CS228115B2 - Production of derivatives of 1-benzyl-1,2,3,6-tetrahydropyridine - Google Patents

Abstract

The invention relates to a process for the production of new ones 1-benzyl-1,2,3,6-tetralhydropyridine derivatives, that inhibit clumping of blood clots. It is already known that various N-benzyl- -4,5,6,7-tetrahydrothieno [3,2-c] pyridine and N- -benzyl-4,5,6,7-tetrihydrofuro [3,2-c] pyridine exhibit anti-inflammatory effects and inhibit platelet aggregation (M. Podesta et al., Europeiain J. Medicinal Chemistry, Chimica Therapeuticia, 1974, 9, 487-490). It has now been found that certain new derivatives those of 1-benzyl-1,2,3,6-itetrahydrate; of the above general formula · I unexpectedly they also inhibit platelet aggregation waiting. A related compound, which is 1-benzyl-1,2, o, 5- -Titrahydropyridine is known to be chemical intermediate (see Petrow i Stephenson, j. Pharm. Pharmaicol., 1962, 14, 306-313j. Except 1- (alkyl- or halobenzyl) - -1,2,3,6-itetrahydiropyridines gpadiaje to broad of the scope of the DOS claims no chemical intermediates) are not however, specifically mentioned herein.

Description

The present invention relates to a process for the production of novel 1-benzyl-1,2,3,6-tetrahydro-pyridine derivatives which inhibit platelet aggregation.

It is already known that various derivatives of N-benzyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and N-benzyl-4,5,6,7-tetralhydrofuro [3,2-c] Pyridine exhibits anti-inflammatory effects and inhibits platelet aggregation (M. Podesta et al., Europeiain J. Medicinal Chemistry, Chimica Therapeuticia, 1974, 9, 487-490). It has now been found that certain novel 1-benzyl-1,2,3,6-itetrahydropyridine derivatives of formula (I) below unexpectedly also inhibit platelet aggregation.

The related compound, which is 1-benzyl-1,2,0,5-teitrahydropyridine, is known as a chemical intermediate (see Petrow and Stephenson, J. Pharm. Pharmaicol., 1962, 14, 306-313j. alkyl- or halobenzyl) -1,2,3,6-itetrahydiropyridines fall within the broad scope of the claims of DOS No. 2 101 998 (directed to chemical intermediates), but are not specifically mentioned herein.

The present invention provides a process for the preparation of 1-benzyl-1,2,3,64-tetrahydropyridine derivatives of formula (I)

in which

R ¹ is hydrogen or C 1 -C 4 alkyl, one of R ² , R ³ , R ² , R ⁵ and R ⁶ is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy 4 carbon atoms, hydroxyl, nitro, cyano, carboxarndo, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoylamino or C 1 -C 4 alkylsulfomylamino, another of R ² , R ³ , R ^{Z |} R ⁵ and R ⁶ are hydrogen or halogen, hydroxyl, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy and the remaining of R ² , R ³ , R ⁴ , R ⁵ and R ^{6 is} destroying the hydrogen atoms ® (when R ¹ represents a hydrogen atom, the benzene ring A does not represent a 2-chlorophenyl radical, and their pharmaceutically acceptable acid addition salts, characterized in that 1,2,3,6- tetrlahydropyridine of formula II

wherein R ¹ is as defined above, is reacted with a benzylhlalogenide of formula. lil

Hal represents a chlorine, bromine or iodine atom and

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ on benzene ring B have the same meaning as the corresponding symbols given above for ring A, with the proviso that where ring A carries a hydroxyl group, ring B contains an alkanoyloxy group with 1 ( and optionally converting the resulting product into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid.

