DK145571B - BETA NITROSTYRENE DERIVATIVE USED AS INTERMEDIATE IN THE PREPARATION OF 4-AMINOAM-FETAMINE DERIVATIVES - Google Patents

Description

as) DENMARK (^)

É | mi PRESENTATION WRITING on 145571B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 4l / 76 (51) | nt.CI.3 C 07 C 87/50 (22) Filing day 7 · j & n- 1976 C 07 D 215/12 (24) Race day 3 · sep · 1974 (41) ) Aim. available Jan. 7 1976 (44) Presented 13 · Dec. 1982 (86) International application no.

(86) International Filing Day (85) Continuation Day "(62) Application No. 4647/74

(30) Priority Sep 4 1 973j 7312002, SE

(71) Applicant ASTRA LEKEMEDEL SHARE COMPANY, S-151 85 Soedertaelje, SE.

(72) Inventor Goesta Lennart Florvall, SE: Svante Bertil Ross, SE: Sven-Ove Oegren, SE.

(74) Clerk of the Office of Industrial Excellence v. Svend Schønnlng.

(54) Beta-nitrostyrene derivative for use as an intermediate in the preparation of 4-aminoampheta = minor derivatives.

The present invention relates to an intermediate product for use in the preparation of novel 4-aminoampheteta derivatives of the kind disclosed in Danish Patent Specification No. 139716.

The intermediate according to the invention is peculiar in that it has the general formula

LO I

UD CH = C-NO2

-, _A

ISLAND

Wherein R and R, which are the same or different, are each a hydrogen atom, an alkyl group having 1-5 carbon atoms or a 3 halogen atom, R is an alkyl group having 1-5 carbon atoms or a benzyl group, R is a hydrogen atom, an alkyl group having 1-5 carbon atoms, a benzyl group or a bridge bonded to the phenyl ring in the ortho position relative to

C

The N substituent and R is an alkyl group having 1-5 carbon atoms, with the proviso that R and / or R is an alkyl group having 1-5 carbon atoms or a halogen atom when and R .

The intermediate of the invention is useful as a starting material in the preparation of novel 4-amino-amphetamine derivatives having a pharmacological profile that suggests potential value as antidepressants and also as a new type of anxiolytic. These in DK publication no.

The above-mentioned 4-aminoamphetamine derivatives have the general formula R6 CH - C-NH-> />

rj2 - I I

T " '.

or are pharmaceutically acceptable salts thereof, in which the formula R and R, which may be the same or different, are each a hydrogen atom, an alkyl group having 1-5 carbon atoms or 3 a halogen atom, R is an alkyl group with 1-5 carbon atoms 4 or a benzyl group, R is a hydrogen atom, an alkyl group having 1-5 carbon atoms, a benzyl group or a C R 2 is a hydrogen atom or a methyl group and R is an alkyl group having 1-5 carbon atoms, with the proviso that R and / or R is an alkyl group having 1-5 carbon atoms or a halogen atom when R is a methyl group, R is a methyl group and R is a hydrogen atom.

145571 3

Illustrative examples of groups included in the above definitions are alkyl group having 1 to 5 carbon atoms: methyl, ethyl, n-propyl and isopropyl, halogen atom: chlorine, bromine, iodine and fluorine.

Compounds of general formula I can be prepared by reducing the substituted β-nitrostyrene of the invention of formula? 6 CH = C-N00

, A

'A1.

R ^ R

wherein R 1, R 2, R 3, R 4 and R 6 have the previously defined meanings to form a compound of formula I wherein R is a hydrogen atom.

The reduction can be carried out by a suitable reducing agent such as lithium aluminum hydride or by catalytic reduction or by other known reducing agents.

The compounds of the invention of formula II are prepared as follows: R6 CHO CH2 C-NO- ^ 6 R CH2% ΛΑ

r3AR4 / 'CH3COOBH <rAeJ

III II

145571 4

An aldehyde of formula III is condensed with excess nitroalkane, preferably in a suitable solvent, such as, for example, n-propyl alcohol, ethanol, acetic acid or similar solvents, in the presence of a base, e.g., ammonium acetate.

3

Formula III aldehydes wherein R represents an alkyl group of 1 to 5 carbon atoms or a benzyl group and R represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a benzyl group or a C in the ortho position relative to the N substituent, is prepared in a step involving the formylation of the substituted aniline according to the Vilsmeyer-Haack reaction:

CHO

poci 'VS

R2 - I JL> R2 - I

DMF

r3 / S \ r4 '/ r ^^ r4'

The formylation is carried out using a mixture of dimethylformamide and phosphorus oxychloride. The preparation can also be carried out using a mixture of phosphorous tribromide and dimethylformamide (Acta Pharm. Suecica 7, 87, 1970).

Compounds other than dimethylformamide which may serve as formylating agents are, for example, N-methylformanilide or formamide. Catalysts other than phosphorus oxychloride and phosphorus tribromide may be used, for example, thionyl chloride, phosgene or aluminum chloride.

