KR810000817B1 - Process for preparing n,n-dimethyl-3-(4-bromophenyl)-3(3-pyridine)-arylamine - Google Patents

Abstract

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Description

Method for preparing N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine

The present invention relates to novel processes for the preparation of therapeutically active compounds of the general formula (I) and pharmaceutically acceptable salts thereof.

The present invention further relates to novel reaction intermediates useful for the preparation of the above structural compounds.

It is an object of the present invention to provide novel and technically advantageous preparations of the compounds of formula (I).

The final product N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine is known from Swedish Patent No. 361,663 and the compound is a therapeutic agent, in particular an antidepressant or anxiety agent. It is considered to be effective.

The patent discloses a method for producing the above-mentioned product by dehydrating a compound of the following structural formula with a dehydrating agent such as concentrated sulfuric acid.

Although the method is carried out in the laboratory and yields an adequate yield, it is not well adapted to the desired range in commercial production. Therefore, on a large scale, the total yield of isomeric pure products was less than 20%. Because of this and other conditions, it is too expensive to prepare the compound by known methods. The reaction is described in the following general schematic in the American Chemical Society 77,4636, (1955).

Formation of the active reaction intermediate of the following structure during the reaction in this system is by electron donating groups R ₁ and R ₂ .

In the corresponding systems of the compounds of the following structures, the formation of similar active reaction intermediates is not easy because there are no electron donors.

However, the inventors tried to carry out the aminomethylation reaction with the above-mentioned compounds under the conditions given in the document. Tried to vary the above conditions, but did not succeed. Surprisingly, however, according to the invention, according to the following table under certain conditions, the reaction can be carried out very advantageously.

Compared to the method presented previously, the present invention has increased yields and has made economic improvements in production. Advances in the production economy are due not only to increased yields, but also that the starting materials used are cheap and unreacted starting materials can be easily collected and reused. In order to carry out the reaction successfully, the reaction conditions must be carefully controlled. Therefore, it was found that an excess of amine should be used for formaldehyde. A suitable molar ratio of the reactants is about 2: 1.

The relative amounts of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene and formaldehyde should generally be used in excess of formaldehyde. The preferred molar ratio is about 1: 2 but can be used in various ways up to 1: 6. This reaction is suitably carried out in solution. Preferred solvent is acetic acid.

Other possible solvents are, for example, lower alcohols. It was found that it is desirable to use very high concentrations of reactants in the solvent. When using acetic acid, the molar ratio of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene: solvent should be about 1: 4-about 1: 8 and about 1: 5 is preferred.

The reaction temperature is suitably about 110 ° -120 ° C., i.e. no access to the preferred solvent. Although the reaction rate is reduced, slightly lower temperatures can be used. The reaction is suitably run for about 4-7 hours. The best conversion takes place in the reaction time and the formation of impurities and byproducts can be essentially avoided. The reaction is promoted by acid. Preferred catalyst is HCl. The effect of the acid catalyst is to make the reactant amines in their acid addition salt form. Dimethylamine hydrochloride is therefore the most preferred amine reactant.

This conversion can be further improved by adding molecular sieves (it is appropriate to have a powder degree of 3 kPa).

The method for obtaining the improved conversion is to distill the solvent portion and replace it with an equal amount of fresh solvent. The process is carried out once or several times during the reaction. The conversion can be beneficial by removing the water produced by the reaction.

After completion of the reaction and removal of the solvents, poor yields of starting material and starting material containing the desired final product are generally obtained. Starting materials are obtained in the form of hydrochloride by extraction with a solvent such as methylene chloride at pH 1-4.

Recovered 1- (4-bromophenyl) -1- (3-pyridyl) -ethene-hydrochloride is converted directly or to 1- (4-bromophenyl) -1- (3-pyridyl) -ethene Then used again. Purification of the recovered starting material is generally not necessary.

From the remaining mixture, the desired compound is obtained by crystallization, where possible crystallizing after decolorizing with an adsorbent such as activated carbon or silica gel.

The desired compounds exist in different stereo-isomeric forms, Z- and E-forms, according to the IUPAC nomenclature (Organols 35,2849-2867, September 1970), which may be separated. It is desirable to isolate therapeutically effective Z-isomers as anti-dominant agents. The ratio of Z-isomer to E-isomer obtained by the present invention is about 2.5: 1.

It is within the scope of the present invention not only to separate the final product into various hydrated crystal forms, but also to form salts of bases or acids (preferably therapeutically acceptable acids).

