CS271342B2 - Method of n-/2-/4-fluorphenyl/-1-methyl-ethyl-n-methyl-n-propinylamine production - Google Patents

Abstract

The compounds of the formula I in the form of race mate or optically active isomers, as well as its addition, salt with acids are prepared in such a way that the compound of the formula VI, where R<4> stands for hydrogen or propynyl and R<5> stands for hydrogen or methyl, is promoted by a phenyl isopropyl derivate of the formula VIII, where R<2> stands for fluor, nitro group or amino group and X stands for halogen or the rest of ester of sulphonic acid, and if R<2 has a different meaning than the atom of fluor, R<2> is carried over into the atom of fluorine by the contingent reduction of nitro group to amino group, by diazotation to fluoroborate aggregation in the presence of fluoroboric acid and by modification of diazonium fluoroborate by means of heating to a temperature of 70 to 90 degrees C of the atom of fluorine. As a consequence, if the substituents R<4> and/or R<5> means that the atom of hydrogen, the acquired compounds change by means of alkylation into the compound of the formula I and thus acquired compound of the formula I contingently splits into optically active isomers or it can be carried over into additional salt with the acid. The produced compounds are effective as selective inhibitors of monoamine oxidase-B and are used in pharmaceutics.<IMAGE>

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of N- [2- (4-fluorophonyl) -1-methyl, C1-N-methyl-N-propinylamine which is predominantly effective as a selective monoamine oxidase-B (MAO-B) inhibitor. intake of biogenic amines and pyramines in the body.

U.S. Patent Nos. 154,060 and 154,655 disclose processes for the preparation of phenylisopropylamine derivatives and related optically active compounds which, as disclosed in particular in U.S. Patent No. 154,060, can be used as coronary artery expanding agents, such as hallucinogenic substances, soothing agents, pain threshold agents and weight loss aids, while U.S. Patent No. 154,655 describes the inhibitory activity of optically active agents of this type on monoacinoid oxidase.

The present invention provides a process for the preparation of N- [2- (4-fluorophenyl) -X-methyl-ethyl-N-methyl-N-propynylamine of formula I].

(I) in the form of the racemate or optically active isomers, as well as the acid addition salts thereof, comprising:

(VI) in which:

R is hydrogen or propynyl; and c

R 'represents a hydrogen atom or a methyl group, which acts as a phenylisopropyl derivative of the general formula VIII

(Vili),

CS 271342 В2 in which

R ^d is fluoro, nitro or amino;

X is a halogen atom or a sulfonic acid ester residue,

2 and when R is other than fluorine, R is converted to fluorine by optionally reducing the nitro group to an amino group, diazotizing the amino group to a fluoroborate moiety in the presence of fluoroboric acid and converting the diazonium fluoroborate by heating to 70-90 ° C to fluorine, se

Optionally, when R and / or R ^y represent a hydrogen atom, the compounds obtained by alkylation are converted to a compound of formula I and the compound of formula I thus obtained is optionally resolved into optically active isomers or is optionally converted into an acid addition salt.

In the starting compound of formula (VIII), X is preferably chlorine, bromine or iodine, or as the sulfonic acid ester residue is preferably alkylsulfonyloxy, for example methylsulfonyloxy or arylsulfonyloxy, preferably benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromosulfonyloxy and p-bromosulfonyloxy.

The reaction of a compound of formula VIII with a compound of formula VI is preferably carried out in the presence of an acid binding agent. In the obtained compound

4, the radical R can be converted to a fluorine atom and / or the radical R can be converted to a propynyl group - &quot; or / and the radical R &apos; to a methyl group when these radicals represent a hydrogen atom. The reactions can be carried out in any order.

Thus, preferably the reaction product of formula IX

CH - N - R ⁵ (IX) in which they are as defined above and

means a hydrogen atom, reacted with an inorganic acid or a methyl ester of an organic sulfonic acid or a mixture of formaldehyde and formic acid.

Methylating a compound of formula IX in which R ² and R are as defined above, and R ^y is hydrogen, can be carried out preferably with dimethyl sulfate, methyl halide, methyl sulfuric acid or trimethyl phosphate.