The invention is illustrated in the following by means of some examples.

5 145571

Preparation of the intermediate according to the invention

Example 1. N, N-Dimethyl-3-methyl-4- (2-nitropropenyl) -aniline a) 4-Dimethylamino-2-methylbenzaldehyde 45 ml of phosphorus oxychloride is added dropwise with stirring and cooling on an ice bath to 145 ml of dimethylformamide. 67.5 g of N, N-dimethyl-m-toluidine are added portionwise to the cooled solution. After the addition, the mixture is heated on a steam bath for 2 hours. The dark liquid is cooled and poured into 1.5 l crushed ice. The solution is alkalized with sodium hydroxide. The crude, semi-solid aldehyde (59.6 g) which is separated is collected and purified by recrystallization from isopropyl ether. Yield 28.6 g, m.p.

65-66 ° C, equivalent weight 163 (calculated 163.22).

The compound can also be prepared as follows: dissolve 67.5 g of N, N-dimethyl-m-toluidine in 250 ml of dimethylformamide and add dropwise with stirring and cooling in water 35 ml of phosphorus tribromide. The temperature must not exceed 50 ° C. The mixture is heated for 1 1/2 hours in a steam bath and poured for approx. 1.5 l of an ice / water mixture. The solution is alkalized with sodium hydroxide and the crude product (46.9 g) which is separated is recrystallized from isopropyl ether. Yield 20.5 g, m.p. 63-65 ° C. Another crystallization from the same solvent gives 14.6 g of the pure aldehyde with m.p.

65-66 ° C.

b) N, N-dimethyl-3-methyl-4- (2-nitropropenyl) -aniline.

A solution of 28.0 g of 4-dimethylamino-2-methylbenz aldehyde, 20 ml of nitroethane and 15 g of ammonium acetate in 200 ml of 1-propanol is refluxed for 4 hours. Then the mixture is poured into ice water. The crude compound (30.2 g) is purified by recrystallization from ethanol / petroleum ether. Yield 12.9 g m.p. 75-76 ° C.

145571 6

Calculated for C 12 H 16 H 2 ° C: C 65.44, H 7.32, N 12.72 Found: C 64.7, H 7.38, N 12.7%

Example 2. N, N-Dimethyl-3-chloro-4- (2-nitropropenyl) -aniline

A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 18 ml of nitroethane and 15 g of ammonium acetate in 150 ml of absolute ethanol is refluxed for 2 hours. Then, the mixture is poured into 1.5 L of water and the compound is excreted as a viscous red oil which crystallizes by scraping. Recrystallization from ethanol gives 18.0 g of the compound, m.p. 93-93 ° C.

Calcd for C 11 H 13 ClN 2 O 2: C 54.89, H 5.44, Cl 14.73 Found: C 54.2, H 5.48, Cl 11.5%.

Example 3. N, N-Dimethyl-3,5-dichloro-4- (2-nitropropenyl) -aniline a) N.N-dimethyl-3,5-dichloroaniline

To a mixture of 40.5 g of 3,5-dichloroaniline and 62.0 g of sodium bicarbonate in 200 ml of 50% aqueous dioxane is added dropwise with stirring and cooling in ice 60 ml of dimethyl sulfate over 2 hours. 100 ml of 30% sodium hydroxide solution is then added and the mixture is refluxed for one hour. After filtration, the solution is extracted with ether. The extracts are dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is recrystallized from methanol. Yield 16.5 g, m.p. 53-54 ° C, equivalent weight 193.5 (calculated 190.08).

b) 2,6-Dichloro-4-dimethylaminobenzaldehyde 9 ml of phosphorus oxychloride is added dropwise with stirring and cooling in ice to a solution of 19.0 g of N, N-dimethyl-3,5-dichloroaniline in 29 ml of dimethylformamide. The mixture is heated for one hour in a steam bath and poured into ice. The solution is alkalized with sodium hydroxide and the crude product is filtered off. Yield 18.5 g, m.p. 152-157 ° C. The compound is purified by recrystallization from ethanol / dioxane. Yield 13.9 g, m.p. 167-168 ° C.

Calculated for C CHH C CNO: C 49.56, H 4.16, Cl 32.51, N 6.42, 0. 7.54

Found: C 49.2, H 4.25, Cl 32.6, N 6.27, 0. 7.46%.

c) N, N-dimethyl-3,5-dichloro-4- (2-nitropropenyl) -aniline

A solution of 13.8 g of 2,6-dichloro-4-dimethylamino-benzaldehyde, 7 ml of nitroethane and 10.0 g of ammonium acetate in 100 ml of 1-propanol is refluxed for 24 hours. Then the mixture is poured into ice water. The precipitate is filtered off and washed with water. Yield 16.8 g, m.p. 105-110 ° C. Recrystallization from aqueous ethanol gives 14.4 g of the analytically pure product, m.p. 113-ll4 ° C.

