FI67696C - PROCEDURE FOR FRAMSTATION OF AV N, N-DIMETHYL-3- (4-BROMOPHENYL) -3- (3-PYRIDYL) -ALLYLAMINE HYDROCHLORIDE MONOHYDRATES WITH ANTIDEPRESSIVE NETWORK - Google Patents

Description

γγ »ι ANNOUNCEMENT / 17 / Q /; ^ B] (11) UTLÄGGNINGSSKRIFT 0/69 6 c (45) I; “I: '.,;.; Ϊ́0χly ~ 5 ^ ^' (51) Kv.lk. * / Lnt.CI. * C 07 D 213/38 SUOMI FINLAND (21) Patent application - Patentansökning 771591 (22) Application date - Ansökningsdag 19.05.77 (EN) (23) Starting date —Giltighetsdag 19.05.77 (41) Has become public - Blivit offentlig 22.11 .77

National Board of Patents and Registration Date of publication and publication. -

Patent and registration authorities'; Ansökan utlagd och utl.skriften publicerad 31.01.85 (32) (33) (31) Pyydetty etuoikeus - Begärd priority 21.05-76

Sweden-Sweden (SE) 7605780-1 (71) Astra Läkemedel Aktiebolag, S — 151 85 Södertälje, Sweden-Sverige (SE) (72) Thore Oskar Värner Rydh, Södertälje, Carl Bengt Johan Ulff, Södertälje,

Sweden i-Sverige (SE) (? K) Berggren Oy Ab (54) Method for depressant N, N-dimethyl-3- (4-bromo-phenyl) -3 '(3-pyridyl) -α-ethylamine The present invention relates to a process for the preparation of an antidepressant network. The present invention relates to a process for the preparation of antidepressants in the preparation of an hydrochloride monohydrate. To prepare N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate.

It is an object of the invention to provide a compound which has improved storage properties and which can be prepared in an advantageous manner compared to the corresponding previously known compounds.

Belgian Patent No. 781,105 discloses the general formula r2 / ch3

R f ^ C = CHCHnN I

Compounds wherein R and R are selected from the group consisting of H, Cl and Br and wherein the pyridyl group is attached at the 2-, 3- or 4-position. Among other compounds, compound 2 67696 is specifically mentioned

X1 / CH3

x'c = chch2n II

Xch3 anhydrous dihydrochloride of therapeutic value in the treatment of depressive disorders.

According to said literature reference, an anhydrous compound is obtained from the corresponding base in ether ether by feeding dry HCl. It has been found that in the purification of a compound by separation and drying, a considerable proportion of the anhydrous compound is, to the greatest extent, unsuitable for the preparation of pharmaceutical preparations. Corresponding compounds have crystallization of the dihydrochloride from ethanol known from the literature reference. This procedure gives ethanolate. However, it has been found that a significant amount of solvent remains upon purification of this compound by separation and drying. To remove this solvent, drying at about 90-100 ° C for about 1-2 days is required.

These conditions, which are uncomfortable as such, can still cause the product to discolor and disperse. The anhydrous compound is not suitable for the preparation of pharmaceutical preparations such as tablets due to its hygroscopic properties. During storage, the anhydrous compound absorbs moisture, forming hard cakes that must be crushed before further processing.

The disadvantages associated with the previously known compound have been successfully overcome by the present invention, which provides for use as a novel compound the dihydrochloride monohydrate of the compound of formula II above, i.e. N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine. dihydrochloride monohydrate.

The compound of the invention exists in two stereoisomeric forms, i.e., the E-form and the Z-form. The therapeutic properties of the compound are mainly in one of the isomers mentioned, namely the Z-isomer. Thus, a preferred embodiment of this invention is Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -alkylamine dihydrochloride raonohydrate of formula III.

II

3 67696 "ΧΧ

· 2HC1 · Η20 HI

^ CH 2 N (CH 3) 2

Pharmaceutical preparations of the novel compound form another preferred aspect of the invention. Thus, the compound can be mixed into various forms of solid pharmaceutical preparations, such as tablets and granules. Suitably the compound is mixed with pharmaceutical preparations for oral use. Usually the active substance constitutes 0.1 to 95% by weight of the preparation, in particular 2 to 50% by weight for preparations suitable for oral use.