Particularly preferred groups of compounds of the present invention are those compounds of formula (I) wherein (i) R ² is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, carboxamido, hydroxyl, nitro or cyano and R ³ , R ⁴ , R ⁵ and R ⁶ represent hydrogen atoms, provided that when R ¹ is hydrogen, R ² does not represent chlorine atom;

[11] R ³ represents a C 1 -C 4 alkyl or hydroxyl group, and R ² , R ⁴ , R ⁵ and R ⁶ represent hydrogen atoms;

(iii) R ⁴ is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyl, nitro, cyano, carboxamido, C 1 -C 4 alkoxycarbonyl in the alkoxy moiety of alkanoylamino; (C 1 -C 4) or C 1 -C 4 alkylsulfonylamidococcus and R ² , R ³ , R ⁵ and R ⁶ represent hydrogen atoms;

(iv) R ⁵ and R ⁶ represent hydrogen atoms, R ² and R ⁴ independently of one another or R ³ and R ⁴ independently of one another are selected from the group consisting of C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups -alkoxy, halogen, hydroxyl and nitro, and R ^3, respectively. R ² is hydrogen, or (v) R ² and R ³ , R ² and R ⁵ , R ² and R ^6, or R ³ and R ⁵ are independently selected from the group consisting of C 1 -C 4 alkyl groups, the halogen atoms and the hydroxyl group and the remaining R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent hydrogen atoms, in which R ¹ represents a hydrogen atom or a C 1 -C 4 alkyl group, as well as their pharmaceutically acceptable acid addition salts mentioned above.

Examples of particularly preferred substituents R ^2, R ^3, R ^4, R ⁵ and R ⁶ on benzene ring A include:

for halogen atoms of fluorine, chlorine or bromine, for alkyl groups of 1 to 4 carbon atoms, methyl or ethyl, for alkoxy groups of 1 to 4 carbon atoms, a melthoxy or ethoxy group, for the alkoxycarbonyl groups of 1 to 4 carbon atoms in the alkoxy moiety methoxycarbonyl or ethoxycarbonyl for C1 -C4 alklancylamino, acetamido and for C1 -C4 alkylsulfonylamino methylsulfonylamido.

Particularly suitable alkyl group having 1 to 4 carbon atoms represented by R ¹ as methyl.

A preferred radical R @ ¹ is hydrogen.

Especially interesting combination of the meanings of R ^2, R ^3, R ^4, R ⁵ and R ⁶ are those cases in which benzene ring A is 2-fluoro-, 2-chloro-, 2-bromo-, 2-methyl-, 2- methoxy-, 2-nitro, 2-cyano- or 2-carboxamidophenyl, 3-methyl- or 3-methoxyphenyl, 4-fluoro-, 4-chloro-, 4-bromo-, 4-meithyl-, 4-methoxy 4-hydroxy-, 4-nitro-, 4-cyano-, 4-carboxamiido, 4-methoxycarbonyl-, 4-acetamide- or 4-methylsulfonylamidophenyl, 2-fluoro-4-chloro-, 2-chloro-4 -fluoro-, 2-chloro-4-birome-2,4-difluoro-, 2,4-dichloro, 2-chloro-4-mitro-, 2-chloro-4-hydroxy- or 2-methyl-4-hydroxyphenyl radical , 2,3-dicbloro- or 2-hydroxy-3-chlorophenyl radical, 2,5-dihydroxy-, 2,5-dimethyl- or 2,5-dicblonophenyl radical, 2,6-dihydroxy-2,6-difluoro- or a 2,6-dichlorophenyl radical,

3,4-dichloro, 3,4-dibromo, 3,4-dihydroxy-, 3-chloro-4-bromo, 3-bromo-4-chloro, 3-chloro-4-methyl-, 3- methyl-4-chloro, 3-hydroxy-4-chloro, 3-chloro-4-hydroxy-, 3-methyl-4-hydroxy- or 3-methoxy-4-hydroxyphenyl, or 3,5-dichlorophenyl .