Starting materials used in the processes described above fall within the broad scope of the present invention. The above starting materials are prepared according to the following scheme from known compounds.

Grignard compounds prepared from dibromo benzene react with 3-acetyl pyridine in ethereal solution to form 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol. These reaction intermediates also fall within the broad scope of the present invention.

The reaction intermediate is then dehydrated to form 1- (4-bromophenyl) -1- (3-pyridyl) -ethene. This is done by heating in acetic anhydride. Ethanol derivative reaction intermediates are not necessarily separated during the process.

As a modification of the process of the present invention, the desired product of formula (I) is prepared from 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol without separating the corresponding substituted ethene. . In this case the substituted ethanol is dehydrated in a dehydrating agent such as acetic anhydride. Then add a small amount of sulfuric acid, if possible. Then, destroy the excess dehydrating agent with an appropriate amount of water. Formaldehyde and dimethylamine are then added and the reaction is continued as originally summarized above.

In clinical trials, the compounds of the present invention, in combination with a pharmaceutically acceptable carrier, may form an active substance in the form of a free base or a pharmaceutically acceptable bitoxic acid addition salt (e.g. hydrochloride, bromate, lactate, acetate, sulfate, or sulfamate). Formulations may be administered using oral, rectal or injection.

Thus, the terminology relating to the novel compounds of the present invention includes both free amine bases and acid addition salts of free bases, provided that the context before and after the term is used (eg in a particular embodiment) is consistent with a broad concept. The carrier is a solid, semisolid or liquid diluent or capsule. Such formulations also fall within the broad scope of the present invention. Usually, the active substance comprises 0.1-95% (% by weight) of the formulation, in particular 0.5-20% (% by weight) in the formulation for injection and 2-50% (% by weight) in the formulation for oral administration.

In order to make a dosage form of an oral dosage unit containing a compound of the present invention, the selected compound is added to a solid powder carrier (e.g., starch, cellulose derivatives such as lactose, sugar, sorbitol, mannitol, potato starch, corn starch or amylopectin). Or gelatin) and a lubricant (eg magnesium stearate, calcium stearate or polyethylene glycol waxes) and then compressed to form tablets. If coated tablets are required, the mass prepared as described above is coated with a concentrated sugar solution containing, for example, gum arabic, gelatin, talcum or titanium dioxide. Tablets may also be coated with a lacquer dissolved in a volatile organic solvent or a mixture of organic solvents. Dyestuffs may be added to these coatings to easily distinguish different drugs or tablets containing different amounts of the drug.

The drug substance is mixed with vegetable oil to produce soft gelatin capsules (pearl capsules) or similar capsules of gelatin and, for example, glycerol. Hard gelatin capsules contain granular medicinal substances such as lactose, sugar, sorbitol mannitol, starch (eg potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal application may be in the form of suppositories in which the drug is mixed with neutral fatty bases or in the form of rectal gelatin capsules in which the drug is mixed with vegetable or paraffin oils.

Liquid formulations for oral application are in the form of syrups or suspensions, for example containing about 0.2-20% (by weight) of the active substance and a balanced solution of sugar and a mixture of ethanol, water, glycerol and propylene glycol. . The liquid formulations contain carboxymethyl cellulose as a pigment, flavor, saccharin and diluent at will.

Parenteral liquids by injection may be prepared in the form of an aqueous solution containing a pharmaceutically acceptable water-soluble salt of the drug substance at a concentration of about 0.5-10% (% by weight). The liquids may contain stabilizers and / or buffers and may conveniently be prepared in ampoules of multiple dosage units.

A therapeutically suitable daily dose of a compound of the invention is 25-250 mg (preferably 50-150 mg) in oral administration and 5-50 mg (preferably 10-30 mg) in parenteral administration. The dosage unit dosage form for oral administration contains 10-50 mg (preferably 10-20 mg) of the active substance per dosage unit.

Formulations for oral administration, such as tablets or granules, preferably contain the active ingredient in the form of dihydrocollide monohydrate.

The invention is further illustrated by the following examples and is not limited thereto.

Preparation of starting materials and reaction intermediates for starting materials.

Example 1

1- (4-bromophenyl) -1- (3-pyridyl) -ethanol

48.8 g (0.206 mol) of 1,4-dibromobenzene was dissolved in 200 ml of ether-petroleum ether (40-60 ° C.-toluene = 7: 1: 1 and transferred to a dropping funnel, 4.88 g of magnesium 0.20 mole) was covered with 15 ml of the above solution, to ignite Grignard, three drops of iodine and methyl iodide were added and the mixture was stirred under argon.

