5,6,7-hexahydro-2-pyrindine is hydrogenated in the presence of platinum oxide to give a ratio of 60: 40 a mixture of trans -4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-ΙΗ-2-pyrindine and the corresponding cis-isomer. crystallize as the picrate and then isolated in the free form trans-4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. mp 40-43 ° C.

Analysis for C16H23NO calculated:

C 78.32, H 9.45, N 5.71%, found:

C 78.26, H 9.31, N 5.61%.

Example 4

A solution of 3.5 g of trans-4- (3-methoxyphenyl) -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine in 35 ml of glacial acetic acid containing 35 ml of a 50% aqueous hydrobromic acid solution is heated to reflux for 15 hours with stirring, and the reaction mixture is cooled to room temperature and diluted with 100 ml of water / ice. The aqueous acidic solution was basified by addition of concentrated sodium hydroxide solution to pH 9.8 and the alkaline aqueous solution was extracted several times with diethyl ether. The ether extracts were combined, washed with water and dried. The solvent was removed by evaporation under reduced pressure to give 1.8 g of solid product. This product was recrystallized from 150 mL of ethyl acetate to give 1.65 g of trans-4- (3-hydroxyphenyl) -2-methyl-2,3,4,4a, 5,6,7, 7α-octahydro-1H-2-pyrindine, m.p. 192-194 ° C.

Analysis for C15H21NO calculated:

C 77.88, H 9.15, N 6.05%, found:

C 77.48, H 8.71, N 5.67%.