Analogously, the reaction product of the general formula (IX) in which R @ ² and R @ 5 can be substituted for the reaction product. R ⁴ is hydrogen, propynyl with propynyl halide, propynyl sulfonic acid or a mixture of formaldehyde and acetylene.

CS 271342 B2

The propynylation is preferably carried out via the corresponding halopropyl and halopropenyl derivatives.

Advantageously, the amine of the formula X can also be ^CH3

(X) in which

R is as defined above, or an amine of formula XII CH ₃

CH,

AND

KH (XII) wherein

R is as defined above, reacted with 1,2-dibromopropene and then the 2-bromopropenyl derivative obtained is cleaved by hydrogen bromide cleavage to the desired propynyl derivative by heating to 80 to 110 ° C or treatment with a base.

The compounds of formula (I) and their isomers and salts are excellent monoamine oxidase inhibitors according to the results of various experiments. They selectively block MAO-B. They also have a long-lasting aphrodisiac effect. These substances also have very low toxicity. Furthermore, it is significant that these substances generally inhibit the uptake of biogenic amines as well as tyramine in addition to the above-mentioned effects.

In view of the above properties, the compounds produced by the process of the invention are particularly useful for treating the elderly. In a more advanced age, the administration of the compounds of formula (I) may improve the general condition, particularly with respect to mood, and further increase sexual activity. Changes in the motor system can be inhibited by the continuous administration of these compounds, thereby improving the general well-being of older people. They appear to be substances that counteract the decrease in the concentration of dopatin in the brain, which continues with age. It allows better brain function without affecting postsynaptic dopamine receptors. In addition, a substance of this type remains effective over many years of administration and has no or almost no adverse side effects.

Unless it is emphasized that it is a particular isomer or a salt of a compound of formula (I), all the isomers and salts of a compound of formula (I) are meant throughout the specification.

The invention is based on the recognition that, in a group of compounds classified as N-alkyl-N-phenylakylamines, the position of the substituents on the phenyl moiety and the position of these substituents on the molecule affect the molecule to such an extent that efficacy cannot be generalized for the group.

Thus, the particular biological activity that could be demonstrated for the compounds produced by the process of the invention could not be ascribed or expected on the basis of the previously known compounds, since this is an effect which has been found only with some particular derivatives.

The process of the invention involves the preparation of a compound of formula I in both racemic and optically active form. Optically homogeneous antipodes can be prepared by resolution at any stage of the synthesis. The separation can be carried out at the initial stage of the starting material. In this case, a left-handed or right-handed starting material of formula VIII is used for the synthesis.

Alternatively, cleavage of the compound of formula (I) may be carried out in a manner known per se by forming a diastereomeric salt pair using a suitable optically active acid such as tartaric acid or dibenzoyltartaric acid.

The oily, fat-soluble compounds prepared according to the invention can be converted to water-soluble salts or the free material can be liberated. 2 Its salts can be prepared with salts and hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, formic, maleic, wine, milk, 3,5-dinitrobenzoic, lemon or oxalate. Biologically inert or acceptable salts or free substances are suitable for use in medicine.

The compounds of formula (I) produced by the process of the present invention can be formulated into pharmaceutical compositions containing the active ingredients.

These pharmaceutical compositions may be prepared in a known manner such as tablets, dragees, suppositories, capsules, solutions, emulsions, injectables, together with conventional additives, carriers, glidants and fillers.

Some of the starting materials, in particular fluorinated derivatives, have not been known in the literature and the preparation of these compounds will be described at least briefly in the Examples section of the application.

Pharmaceutical compositions containing the compounds of the present invention may be administered to geriatric initiators at a dose of 1-5 mg as an antidepressant at a dose of 20 to 50 mg, as an anti-Parkinson's drug at a dose of 5 to 10 mg per day. ·

The invention will be illustrated by the following examples:

Example 1

To a solution of 8,3 g (0,05 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine,

5.4 g (0.1 mol) of propargylaldehyde are added in one portion and then 100 ml of 96% ethanol and 3 g of mercury (II) chloride-activated aluminum foil are added in portions at a temperature of 20-30 ° C. The reaction mixture was stirred at room temperature for 24 hours, then filtered and the filtrate was evaporated. The residue was dissolved in 10% hydrochloric acid, extracted with benzene, basified by addition of 40% aqueous hydroxide solution.