To prepare pharmaceutical preparations containing a compound of the invention in unit dosage form for oral use, the selected compound may be mixed with a solid powdered carrier, e.g., lactose, sucrose, sorbitol, mannitol, , calcium stearate or polyethylene glycol waxes and then compressed to form tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, acacia, gelatin, talc or titanium dioxide. Alternatively, the tablet may be coated with a varnish dissolved in a mobile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to separate tablets containing different active ingredients or different amounts of active compound.

rectal dosage units intended for use can be prepared as suppositories, contain the active substance mixed with a neutral fat base material, or rectal gela-capsules which contain the active substance in admixture with vegetable oil or paraffin oil.

The compound of the invention can be prepared as follows: 4 67696 a) N, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine is reacted as a solution with aqueous hydrogen chloride and the precipitate formed is collected. , or b) anhydrous N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine dihydrochloride is reacted as a solution with water and allowed to crystallize.

The starting material a) of the above reaction can be obtained aa) by dehydrating a compound of formula Br

Av / 0H

/ CH 3

A J XCH „CH„ N V

I 2 2 \ CH3

Dehydration can be accomplished by treatment with sulfuric acid and heating the reaction mixture, other types of acid catalysis, or catalysis using a solid dehydration catalyst at a temperature of 300-500 ° C.

ab) alkylating dimethylamine with a compound of formula λ Br

iJL LJ

c \\

CHCH 2-y

wherein Y is leaving to form a compound of group formula II.

Illustrative examples of Y are halogens such as Cl,

Br and J or sulfonates such as methanesulfonate, toluene sulfonate and benzenesulfonate.

67696 ac) by mono- or dimethylation of a compound of formula

Ok χτ

II

CHCH2NH-R

wherein R is CH 2 or H.

The starting material for the above reaction b) can be obtained by treating a compound obtained according to one of the reactions aa), ab) or ac) with dry Helium.

An isomerically pure product, e.g. the preferred isomer of formula III, can be obtained either by isomer separation or resolution of the isomer mixture of the final product, starting material or intermediate of a reaction step, provided that a double bond of the final product is present in said starting material or intermediate and is not cleaved in subsequent reactions.

Example 1 90 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine were dissolved in acetone (900 ml) and 2 equivalents of concentrated hydrochloric acid were added under cooling. After cooling at about 0 ° C for 1 hour, the precipitate was filtered off and washed with acetone. Recrystallization was performed from isopropanol (800 mL) and water (15 mL).

(Z) -N, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate was obtained after washing with isopropanol and drying at about 50 ° C. Sp. 195-200 ° C (decomposed). Karl-Fisher analysis showed a water content of 4.4% by weight.

The IR spectrum was obtained by the KBr tablet technique (1 mg in 250 mg KBr). Areas: 4000-650 cm Device: Perkin-Elmer IR Spectrometer.

Significant absorption (generally less than 50% transmittance) was measured at the wavelengths shown below along with their assumed corresponding components.

67696 6

Wave number “.

_ · ^ Component _cm_

3300 water OH

2600-2400 ammonium 1650 carbon double bond (transmittance 60%) 1490 and 1470 aromatic double bonds 820 disubstituted benzene NMR spectrum was obtained from a solution of 100 mg of the compound in 0.5 ml of deuterium oxide. Tetramethylsilane (TMS) was used as an internal standard. Device: Varian T 60 (60 MH2). The chemical cycles are as follows:

Proton Chemical sequence (ppm) A 3.12 B 4.12 C 4.88 D 6.73 E 7.23-7.84 F 8.24-8.87 G 8.90-9.30 0 (ψ) ® © · 2HC1 · H20 © © H® p® CH, CH-> ® ®

Example 2 30.06 g of crude N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine were dissolved in 300 ml of ether and 95 ml of 2.6 N HCl in ether were added. The crude anhydrous dihydrochloride was obtained, which

II

7,67696 was filtered and vacuum dried. The anhydrous dihydrochloride was dissolved in 150 ml of isopropanol and 4 ml of water (5 equivalents) under heating and the product was allowed to crystallize. Yield 20 g of (Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate. Karl Fisher analysis showed a water content of 4.5% by weight.

Example 3: Preparation of intermediates

Step 1: 1- (4-Bromophenyl) -3-dimethylamino-1-propane This compound was prepared by reacting 4-bromoacetophenone with paraformaldehyde and dimethylamine hydrochloride in a conventional Mannich reaction.