After purification, the remaining dibromobenzene solution was added at a rapid reflux rate. This process took 15 minutes and the reaction temperature was 36-38 ° C. After complete addition the reaction mixture was stirred for a further 60 minutes at room temperature and cooled to 18-20 ° C. 18 g (0.15 mol) of 3-acetylpyridine was dissolved in 80 ml of ether, and the reaction temperature was added at a rate not exceeding 25-27 ° C.

Then the reaction was allowed to proceed for 1 hour at room temperature and cooled to 15 ° C. 25 ml of 25% ammonium chloride was added dropwise and the clear reaction solution was separated from the precipitate. The precipitate was washed with 200 mL of hot MIBK containing 10 mL of 25% ammonium chloride, filtered and further washed with 50 mL of MIBK. The combined organic solvents were extracted four times with 100 mL of 1N hydrochloric acid, the aqueous layer was neutralized with 30% sodium hydroxide, and then extracted four times with 100 mL of methylene chloride. The organic layer was evaporated. 42 g of the crude product were dissolved in 60 ml of ethanol and 20 ml of concentrated hydrochloric acid was added dropwise. About 40-50 mL of ether was added and then 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol-hydrochloride was determined. The product was collected by filtration and dried. Yield 25.4 g (54%) Melting point 191 ° -194 ° C A small amount of the sample was further crystallized from ethanol and the melting point was 199 ° -200 ° C. Extracted with carbonate-methylene chloride and crystallized from toluene-petroleum ether to give 90-95% organic base. Melting point 104-105 ℃

Different amounts of 3-acetyl-pyridine were repeated with the same amount of solution and reagents. The amounts and yield of 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol-hydrochloride are as follows.

Example 2

1- (4-bromophenyl) -1- (3-pyridyl) -ethene

Dissolving 101 g (0.32 mol) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol hydrochloride in 280 ml of acetic anhydride was heated at 130 ° C. under reflux and argon in a closed system. The solution was cooled to 90 ° C. and 4 ml of 6N hydrochloric acid was added dropwise. The reaction solution was cooled to room temperature and 400 ml of dropwise ether was added under stirring to complete the precipitation. This precipitate was filtered off, washed with ether and dried. 85 g (89%) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene-hydrochloride were obtained. Melting point 230-233 ° C. Extraction with carbonate-methylene chloride gave the organic base in oil form. The boiling point of the free base after crystallization of boiling point 115-120 ° C./0.1 Torr was 44.5 ° -46.5 ° C.

Example 3

1- (4-bromophenyl) -1- (3-pyridyl) -ethanol

187 ml of thionyl chloride was added to 50 g (0.406 mol) of nicotinic acid to the extent that reaction temperature was maintained at 40 degreeC on an ice bath. The mixture was heated at 40 ° C. for half an hour, at 50 ° C. for 1 hour and at 70 ° C. bath temperature for 1 hour and a half.

Excess thionyl chloride was distilled off under reduced pressure and the suspension was cooled. 100 ml of ether was added and the crystals were filtered. 68 g of nicotinic acid chloride hydrochloride were obtained. Yield 94%.

14.24 g (0.08 mol) of nicotinic acid chloride-hydrochloride were suspended in 70.65 g (0.45 mol) of bromobenzene. 26.7 g (0.2 mol) of aluminum trichloride were added with stirring well so that the reaction temperature did not exceed 35 ° C. At the end of the addition, the reaction temperature was dropped to about 30 ° C. The mixture was then heated at a bath temperature of 80 ° C. for 45 minutes. Hydrogen chloride gas emissions started at 70 ° C and the color changed from dark yellow to dark reddish brown. The solution was stirred at a bath temperature of 80 ° C. for 17 hours.

The warm mixture was poured into 600 g of ice crusher containing 16 ml of concentrated hydrochloric acid. The organic layer was separated and the acidic aqueous layer was extracted three times with ether. The aqueous portion was basified with 50% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated to afford 17 g of crude product.