And then extracted again with benzene. The benzene solution was dried and evaporated. The residue is distilled under vacuum at 1 mmHg. 5.6 g of (+) - N-methyl-N-propynyl [2- (4-fluorophenyl) -1-methyl] -ethylamine are obtained, b.p. 120-123 [deg.] C. at a pressure of 266 Pa. = 1.5055. The melting point of the hydrochloride is 130-132 ° C.

Example 2

To a solution of 6.0 g (0.036 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine and 60 ml of acetone was added 33.6 g (0.24 mol) of potassium carbonate and then 7.45 g (0.037 mol) of 2,3-dibromopropene dropwise at 25-30 ° C with stirring over 20-25 minutes. The reaction mixture was heated at reflux for 6 hours and then filtered and evaporated. The residue is distilled under vacuum at a pressure of 5 mmHg. 6.52 g of (+) - N-methyl-N- (2-bromo-3-propenyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine are obtained, yield 63.3%. Boiling point 142-143 ° C, _n 2 ° = 1.5234.

2.5 g of the above product are dissolved in 35 ml of ethanol and then 5 ml of 50% potassium hydroxide solution are added. The reaction mixture was heated at reflux for 16 hours and then evaporated. The residue was dissolved in water and the solution was extracted with benzene. The benzene solution is acidified with ethanolic hydrogen chloride solution. The precipitated product is collected by filtration and dried. 2.2 g of (+) - N-methyl-N-propynyl / 2- (4-fluorophenyl) -1-methyl] -ethylamine hydrochloride are obtained, m.p. 131-133 ° C.

Parmacological tests

The following abbreviations will be used for the active substances during each test;

IA = (+) - N-methyl-N - [(2-propynyl) -2- (4-fluorophenyl) -11-methyl] ethylamine hydrochloride

ΣΒ - (-) N-methyl-N - [(2-propynyl) -2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride pCIP = (+) - N-methyl-N - / (2-propynyl) - 2- (4-chlorophenyl) -1-methyl / ethylaroinohydrochloride pBrP = (+) -N-methyl-N - / (2-propynyl) -2- (4-bromophenyl) -1-methyl / ethylacyl hydrochloride

1. Monoamine oxidase inhibitory activity (МАО)

1.1. In vitro experiments.

1.1.1. Measurement for Kernel-Free Rat and Kidney Homogenidase The method of Biochem is used. Pharmacol. 1963, 12, 1417 and 1978, 27, 1939

Substrates: ¹

MAO-B: ^ C-PEA: 0.2 mM, specific activity 0.5 µCi / ml, MAO-A: ^ C-5HT: 5.0 mM, specific activity 0.25 µCi / ml.

organ IB IA pCIP pBrP ^IC 50 MAO-B brain liver 4.57x10 ”® 1.98x10 ”® 4.17x10 ”® 1.19x10 ”® l 48xlO ^'7 lxlO ^"7 3.98x10 ⁷ L, 64x10 ⁷ ” selective index liver 238.38 580.67 43.47 51.28

IC ₅₀ MAO-A selective index

_N IC_ MAO-B

Measurement on rat brain mitochondria

Method: Mitochondria are prepared from the brains of male CFY rats weighing 200-250 g as follows:

After decapitation, tissue homogenate is prepared in 0.25M sucrose. The homogenate is centrifuged for 10 minutes at 1000 g and the supernatant is again centrifuged for 15 minutes at 9000 g, the sediment is mixed with 0.25 M sucrose.