Step 2: 1- (4-Bromophenyl) 1- (3-pyridyl) -3-dimethylamino-1-propanol-3-pyridyllithium intermediate formed by treating 3-bromopyridine with butyllithium in ether at low temperature was treated with 1- (4-bromophenyl) ) -1-dimethylamino-1-propanol dissolved in ether to give 1- (4-bromophenyl) -1- (3-pyridyl) -3-dimethylamino-1-propanol.

The reaction mixture was hydrolyzed with ice and water, the aqueous phase was extracted with methylene chloride at pH 4, followed by ether extraction at pH 10. The residue after evaporation was triturated with a mixture of petroleum ether and ether. The crystalline product was recrystallized from isopropanol.

Step 3: N, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine

The product from step 2 was dehydrated with acetic anhydride and sulfuric acid. The reaction mixture was poured onto ice and the aqueous phase was extracted with ether at pH 10. Evaporation of the solvent gave a base.

comparison Tests

Stability at constant humidity and room temperature The compound of the invention was compared with the corresponding anhydrous dihydrochloride and dihydrochloride containing one equivalent of ethanol.

8 67696

table 1

Weight at various relative humidities after storage Relative humidity_Monohydrate_Anhydrous_Ethanolate 40% unchanged increased 4.6% decreased 5% (1 week) (1 day) (4 days) 60% unchanged increased 4.6% decreased 4% (1 week) (1 day) (5 days) 90% increased 12% increased 50% unchanged (8 h) (1 week) (6 days) ha- increased 11% divided (4 days)

Result: The monohydrate is stable at 40 and 60% relative humidity at room temperature, under which conditions the anhydrous compound and ethanolate are not stable.

Stability in vacuum drying

Ethanolate: Drying at 110 ° C for approximately 24 hours was required to reduce the amount of ethanol below an acceptable level of 0.5%. Increased turbidity after drying, color (A4Q5nm = 0.165) and extra spots in the thin layer chromatogram indicated dispersion.

Monohydrate: Approximately 2-4 hours of drying at 40 ° C was required to obtain a product suitable for the preparation of solid pharmaceutical preparations. Degradation could not be detected by examination of turbidity, color, or thin layer chromatogram. After 6 days of storage at 45 ° C, A.nc- = 0.05.

J 405nm 67696 An uptake of this compound is obtained for the preparation of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine dihydrochloride monohydrate with an antidepressant network.

Ändamälet med upffinningen är atthälla en förening somar förbättrade lagringsegenskaper och som kan framställas pä ett fördelaktigt sätt jämfört med, nidigare kända föreningar.

According to Belgian Patent No. 781,105, there are all different forms of r1 \ / ch3 1 R2 ^ C = CHCH2nC ^ ^ CH3 ^ N '1 2 kända, colors R and R are dominated by groups H, Cl and Br, and colors pyridyl groups are bundled in the 2-, 3- or 4-position.

The specificity of this is that of the water in the form of dihydrochlorides of 1 H / CH 3 N, C = CHCH 2 N.

^ 1 'XcH3 is used therapeutically in the treatment of depressive disorders.

However, these references may be used for the purpose of determining the basis for the determination of the genome of HCl. In this case, it is possible to use genomic separation and digestion for the purpose of obtaining genomics for the purposes of the present invention. For this purpose, crystallization from the dihydrochloride of ethanol is carried out as a reference. The genome of the compound is ethanolate. If the emellers are to be used for uptake of the genomic separation and torking of the quarry and the envelope of the playing field. For the averaging range, the temperature is maintained between 1-2 and 67696 ° C and a temperature of 90-100 ° C. In this case, it is considered to be in good condition, which means that the product is present and the product falls off. The use of such products is also possible for the production of pharmaceutical products in the form of tablets, which are the subject of hygroscopic devices. Vid lagring absorberar den vattenfria föreningen fuktighet account bildning av härda kakor, vilka mäste brytas upp före vidare behandling.

The compounds of this form are further prepared from the addition of a compound of formula II, such as N, N-dimethyl-3- (4-bromine). pyridyl) -allylamine dihydrochloride monohydrates.

For example, the stereoisomer exists in the former, i.e., in the E-form and in the Z-form. The therapeutically exemplary group is preferably an isomer of these isomers, the Z-isomers being present. For example, Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate is used as the compound of formula III.