Particular groups of special interest are compounds according to the vynále228115 zu forms (those compounds of the formula I wherein (i) R ² dizzy hydrogen, halogen or alkyl with 1 to 4 carbon atoms, R ⁴ represents a halogen atom, hydroxyl C 1 -C 4 alkylsulfomylamido and R ³ , R ⁵ and R ⁶ are hydrogen;

(ii) R ³ is halogen, alkyl having 1 to 4 aitomy atoms, alkoxy of 1-4 carbon atoms or hydroxy nominal Grp ¹ nu R ⁴ represents a halogen atom or a hydroxyl group and R ^2, R ⁵ and R ⁶ represent or (III) R ³ and R ⁵ represent the same or different halogen atoms and R ² , R ⁴ and R ⁶ represent hydrogen atoms, each of which R ¹ (hydrogen atom or methyl group) and a pharmaceutically acceptable useful acid addition salts of these compounds.

Another particularly preferred group of compounds are those compounds of formula I wherein R ^2, R ^3, R ^4, R ⁵ and R ⁶ Maia arbitrary from the meanings given above for groups (i) - (IIIj ai R ^L = hydrogen, and pharmaceutically acceptable acid addition salts thereof.

Particularly preferred compounds of the invention are exemplified, but the following are of particular interest:

1- (3,4-dichlorobenzyl) -1,2,3,6-tetrahydro-pyridine, 1- (3,5-dichlorobenzyl) -1,2,3,6-tetrahydropyridine, 1- (3,4-dihydride); Oxybenzyl) -1,2,3,6-tetrahydropyridine,

1- (4-hydroxybenzyl) -1,2,3,6-tetrahydropyridine

1- (4-Methylsulfonylamidobenzyl) -1,2,3,6-tetrahydropyridine

1- (2-chloro-4-hydroxybenzyl) -1,2,3,6-itetoaihydropyridine, 1- (4-hydroxy-3-methylbenzyl) -1,2,3-tetrahydropyridine,

1- (4-hydroxy-3-methoxybenzyl) -1,2,3,6-teitrahydropyridine and 1- (4-chloro-3-hydroxybenzyl) -1,2,3,6-tetrahydropyridine, and pharmaceutically acceptable addition salts thereof salts with acids.

Examples of suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) include salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates or phosphates, or salts with organic acids giving a pharmaceutically acceptable anion such as tantrates, citrates, laictates, fumarates, -toluene sulfonates or oxalates.

It will be appreciated that those compounds of formula (I) wherein R ¹ is C 1 -C 4 alkyl contain an asymmetric carbon atom and can thus be isolated in racemic form or in two optically active forms. The invention encompasses both the racemic forms of the compounds of formula (I) and those optically active forms having the aforementioned useful biological properties, and is well known in the art. How can optically active forms be prepared by racemate resolution or synthesis from optically active starting materials, and how the biological activity of the individual isomers can be evaluated by standard assays, such as those set forth below.

The above process is conveniently carried out in the presence of a base, for example an alkali metal hydroxide or carbonate, such as sodium or potassium hydroxide or carbonate. Alternatively, an excess of tetrahydropyridine (II) may be used.

The reaction is preferably carried out in a suitable solvent or diluent, for example in a C 1 -C 4 alkamol, such as in ethanol. or 2-propanol, at a temperature in the range, for example, 20 to 120 T.

The required starting materials can be prepared by conventional methods known in the art.

It will be understood that to prepare a compound of formula (I) in which R 'is a compound of formula (I) ^. R ^{@ 3} , R ^{@ 4} , R ^{@ 5} or R ^{@ 6} represents a hydroxyl group, a benzyl halide of the formula III in which the corresponding substituent on the benzene ring B is. ¹ alkanoyloxy of 1 to 4 carbon atoms, for example acetoxy, hydroxybenzylhalogenidy because they are very unstable compounds. It is further understood that during the reaction according to the invention, these acyloxy groups are hydrolyzed so that the resulting product is a compound bearing a hydroxyl substituent on the benzene ring A. If a pharmaceutically acceptable acid addition salt is to be prepared, the compound of formula (I) is left. I react in a conventional manner with a suitable acid.

The compounds of formula I are preferably isolated and used in the form of their acid addition salts.