Substrates:

MAO-A: 6x10 ⁴ Μ 5ИТ

MAO-B: 2 x 10 ^ ⁵ у. ррд

Results:

values

MAO-A: 5 x 10 (M) n-5

IA

MAO-B: 3 x 10 ⁸

1.2. In vivo experiments using nuclear-free homogeneity of rat brain and rat liver

Method: Rats were dosed subcutaneously with a different dose of the test substance and the organs were removed four hours after administration, and the MAA activity was measured as described in paragraph 1.1.1.

The results are shown in the following table.

organ IB IA pBr? ^ID 50 brain 0.104 0,076 5.61 MAO-B liver 0,772 0.292 8.85 (mg / kg) selective index liver 148.8 168.6 13.33

selective _ ΙΏ ^ θ ^WA0 “ ^A

After administration for 21 days at a daily dose of 0.25 mg / kg of Compound 1a, MAO-B inhibition was 92-94% expressed in% of control and MAO-A inhibition was 0

2. Inhibitory activity on tyramine uptake in rabbit pulmonary artery

Rabbits of both sexes weighing 2 to 4 kg were sacrificed by a blow to the back of the neck and immediately thereafter the heart was removed and placed in Krebs' solution supplied with oxygen. The composition of the Krebs solution was as follows (mmol / liter): sodium chloride 111, potassium chloride 4.7, calcium chloride 2.52, magnesium sulfate 1.64, sodium bicarbonate 25, potassium dihydrogen carbonate 1.2, glucose 11. The vessel was cleaned of connective tissue and a 1.5 mm spiral width was excised from the tissue. The vessel segment thus obtained was placed in a 5 ml organ bath containing Krebs solution, a gas mixture consisting of 95% oxygen and 5% carbon dioxide was bubbled through the bath, the bath temperature was maintained at 37 ° C · Activity was recorded by a semi-isomeric compensator at application of prestressing 1 g.

Tyramine uptake was inhibited on the above preparation by compound IB, depending on the dose used. IC ^ q = 5.4 x 10 M.

3. Inhibition of biogenic amine uptake (method: J. Pharm. Exp. Ther. (1969) 165, 78-86)

concentration IA substance weighing region substances (M) IC ₅₀ (M) 5 x ⁸ ' ⁸ hypothalamuad 8 x 10 ^_ 5HT 1 x 10 ⁷ hypocampus 6 x 10 ⁴ DA 1 x 10 ~ ⁷ striatum 2 x 10 ' ⁷

ON: @ 1 H-noradrenaline 5HT: 1H-5-hydroxytryptamine DA: 1 H-dopamine

4. Stimulation of in vivo activity of external phenethylamine (PEA) (MAO-B)

4.1. Stimulating effect on the membrane nictitating on an anesthetized cat

The nictitating membrane contracts after intravenous administration depending on PEA. The dose-response curves of PEA are shifted to the left after intravenous administration of compound IA at a dose of 0.1 or 0.25 mg / kg.

4.2. Increase in stereotyped behavior induced by PEA

Method: Arzneimittel Porsch. (Drug Research) 22, 1178 (1972).

The results are shown in the following table:

compound mg / kg max. score total score control - 0.5 + 0.22 1.17 + 0.54 IA 0.25 2.17 + 0.31 8.17 + 0.87 0.1 1.67 + 0.21 5.67 + 0.49 0.05 1.0 + 0.37 2,8311,01

The efficacy of PEA at a dose of 40 mg / kg is potentiated by compound IA at a dose of 0.05 to 0.25 mg / kg subcutaneously depending on the dose level.

CS 271342 В2

5. Experiments with the central nervous system

5.1. Modified plate test

Compound IA did not inhibit the defense reflexes in the rat at a dose of 15 mg / kg (Knoll method 1963).

5.2. Metabolic test

Compound IA at 5 mg / kg did not increase rat metabolism (Issekutz method 1942).

5.3. Effectiveness on food intake

The experiment was performed after 96 hours of fasting on groups of 10 to 13 rats. Compound IA, when administered subcutaneously at a dose of 5 mg / kg, decreased food intake statistically significantly predominantly in the first hour after dosing; at higher doses of 10 to 15 mg / kg subcutaneously, there was a statistically significant decrease in food intake.