· 2HCl · H 2 O III

CH2N (CH3) 2

Pharmaceutical research is based on the above-mentioned aspects of the active pharmaceutical market. For example, the former is present in the former pharmaceutical product as a tablet or granulate. The same conditions apply to pharmaceutical preparations for oral administration. It is possible for assets to be active at 0.1 to 95% of the price, with a specific value of 2 to 50% in the case of oral administration.

For the purposes of oral pharmaceutical processing, in the case of oral administration in the form of oral administration, which may be used for the manufacture of fast powders.

II

11 67696 bärare t.ex. lactose, sackose, sorbitol, mannitol, starch or potassium starch, corn starch or amylopectin, cellulose derivatives, or gelatin, and magnesium stearates, calcium stearates or polyethylene glycol extruders, In the case of tablets which form part of a frying sphere, it is indicated that the average quantity of the product is concentrated in the t.ex. gum arabic, gelatin, talc or titanium dioxide. Alternatively, the tablets may be coated or leached with an organic lozenge or bleached with an organic lozenge. For the first time, the account was taken for the duration of the contract.

Doseringsenheter for the rectification of the active substance in the form of a mixture of active substances with a neutralizing agent, or a rectal gelatin capsule with an active substance in the bleaching of a vegetable or paraffinic oil.

For example, the addition of basic N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamin with the addition of chlorinated chlorine, and the addition of the same is preferred. the dihydrochloride monohydrate is used, or b) a solution of the N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine in water and crystallization.

Reactive material for the reaction a) ovan kan erhällas aa) genomic dehydration in the first step

Br ^

/ 0A

C CH

/ v / - \ ✓ 3 ^ V xch2ch2nx> -N ^ CH3

Dehydration can be carried out on the genome by means of a reaction and uptake of the reaction reaction, the genome being either 12 to 67696 by syrupation or by genomic catalysis with a fast dehydration catalyst at a temperature of 300-500 ° C.

ab) genomic alkylation of dimethylamine with an enligt form of Br Q. o

CHCH 2-y

color Y is a group of images for the purposes of Formula II.

Belysande exempel pä Gruppen Y är halogener säsom Cl, Br, I eller sulfonater säsom methanesulfonat, toluensulfonat och bensensulfonat.

(ac) genomic mono- or di-methylation of a compound of formula

CHCH2NH-R

color R är CH ^ eller H.

Reagents for the reaction b) can be used in the genome to react with the reaction of aa), ab) or ac) with HCl.

The isomer product t.ex. The preferred isomers of formula III are different genomic isomerseparations or alternatives to the isomeric products, and the reaction materials or the by-products are reacted, it is supposed to be a reaction.

13 67696

Exempel 1 90 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine are taken up in acetone (900 ml) and 2 equivalents of concentrated salt are added under stirring. After cooling to 0 ° C and then filtering with acetone. The crystallization was carried out from isopropanol (800 ml) and water (15 ml). (Z) -N, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine dihydrochloride monohydrate is added after treatment with isopropanol and heating at 50 ° C. Smp. 195-200 ° C (sönderfall). Karl Fisher's analysis shows that the water content is 4.4 wt%.

The IR spectrum was determined using KBr pellet techniques (1 mg to 250 mg -1 KBr). Omraden: 4000-650 cm. Instrument: Perkin-Elmer IR Spectrometer.

The absorption markers (all of which are 50% transmittance) are determined to be negligible without the use of a structural element.

Vagtal Strukturelement -1 cm _ 3300 OH i vatten 2600-2400 Ammonium 1 650 To double band (transmittance ~ ^ 60%) 1490 and 1470 Aromatic, double band 820 Disubstituted benzene

The NMR spectrum was determined to be 100 mg with 0.5 ml of deuterium oxide. Tetramethylsilane (TMS) is an internal standard. Instrument: Varian T 60 (60 MH2). The chemical skins are also used in foliar.

Proton Chemical Scale (ppm) A 3.12 B 4.12 C 4.88 D 6.73 E 7.23-7.84 F 8.24-8.87 G 8.90-9.30 1 4 67696

Br A o ^ © © Γ ® © \ x © • 2HC1 · H20 / \ © © © Λ CH2 © @ ch3 / N \ ch3 ® ®

Exempel 2 30.0 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine are taken up in 300 ml of ether and 95 ml of 2.6N HCl in ether.