As mentioned above, the compounds of formula I inhibit platelet aggregation. This property can be demonstrated in vivo using standard tests in laboratory animals, such as the following test in rabbits.

In this test, blood samples are taken from the rabbit central ear artery by standard technique (free discharge). These samples are added to a 3.8% (w / v) solution of trinatrium citrate as an anticoagulant and then centrifuged first at 150 grams and then at 1000 g to obtain platelet-rich and plasma poor fractions of the blood. platičky. These fractions are used to calibrate the optical transmittance (transmiitainice) instrument and thereby the extent of platelet aggregation. Determine the extent of platelet aggregation in the platelet-rich fraction after addition of adenosine 5'-diphosphate (final concentration 0,5, 1,0, 2,0, 4,0 or 8,0 μΜ) and record the value of maximum aggregation in dependence on individual concentrations of adeiniosine-5'-diphosphate.

Rabbits are then orally administered the test compound and arterial blood samples are taken at various time intervals after administration. Platelet-rich plasma fractions are prepared from these samples and the extent of aggregation is determined by measuring the optical transmittance of the sample. This value is compared to that found in the same rabbit prior to administration of the test compound to determine the extent of inhibition of adenosine-5‘-diphosphate-induced platelet aggregation. For example, 1- (4-methylbenzyl) -1,2,3,6-tetrahydro-pyridine according to the invention results in a 62% inhibition of adenosine-induced platelet aggregation 2 hours after oral administration (as hydrochloride) at 100 mg / kg. 5'-diphosphate.

In general, the compounds of formula (I) show marked inhibition of platelet aggregation when administered orally at doses of 100 mg / kg or less in the above test, with no evidence of toxicity at effective doses.

Platelet aggregation inhibiting compounds, such as acetylsalicylic acid or ticlopidine, are used in the treatment or pro-haalixithrombosis or exclusive vascular diseases, and it is therefore contemplated that the compounds of formula (I) will generally be used in the same manner and for the same clinical indications.

When used to inhibit platelet aggregation in warm-blooded animals, including humans, the compounds of Formula I may be administered orally at a daily dose of from 1 to 30 mg / kg, preferably from 1 to 10 mg / kg, or an equivalent amount. in the case of administration of a pharmaceutically acceptable salt thereof. This dosage corresponds to approximately 0.07 to 2.1 g orally, in humans, orally administered daily. 0.07 to 0.7 g, or an equivalent amount of a pharmaceutically acceptable salt.

Example number substituent on benzene ring A

The compounds of formula I are preferably administered in the form of pharmaceutical compositions.

The invention is illustrated by the following non-limiting examples. The yields reported in the examples are by no means the maximum achievable yields. Evaporation is carried out under vacuum to dryness (where possible) using a rotary evaporator. Melting points were determined in sealed glass capillaries. The abbreviations used in the tables have the following meanings:

Me = methyl Et = ethyl Pr = propyl Ac = acetyl

Example 1

To a mixture of 11.8 g of 2-cyainbenzyl bromide a

9.16 g of potassium carbonate in 80 ml of ethanol are added 5.0 g of 1,2,3,6-teitrahydropyridine. The mixture was heated at reflux for 2.5 hours, cooled, evaporated, the residue was stirred with 120 ml of water and the resulting oily mixture was extracted three times with 50 ml of ether each time. The combined extracts were washed with water and dried over magnesium sulfate and evaporated. The oily residue was dissolved in > 20 mL toluene and a small excess of methainolic hydrogen chloride was added to the solution. The mixture was evaporated, the solid residue was triturated with acetone, the solid product was filtered off and recrystallized from ethanol / ethyl acetate to give 7.1 g of 1- (2-cyanobenzyl) -1,2,3,6-tetrahydropyridine hydrochloride as colorless m.p. 219-221 ° C. Examples 1 to 2

In analogy to Example 1, the correspondingly substituted benzyl chloride or bromide III is prepared in yields of 60 to 80% by weight. the following compounds of formula I in the form of the hydrochlorides:

melting point crystallization solvent (° C)