5.4. Effect on catalepsy

Catatonia induced by a dose of 3 mg / kg tetrabenzine was inhibited in a dose-dependent manner by compounds IA and IB.

ΕΌ ^ θ-ΙΑ = 2.6 mg / kg

ED ₅₀ -IB = 2.9 mg / kg.

6. Influence on sexual activity in male rats

In male rats, compound IA was a potent long-lasting stimulant. After a single dose of 0.1 mg / kg and 0.25 mg / kg, the compound significantly increased the number of ejaculations 24 hours, 2 to 3 weeks and 4 weeks after administration compared to control animals. Thus, the aphrodisiac effect of this compound has been demonstrated in the method described in Medical Science 33, 179-180 (1982).

7. Toxicity

The tests were performed on both white male and female CFY rats weighing 100-120 g. The compounds were administered intravenously. the animals were observed for 48 hours.

The results are shown in the following table:

IA IB pCIP

LD ^ q 60 64 35 mg / kg

Pharmaceutical preparations

Example A

The following ingredients are mixed:

g (+) - N-methyl-N-propargyl - [+] - (4-fluorophenyl) -1-methyl / ethylamine hydrochloride g talc g magnesium stearate g polyvinyl pyrrolidone g corn starch

170 g lactose

62

The ingredients are homogenized and 1000 tablets are compressed from the mixture obtained.

Example В

The following ingredients are mixed:

110 g of (-) -N-methyl-N-propargyl 1- [2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride g talc g magnesium stearate g polyvinylpyrrolidone

100 g potato starch

150 g lactose

All ingredients are mixed thoroughly and the mixture is compressed to 1000 tablets.

The invention will be further elucidated by further examples of the manufacture of active ingredients.

Example 3

16.7 g of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine are dissolved in 150 ml of acetone and 69.2 g of sodium carbonate are added with stirring. Then add yet

13.3 g of allyl bromide are added and the reaction mixture is refluxed for Θ hours and then filtered. The filtrate was evaporated and allowed to distill under vacuum. 15.2 g of (+) - N-methyl-N- (2-propenyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine are obtained. This product was dissolved in 100 mL of carbon tetrachloride and 11.8 g of bromine was added dropwise. After stirring for an additional 8 hours, the solution was evaporated and the residue was dissolved in 400 ml of ethanol. 100 ml of 50% strength aqueous sodium hydroxide solution were added and the reaction mixture was heated under reflux for 20 hours. After the ethanol was evaporated, water was added and the mixture was extracted with benzene. The benzene solution was extracted with 2N hydrochloric acid and, after addition of sodium hydroxide and benzene extraction, repeated. The benzene extract was dried over sodium sulfate, filtered and evaporated. The residue was distilled under vacuum to give 5.6 g of (+) - N-methyl-N- (2-propynyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine. Boiling point 90-93 ° C at 80 Pa.

Example 4

1.72 g of 1- (4-fluorophenyl) -2-chloropropane (Acta chim. Acad. Sci. Hung. 79 (1973) 433) and 1.4 g of N-methylpropargylamine were heated in a sealed tube for 5 hours. The reaction mixture was then dissolved in 30% aqueous ethanol containing hydrochloric acid and evaporated. 0.35 g of (+) - N-methyl-N- (2-propynyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride is obtained as a residue, m.p. 130 DEG-132 DEG.

Example 5

A solution of 8.2 g (0.05 mol) of (+) - N-methyl-2- (4-aminophenyl) -1-methylethylamine (Hungarian Patent Specification 154 060) to 30 ml of 56% fluoroboric acid and 3.5 g (0.051 mol) of sodium nitrite in 25 ml of water is simultaneously added dropwise to 100 ml of 56% fluoroboric acid with stirring and cooling to -5 to -7 ° C so that a small excess of ni trium solution is always present in the reaction mixture during the addition. The mixture was then stirred for an additional 30 minutes at -5 to -7 ° C, while 2.5 g of freshly prepared cuprous chloride was added in small portions. The mixture is then allowed to melt for two hours at room temperature and then for a further two hours at 80-90 ° C. The mixture was cooled, extracted with ether and the acidic aqueous layer basified

CS 271342 82, by adding concentrated ammonium hydroxide and then extracting with benzene. After drying, the benzene extract was evaporated and the residue was extracted at 1330 Pa. 5.6 g of (+) - N-methyl-2- (4-fluorophenyl) -1-methylethylamine having a boiling point of 87-90 DEG C. at a pressure of 1330 Pa were obtained as the main fraction.