The products are treated with dihydrochlorides, filtered and vacuum-charged. The water dihydrochloride is taken up in 150 ml of isopropanol and 4 ml of water (5 eq) are added and the product is crystallized. 20 g of (Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine dihydrochloride monohydrate are obtained. Karl Fisher's analysis was performed at 4.5 wt%.

Exempel 3; Framställning av mellanrpodukter Steg 1: 1- (4-bromophenyl) -3-dimethylamino-1-propane

For example, 4-bromoacetophenone with paraformaldehyde and dimethylamine hydrochloride is reacted in a conventional Mannich reaction.

Step 2: 1- (4-Bromophenyl) -1- (3-pyridyl) -3-dimethylamino-1-propanol Mellan products of 3-pyridyllithium, which are genomically treated with 3-bromopyridine with butyllithium in ether at room temperature, are treated with 1- (4-bromophenyl) -1-dimethylamino-1-propanone, ether, 1- (4-bromophenyl) -1- (3-pyridyl) -3-dimethylamino-1-propanol.

The reaction hydrolysis is carried out with water and water, the water is extracted with methylene chloride at pH 4, and the ether extraction is carried out at pH 10. The reaction is then carried out with petroleum ether and ether. The product was crystallized by crystallization from 1 5 67696 ur isopropanol.

Step 3: N, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine The products of Step 2 are dehydrated with acetic anhydride and the like. Reaction conditions are maintained at the head and in the form of water extracts with a pH of 10. The reaction is preferably carried out on a base.

Jämförelseförsök

Stability at constant equilibrium and rum temperature For the addition of a mixture of water and the dihydrochloride and dihydrochloride in a solution of 1 eq. ethanol.

Table 1

Vikt efter lagring vid olika relativ fuktighet

Relativ fuktighet Monohydrat_Vattenf ri_Etanolat__ 40% oförändrad (1 vecka) ekad 4,6% (1 dygn) minskad 5% (4 dygn) 60% oförändrad (1 vecka) ekad 4,6% (1 dygn) minskad 4% (5 dygn) 90% furrows 12% (1 fence) furrows 50% (6 furrows) of furrows (8 h) sönderfluten furrows 11% (4 furrows)

Result: The monohydrate is stable at 40 to 60% relative performance at rum temperature, under vigorous equilibrium with water and ethanol in stable.

Stability in vacuum loading

Ethanol: Melting at 110 ° C for 24 hours is allowed to add ethanol to 0.5% at room temperature. After torkning antyddes sönderfall av ökad turbiditet, färg ^ A405nm = 0/165) och extra fläckar pä TLC.

Monohydrates: Melting at 40 ° C and 2-4 times the temperature of the product and the product are obtained from the pharmaceutical industry. Sönderfall kunde icke upptäckas genom att Studera turbiditet, färg eller TLC. After drying at 45 ° C for 6 hours, A405nm = 0.05.

Claims (7)

16 67696 A process for preparing an antidepressant N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate, characterized in that a) N, N-dimethyl-3- (4- bromophenyl) -3- (3-pyridyl) allylamine base is reacted as a solution with aqueous hydrogen chloride and the precipitate formed is collected, or b) anhydrous N, N-dimethyl-3- (4-bromophenyl) -3- (3 -pyridyl) -allylamine dihydrochloride is reacted as a solution with water and allowed to crystallize. Process according to Claim 1, characterized in that 7-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate is prepared. Process according to Claim 1 or 2, characterized in that a polar solvent, such as acetone, is used in process a). Process according to one or more of Claims 1 to 3, characterized in that process a) is carried out under cooling. Process according to one or more of Claims 1 to 4, characterized in that the aqueous hydrogen chloride used in process a) is concentrated hydrochloric acid. A process for the preparation of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate with an antidepressant network, which comprises a) N, N-dimethyl-3 - (4-bromophenyl) -3- (3-pyridyl) -allamine and reacting with water-containing chlorates and the corresponding surface form, or b) water-N, N-dimethyl-3- (4-bromophenyl) -3- ( 3-Pyridyl) -allyl-amine dihydrochloride is preferably added to the water and crystallized. A compound according to claim 1 is converted to Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allamine dihydrochloride monohydrate.