The crude product contained 4-bromophenyl- and 2-bromophenyl-3-pyridineketone. 4-bromophenyl compound was crystallized from toluene-hexane. Crystal melting point of 10.5 g 120-125 ℃ yield 50%

10.8 g (41.2 mmol) of 4-gain bromophenyl-3-pyridylketone was added to 60 ml of an ethereal solution containing 60 mmol of methylmagnesium bromide with stirring so that the reaction temperature was maintained at 5 ° C. The reaction mixture was stirred at room temperature for 1 hour. After adding 20 mL of THF, the reaction mixture was heated to 40-45 ° C. for 4.5 h. Up to this point almost all ketones reacted.

The reaction mixture was poured onto ice and the organic layer was separated. The aqueous solution was extracted with methylene chloride. The organic phase was washed with saturated brine, dried over magnesium yellow and evaporated. 12 g of residue was crystallized from toluene / petroleum ether. 10.45 g of 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol was obtained in the form of white crystals having a melting point of 104-106.5 占 폚. Yield 91%

Preparation of the final product

Example 4

Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine

2.6 g (10 mmol) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene, 2.6 g (31.9 mmol) of dimethylamine hydrochloride 0.6 g (20 mmol) of paraformaldehyde and 4.5 mL of acetic acid Heated to 115 ° C. under argon. Acetic acid was distilled off under reduced pressure when the solution became clear. After the reaction for 2 hours, 1.3 g (15.95 mmol) of dimethylamine-hydrochloride and 0.4 g (13.2 mmol) of paraformaldehyde were further added. After reacting for a total of 5 hours, all acetic acid was removed as much as possible and the reaction solution was cooled to 80 ° C.

20 ml of water and 5 ml of 2N hydrochloric acid were added and the solution was cooled. The aqueous solution was extracted three times with 20 ml of chloroform and the chloroform layers were washed with bicarbonate, dried over magnesium sulfate and evaporated. The residue was dried at 40 ° C./100 Torr to recover 1.15 g (4.45 mmol, 44.5%) of unreacted 1- (4-bromophenyl) -1- (3-pyridyl) -ethene. The aqueous layer was basified with 30% sodium hydroxide and extracted three times with 25 ml of methylene chloride. The organic layers were washed with saturated brine, dried over magnesium sulfate and evaporated.

The dark brown residue was dried at 40 ° C./100 Torr and filtered over 2.5 g of activated carbon with hot ethanol. Ethanol was evaporated to give 1.65 g of crude product. This acetic acid was dissolved in 15 ml of an ethanol-ether (1: 1) solution, and 1 ml of concentrated hydrochloric acid was added dropwise. Ether (about 3-5 mL) was added dropwise while stirring continued until the solution became cloudy.

Crystallization easily occurred and the suspension was left at room temperature for 2-3 hours. Filtration and colorless crystals gave 1.15 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine-dihydrochloride. Melting point 185 ° C.-187 ° C. The reaction product was recrystallized from 50.5% ethanol to obtain 1.02 g (44.7%) of the compound. Melting Point 193-196 ℃

Example 5

1- (4-bromophenyl) -1- (3-pyridine) -ethene 80.0 g (0.308 mole) paraformaldehyde 22.6 g (0.745 mole), dimethyl amino-hydrochloride 123.0 g (1.51 mole), hydrokinone 50 mg And 8.0 g of molecular sieves of 3A were heated to 115 ° C. under argon in 123 ml of acetic acid. After 2 hours, 35 ml of acetic acid was removed.

The reaction was run for a total of 6 hours. All the acetic acid was distilled off and then 400 ml of 0.5N hydrochloric acid was added. Extraction with chloroform (five times with 200 mL) recovered 49.5 g, 62% of unreacted starting material. The aqueous solution was neutralized with 30% sodium hydroxide and extracted with methylene chloride (five times with 200 ml) to give a crude product 34 g.

This brown oil was filtered over 60 g of activated carbon with hot ethanol. Ethanol was removed to about 150 mL, ether 150 mL was added and 14 mL concentrated hydrochloric acid was added dropwise. Crystallization gave 19.8 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine-dihydrochloride having a melting point of 187 ° -191 ° C.

Example 6

18.0 g (60.7 mmol) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene hydrochloride, 7.2 g (240 mmol) of formaldehyde, 40.0 g (490 mmol) of dimethylamino-hydrochloride and acetic acid 19 mL was heated to 115 ° C. under argon. 2.4 g (30 mmol) of sodium acetate was added and the reaction proceeded for 7 hours. If possible, all acetic acid was removed (approx. 8 ml) and 140 ml of 2N hydrochloric acid was added when the temperature of the reaction solution dropped to 80 ° C. This suspension was cooled and left overnight.