2 3 4-methyl 2-fluoro 232—233 179—180 i-PrOH / EtOAc i-PrOH / EtOAc 4 2-nitro 178—181 EtOH / Me ₂ CO 5 4-methoxy 203—204 i-PrOH / EtOAc 6 3-methyl 191-192 EtOH / Me ₂ CO

Example. 7

Roatoku To 50.0 g of 4-acetoxyfoluenu 10 miligrlamů and 2,2'-azobis ^(2-i m ethylpropioniitrilu) in 300 ml tetrachlormethainu under reflux and under irradiation with a tungsten lamp (275 W) over 40 minutes in portions 60.0 g of N-bromosuccinimide are added. Heating and irradiation are continued for 80 minutes after the addition is complete, then the mixture is cooled and filtered. The solid residue is washed with 100 ml of carbon tetrachloride, the filtrate is combined with the washings and evaporated. 4-Acetoxybenzyl bromide is obtained as a viscous residue which is dissolved in 300 ml of ethanol without further purification. 83.0 g of 1,2,3,6-teitrahydropyridime are added to the solution over 10 minutes, the mixture is not allowed to react at 20-25 ° C for 16 hours and then evaporated. 300 ml of water are added to the residue, the mixture is acidified with dilute hydrochloric acid to spH2, extracted twice with 100 ml of ether each time and the extracts are discarded. The aqueous phase was basified to pH 9 by the addition of sodium hydroxide solution and extracted three times with 100 ml of ether each time.

The extracts were washed with water (2 x 50 ml) and dried (MgSO4). The residue was dissolved in 200 ml of acetone, the solution was filtered and the filtrate acidified to pH 2 with ethereal hydrogen chloride to give 1- (4-hydroxybenzyl) -1,2,3,6-itetrahydropyridine hydrochloride which, after recrystallization from methanol and ethyl acetate yields 34.6 g of pure product, m.p. 234-236 ° C.

Examples 8 and 9

In analogy to Example 1, using the appropriate benzyl bromide as starting material, the following compounds are obtained in yields of 65 to 80%:

1- (3,4-dichlorobenzyl) -1,2,3,6-tetrahydropyridine hydrochloride (Example 8), melting after recrystallization from isopropanol / ether at 247-250 ° C, and

W 1- (3,5-dichlorobenzyl) -1,2,3,6-tetrahydropyridine hydrochloride (Example 9), melting after recrystallization from a mixture of methanol and ethyl acetate at 231-234 ° C.

Example 10

Analogous to Example 1, using 19.5 g of 4-cyanobenzyl bromide a

As starting materials, 8.3 g of 1,2,3,6-tetrahydropyridine gave 12.0 g of 1- (4-cyanobenzyl) -1,2,3,6-tetraihydropyridine hydrochloride melting after recrystallization from a mixture of ethanol, meitbainol and acetone. at 259-261 ° C.

EXAMPLE 11 g of 4-acetoxybenzylbromide and 2.2 g of pyridine are heated to reflux in 25 ml of acetone for 3 hours. The solvent was decanted off and the residue was triturated with dioxane. 5.1 g of hygroscopic solid 4- (oetoxybenzyl) pyridinium bromide are obtained, which is dissolved in 60 ml of ethanol. Sodium borohydride (2.95 g) was added to the solution, the mixture was stirred at 25 ° C for 24 hours and then concentrated to a small volume in vacuo. The residue is diluted with 50 ml of water, acidified to pH 2 with 2N hydrochloric acid, stirred for 20 minutes, then basified to pH 9 with 5% (w / v) sodium carbonate solution, the precipitated solid product is filtered off and stirred with acetone.