Example 6

To 7.65 g (0.05 mol) of (+) -2 - (4-fluorophenyl) -1-methylethylamine (Belgian patent 609 630) in 25 ml of benzene, 5.3 g (0, -, (Mol) of distilled benzaldehyde and the solution obtained is allowed to stand overnight and then dried. To the dried solution was added 6.3 g (0.05 mol) of dimethyl sulfate, then the mixture was refluxed for three hours, then cooled with stirring, and then a solution of 2 ml of concentrated hydrochloric acid in 50 ml of water was added. After stirring for 1 hour, the two layers were separated, the acidic aqueous layer was basified by addition of sodium hydroxide and then extracted with benzene. The benzene solution was dried and evaporated and the residue was distilled in vacuo. 4.15 g of b.p. 87 DEG-90 DEG C. at 1 mmHg are obtained. This was dissolved in 40 mL of toluene, 23.5 g (C, 17 mol) of potassium carbonate was added, followed by dropwise addition of a solution of 3.65 g (0.031 mol) of propargyl bromide in 60% toluene and stirred at room temperature for 14 hours. . The mixture was then filtered and the filtrate was acidified to pH 3 with ethanol containing 31% hydrochloric acid. The crystalline product is collected by filtration and recrystallized from ethanol / ether. 2.1 g of (+) - N -methyl-N-propenyl-2- (4-fluorophenyl) -1-methyl-1-ethylamine hydrochloride are obtained, m.p. 130 DEG-132 DEG.

Example 7 ·

8.34 g (0.03 mol) of 1- (4-fluorophenyl-2-propyl p-toluenesulfonate (org. Synth. Col. Vol. III, 306)) and 8.26 g of N-propargylamine are reacted in a sealed state The mixture was dissolved in benzene and extracted with aqueous hydrochloric acid, the aqueous layer basified, extracted with benzene, dried, filtered and evaporated and the residue distilled under reduced pressure.

2.65 g of the (+) -N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine thus obtained (b.p. 117 DEG-126 DEG C. = 1.5072) are dissolved in 16 ml of acetone and 2.65 g of potassium carbonate are added to the obtained solution, and 2.65 g of methyl iodide are then added dropwise with stirring. The reaction mixture was heated under reflux for 2 hours, then filtered and the filtrate was evaporated. The residue is dissolved in a 10% hydrochloric acid solution, the solution is clarified and filtered. The filtrate was basified and extracted with toluene. After drying the toluene solution, this solution is acidified with ethanolic hydrogen chloride. The precipitated product is filtered off and dried. 2.1 g of (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride of melting point 131 DEG-133 DEG C. are thus obtained.

Example 8

16.77 g (0.05 mol) of 1- (4-nitrophenyl) -2-propyl p-toluenesulfonate (J. Am. Soc. 100, 228-246, 1978) was reacted with 7 g (0 (1 mol) of N-methylpropinylamine in a sealed tube for 5 hours at 70-80 ° C. After cooling, the reaction mixture was dissolved in 30% ethanolic hydrogen chloride and then the solution was evaporated. The residue is recrystallized repeatedly from ethanol. 6.7 g of N-methyl-N-propynyl- [2- (4-phenyl) -1-methyl] ethylamine hydrochloride of melting point 164 DEG-167 DEG C. are obtained.

g (0.018 mol) of the thus obtained N-methyl-N-propynyl- [2- (4-phenyl) -1-methyl] ethylamine hydrochloride is dissolved in a mixture of 10 ml of water and 3 ml of concentrated hydrochloric acid and then added to the solution. 4.7 g of zinc powder. The reaction mixture was stirred at 75 ° C for 2 hours. The solution was then basified and extracted with benzene. After drying, the organic layer was filtered and the filtrate was evaporated. 5 g of crude (+) - N-methyl-N-propynyl- [2- (4-aminophenyl) -1-methyl] -ethylamine are obtained which is diazotized in fluoroboric acid and the diazonium fluoroborate thus obtained is decomposed by addition of chlorite (gentle at temperature 80 DEG C. (described in more detail in Example 5) to give (+) - N -methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] -ethylamine. The organic layer was dried, filtered and evaporated and the residue distilled under reduced pressure.