Filtration recovered 7.55 g (42%) of unreacted starting material. The filtrate was further diluted with 30 mL of water and extracted three times with 70 mL of chloroform. Washed with chloroform bicarbonate, dried and evaporated to further recover 1.65 g (10.4%) of unreacted starting material in the form of free base.

30% of the acidic brown aqueous solution was basified with sodium hydroxide and extracted four times with 50 ml of methylene chloride. The combined organic layers were dried and evaporated to give 9.6 g of crude product. The crude product was dissolved in ethanol and warm filtered over 8 g of activated carbon. Ethanol was removed to make a solution of about 50 ml, and 70 ml of ether and 4.6 ml of concentrated hydrochloric acid were added. 6.0 g of precipitate was filtered off and dried. Melting point 185-187 ° C Recrystallization from ethanol yielded 5.15 g of ZN, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine-dihydrochloride having a melting point of 195-198 ° C. .

Example 7

50.0 g of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene-hydrochloride, 0.5 g (0.349 mol) of paraformaldehyde, 57.0 g (0.349 mol) of dimethylamino-hydrochloride and 50 ml of acetic acid The mixture was heated to 115 ° C. under argon with gentle stirring. 12.0 g (0.147 mol) of sodium acetate was added 2 g at 5 minute intervals. After 4 hours, 4.0 g (0.133 mol) of paraformaldehyde and 25 ml of fresh acetic acid were further added.

After 4.5 hours all acetic acid was removed. The mixture was cooled to 80 ° C. and 80 ml of water and 10 ml of 6N hydrochloric acid were added. The cooled reaction solution was finished as in Example 6. Filtration recovered 17.6 g (35.2%) of unreacted starting material. Extraction with chloroform gave 5.4 g (12.3%) of unreacted starting material in the form of free base. Crystallization gave 14.9 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine-dihydrochloride having a melting point of 184 ° -187 ° C.

Example 8

11.12 g (40 mmol) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol was heated to 130 ° C. under argon in 20 ml of acetic anhydride containing 0.65 ml of concentrated sulfuric acid. (Sulfate was previously added to acetic anhydride at 0 ° C.)

In order to cool the reaction solution to 65 ° C. and destroy unreacted acetic anhydride, 2.95 g of water was added dropwise at a rate capable of maintaining the reaction temperature at about 80-0 ° C. After cooling, 13.04 g (160 mmol) of dimethylamino-hydrochloride and 2.4 g (80 mmol) of paraformaldehyde were added. This suspension was heated to 115 ° C. and all acetic acid was removed. After 3 hours, 1.0 g (33 mmol) of paraformaldehyde and 25 ml of acetic acid were added. After 3.5 hours the acetic acid was removed again. After 6 hours of reaction time, the reaction was stopped, and 18 ml of water was added and 6N hydrochloric acid was appropriately added to lower the pH to 1. The finishing treatment was the same as in Example 6.

Filtration gave 1.4 g (12%) of 1- (4-bromophenyl) -1- (3-pyridyl) -ethene-hydrochloride and extracted with chloroform to slightly impure 1- (4-bromophenyl) -1 1.345 g (13%) of-(3-pyridyl) -ethene was recovered and converted to 1.1 g (72%) of its hydrochloride. A total of 2.5 g (21.5%) of salt was recovered.

8.74 g of crude product was dissolved in ethanol and warm filtered over 20 g of activated carbon. This clear crude product was dissolved in 60 mL of ethanol-ether (1: 1), treated with 1.2 g of hydrochloric acid, and then dissolved in 10 mL of ethanol. The first crystallization yielded 4.85 g having a melting point of 184 ° -187 ° C. A second crystallization yielded 4.55 g with a melting point of 193 ° -196 ° C.

Example 9

5.56 g of 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol was reacted in the same manner as in Example 8. 2.22 g (42.7%) of unreacted 1- (4-bromophenyl) -1- (3-pyridyl) -ethene was recovered. 1.785 g (49%) of ZN, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine-dihydrochloride having a melting point of 189 ° -194 ° C Got it.

Claims (1)

A product formed by reacting a compound of formula (II) or a salt thereof with an excess of formaldehyde and dimethylamine or formaldehyde in an organic solvent under acid catalysis, if necessary, into one of its geometric isomers A process for preparing N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine of formula (I) below characterized by conversion or separation.