The resulting solution was filtered and the filtrate acidified with concentrated hydrochloric acid to precipitate 0.4 g of 1- (4-hydroxybenzyl) -1,2,3,6-tetrahydropyridine hydrochloride, m.p. 234-236 ° C. Examples 12 to 36

In analogy to Example 1, the following compounds of formula I (wherein R ¹ is hydrogen unless otherwise specified) are obtained in each case using an appropriately substituted benzyl chloride of a non-bromide of formula III (where R ¹ is hydrogen unless otherwise specified). hydrochloride form:

Example Substituent (s) on benzene yield melting point (° C crystallization solvent number Circle A (%) 12 3-bromo-4-chloro 34 245—246 EtOH / MeOH / BtiO 13 3,4-dibromo 52 249—251 EtOH / MeOH / EtOAc 14 4-bromo 53 241—243 EtOH / EtOAc 15 Dec 4-nitro 37 207—210 i-PrOH / Et ₂ 0 16 4-chloro 13 240—242 i-PrOH / EtOAc 17 2-fluoro-4-chloro 56 206—209 MeOH / EtOAc 18 2-bromo 46 196—201 EtOH / Me ₂ iCO 19 Dec 2-ohloir 56 oil (and) 20 May (R ¹ -Methyl) 2-chloro-4-fluoro 49 203—213 EtOH / Me 2 CO 21 2-mothoxy 10 138—142 Me.CO.Et 22nd 2,3-dichloro 32 186—188 i -PrOH / EtQAc 23 3-chloro-4-methyl 62 230—235 MeOH / EtOAc 24 3-chloro-4-bromo 60 246—252 2N — HCl 25 2,6-dihydroxy * ⁾ 17 187—189 i-PrOH 26 1-Meithylsulfonylamido 26 198—201 ErtOH 27 Mar: 2,6-dichloro 22nd 174—176 EtOH / Me ₂ CO 28 2-chloro-4-bromo 19 Dec 191—193 EtOH / EtOAc 29 2,5-dimethyl 50 220—233 i-PrOH / Et ₂ O 30 2,6-difluoro 19 Dec 187—188 EtOH / EtOAc 31 2-Meithyl 52 186—189 MeOH / EtOAc 32 2,4-difluoro 30 211—213 EtOH / EtOAc 33 3-methyl-4-chloro 14 240—243 - 34 3-hydroxy-4-chloro * ⁾ 43 140—142 (bj 35 2-chloro-4-nitro 30 (free base ·) 197—199 i-PrOH 36 2-hydroxy-3-chloro * ¹ 32 169—172 1-PrOH Legeradia: * ^F Jaiku starting materials in Examples 25, 34 and 36 se used 2,6-diaceitoxybenzylbro-

mid, 3-acetoxy-4-chlorobenzyl bromide, respectively. 2-iacetoxy-3-chlorobenzyl bromide;

(a) the product isolated as the free base with a compliant NMR spectrum (100 MHz, DMSO-d6): 1.05 (3H, doublet,], 3.65 (2H, doublet, 5.61 (2H, multiple)), 7.35 (4H, multiplet), 2-methyl-1,2,3,6-tetrahydropyridine as starting material;

(bj product purified as the free base by sublimation.

Example 37

Analogous to Example 1, 1- (2,4-dlchlorobenzyl) -1,2,3,6-fetirahydropyridine hydrochloride is obtained in 16% yield, m.p. after recrystallization from a mixture of isopropiainol and ether at 175-179 ° C.

Example 1 8

In an analogous manner to Example 1, 2-methyl-1,2,3,6-tetrahydropyridine and 4-aceitoxybenzyl bromide were used except that the reaction was not carried out with ethereal hydrogen chloride but the oily product was stirred with petroleum ether (boiling point). 60-80 ° C], 1- (4-hydroxybenzyl) -2-methyl-1,2,3,6-tetrahydropyridine is obtained as the free base (m.p. 109-112 ° C).

The starting 4-acetoxybenzyl bromide was obtained as described in Example 7.