1.7 g of (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine, b.p. 120 DEG-122 DEG C., = 1.5054, are obtained.

Example 9

8.6 g (0.05 mol) of 1- (4-fluorophenyl) -2-chloropropane (Acta Chim. Acad. Sci. Hung.

79, 433, 1972) and 25 ml of 25% methylamine are reacted in a sealed tube at 70-80 ° C for 5 hours. The mixture was cooled, basified and extracted with benzene. The combined organic phases were dried, filtered and evaporated. The residue was distilled under reduced pressure.

4.6 g of the thus obtained (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine (boiling point 87-90 ° C, η = θ = 1.4920) are dissolved in 48 ml of acetone and 25.28 g (0.19 mol) of potassium carbonate were added to the obtained solution, and 4.0 g (0.034 mol) of freshly distilled propargyl bromide was added dropwise with stirring. The reaction mixture was stirred at 55 ° C for 3.5 hours, then filtered under cooling, washed with acetone, and the filtrate was evaporated. The residue was distilled under reduced pressure.

3.1 g of (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine are obtained. Boiling point 120-122 ° C, = 1.5050.

Claims (6)

SUBJECT OF THE INVENTION A process for the preparation of N- [2- (4-fluorophenyl) -1-methyl] ethyl-N-methyl-N-propynylamine of the formula I with ₃ to ₃ (I) in the form of the racemate or optically active isomers, and addition salts thereof with acids, characterized in that the compound of formula (VI) in which: R ⁴ R ⁵ represents a hydrogen atom or a propynyl group and represents a hydrogen atom or a methyl group, acts with a phenylisopropyl derivative of the general formula (VIII): -2 with fluorine, nitro or amino; X is a halogen atom or a sulfonic acid ester residue, And if R is other than a fluorine atom, R is converted to a fluorine atom by optionally reducing the nitro group to an amino group, diazotizing to a fluoroborate moiety in the presence of fluoroboric acid and converting the diazonium fluoroborate by heating to 70-90 ° C to a fluorine atom. when R @ ⁴ and / or R @ 4 represent a hydrogen atom, the compounds obtained are alkylated to a compound of formula I and the compound of formula I thus obtained is optionally resolved into optically active isomers or optionally converted into an acid addition salt. 2. A process according to claim 1, wherein the reaction product of the general formula (IX) in which: 9 л R and R ⁴ have the meanings given in 1 ac R1 is hydrogen, reacted in an inorganic acid or with an organic sulfonic acid methyl ester or a mixture of formaldehyde and formic acid. 3. A process according to claim 2, wherein the methylation of the compound is carried out The formula II in which R and R are as defined in 1 and R 'is hydrogen is carried out by treatment with dimethyl sulphate, methyl halide, trimethyl phosphate or methylsulphuric acid. 4. A process according to claim 1, wherein the reaction product is a general product The formula II in which R and R ^ are as defined in point 1 and R is hydrogen is treated with propynyl halide, propynyl sulfonic acid ester or a mixture of formaldehyde and asylene. 5. Process according to claim 1, characterized in that the propynylation is carried out successively over the corresponding halopropyl and halopropenyl derivatives. 6. The process of claim 5, wherein the amine of formula (X) CH ₇ I - CH - R ² in which R is as defined in point 1, or an amine of formula XII CE ₃ CH ₃ (XII), as defined in 1, is reacted with 1,2-dibromopropene and then the 2-bromopropenyl derivative obtained is converted to the desired propynyl derivative by heating to 80-110 ° C or treatment with a base.