Examples 3 9 to 4 9

Using the corresponding benzyl chloride or bromide as starting material, the following compound of the formula (I) is obtained in the form of the hydrochlorides in a yield of 39 to 60% by analogy to Example 1:

Example No. Substituent (s) Temperature / crystallization solvent on benzene ring A Melting point (° C)

39 4-CO ₂ Me 224—226 MeOH / Et2O 40 4-fluoro 220—221 i-PrOH / BtOAC 41 3-methyl-4-hydroxy * ¹ 192-194 EtOH / Me ₂ CO 42 3-methoxy-4-hydroxy * ¹ 188—189 i-PrOH 43 2-chloro-4-hydroxy * ¹ 204—205 EtOH 44 2,5-dihydroxy 194—200 EtOH / Me ₂ CO 45 3-hydroxy * ¹ 144—146 EtOH / Me ₂ CO 46 2-hydroxy * ’ oil**' i-PrOH / MeOH / Et ₂ O 47 2,5-dichloro 221—223 48 4-aicetamido 164—165 (free base) Me ^ CO 49 2-carboxiamido 196—198 Me ₂ CO / Et ₂ O

Legend:

The starting materials are the corresponding acetoxybenzyl bromides (e.g., 3-methyl-4acetoxybenzyl bromide in Example 36) obtained by bromination of the corresponding acetoxytoluenes as described for the preparation of 4-acetoxybenzyl bromide in Example 7 '.

Microanalysis: for Ο ^ Η ^ ΝΟ calculated: found:

C, 76.2; H, 7.9; N, 7.4; H, 8.2; N, 7.5.

NMR (100 MHz, perdeuterodimethylsulfoxide, tetramethylsilane as internal standard, δ values in ppmj:

3.6 (2H, singlet), 4.72 (2H, quartet), 6.32 (1H, doublet), 6.55 (2H, doublet).

Claims (5)

OBJECT A process for the preparation of 1-benzyl-1,2,3,6-tetrahydropyridine derivatives of the general formula I OF THE INVENTION acid addition salts, characterized in that 1,2,3,6-tetrahydropyridine of the formula II in which: R ¹ is hydrogen or C 1 -C 4 alkyl, one of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy carbon atoms, hydroxyl, nitro, cyano, carboxamido, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoylamino or C 1 -C 4 alkylsulfonylamino, another of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen or halogen, hydroxy, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy and the remaining of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, provided that when R ¹ is hydrogen, the benzene ring A is not a 2-chlorophenyl moiety, and their pharmaceutically acceptable compounds wherein R ¹ is as defined above, are reacted with a benzyl halide of formula III in which Hal represents a chlorine, bromine or iodine atom and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ on the benzene ring B have the same meaning as the corresponding symbols given above for ring A, except that the muzzle where ring A carries The hydroxyl group contains ring B of a (C 1 -C 4) alkanoyloxy group, and the resulting product is optionally converted by reaction with a suitable acid to form a pharmaceutically acceptable acid addition salt. 2. The process of item 1, for the preparation of compounds of formula I, wherein R @ ¹ is hydrogen, one of R @ ² , R @ ³ , R ^{@ 4} , R @ ⁵ and R @ ⁶ is halogen; C 4 -C 4 alkoxy, C 1 -C 4 alkoxy, hydroxyl, nitro, cyano, carboxamido or C 1 -C 4 alkanoylamino, another of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen or halogen, hydroxyl, nitro, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy, and the other of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, when R ¹ is hydrogen, a does not represent a benzene ring, 2-chlorophenyl radicals, and their pharmaceutically acceptable acid addition salts, characterized in that as the starting compounds of formulas II and III, wherein Hal is VYZ as in 1 and the remaining general symbols have the same meaning in this point. 3. The process of claim 1 wherein the reaction is carried out in the presence of an alkali metal hydroxide or carbonate. 4. The process of claim 3, wherein the alkali metal hydroxide or carbonate is potassium hydroxide or potassium carbonate. 5. A process according to any one of Claims 1 to 4 wherein the reaction is carried out in the presence of a suitable diluent or solvent at a temperature of 20 to 120 ° C.