Calcd for C 11 H 12 Cl 2 N 2 ° C: C 48.02, H 4.40, Cl 25.77, N 10.18, 0 11.63

Found: C 47.8, H 4.43, Cl 26.1, N 9.95, 0. 11.6%.

Example 4. N-methyl-β- (2-nitropropenyl) -1,2,3,4-tetrahydroquinoline a) N-methyl-1,2,3,4-tetrahydroquinoline

To a mixture of 100 g of 1,2,3,4-tetrahydroquinoline and 100 g of sodium bicarbonate in 600 ml of 50% aqueous dioxane is added dropwise with stirring and cooling in ice 100 ml of dimethyl sulfate over 2 hours. After the addition, the mixture is stirred overnight at room temperature. Then 200 ml of 30% sodium hydroxide solution is added and the mixture is refluxed for one hour. After filtration, the solution is extracted with ether. The extracts are dried over anhydrous sodium sulfate and the solvent is evaporated. The remaining oil (63.2 g) is distilled. Yield 50.4 g, b.p. 108-110 ° C / 10 mmHg, equivalent weight 148 (calculated 147.22).

b) 6-Formyl-1-methyl-1,2,3,4-tetrahydroquinoline 31 ml of phosphorus oxychloride is added dropwise with stirring and cooling in ice to 100 ml of dimethylformamide. To the solution under stirring and cooling, 50.0 g of N-methyl-1,2,3,4-tetrahydroquinoline are added portionwise. After the addition, the mixture is heated on a steam bath for one hour. The liquid is cooled and poured into crushed ice. The solution is alkalized with sodium hydroxide and extracted with ether. The extract is dried over anhydrous sodium sulfate and the solvent is evaporated. The remaining oil is distilled off. Yield 47.4 g, b.p. 175-178 ° C (6 mmHg, equivalent weight 178) (calculated 175.23).

o) N-methyl-6- (2-nitropropenyl) -1,2,3,4-tetrahydroquinoline

A solution of 47.1 g of 6-formyl-1-methyl-1,2,3,4-tetrahydroquinoline, 24 ml of nitroethane and 20 g of ammonium acetate in 200 ml of 1-propanol is refluxed for 5 hours. Then the mixture is poured into ice water. The precipitated oil is extracted with ether and dried with anhydrous sodium sulfate. Evaporation of the solvent gives 54.8 g of a dark yellow oil which, however, cannot be recrystallized. The product is used directly without further purification in the subsequent step.

Example 5 N, N-Dimethyl-3-bromo-4- (2-nitropropenyl) -aniline a) 2-Bromo-4-dimethylaminobenzaldehyde 14.5 ml of phosphorus oxychloride is added dropwise with stirring and cooling to a solution of 31.6 g N, N-dimethyl-3-. bromaniline in 46 ml of dimethylformamide. The mixture is heated for one hour on a steam bath and poured into ice. The solution is alkalized with sodium hydroxide. The precipitate is filtered off and recrystallized from aqueous ethanol. Yield 19.6 g, m.p. 81-82 ° C.

Calcd for C 9 H 15 BrNO: C 47.39, H 4.42, Br 35.04, N 6.14, 0. 7.01

Found: C 47.1, H 4.38, Br 35.0, N 6.11, 0. 7.40%.

b) N, N-dimethyl-5-bromo-4- (2-nitropropenyl) -aniline

A solution of 19.0 g of 2-bromo-4-dimethylaminobenzaldehyde, 10 ml of nitroethane and 15 g of ammonium acetate in 100 ml of 1-propanol is refluxed for 7 hours. The mixture is then poured into ice water. The precipitate is filtered off and purified by recrystallization from aqueous ethanol. Yield 10.2 g, m.p. 102-103 ° C.

Calcd for C11 H13 BrN2 ° 2: C 46.33, H 4.59, Br 28.03, N 9.82, 0.11.22

Found: C 45.9, H 4.57, Br 28.0, N 9.63, 0 11.3%.

Example 6. N, N-Dimethyl-3-chloro-4- (2-nitro-1-butenyl) -aniline

A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 25 ml of 1-nitropropane and 20 g of ammonium acetate in 150 ml of 1-propanol is refluxed for 15 hours. Then the mixture is poured into 1.5 L of water, which separates the compound as a viscous red oil. Recrystallization 2 times from aqueous acetic acid gives 5.0 g of the compound which melts at 90-91 ° C.

Calcd. For C12 H15 G1 N2 ° 2: C 56.58, H 5.94, U 13.92, N 11.00, 0.12.56

Found: C 56.8, H 5.6, Cl 14.00, N 10.9%.

Use of the intermediate of the invention for the preparation of 4-aminoamphetamine derivatives of formula I

Example 7, 2-Methyl-4-dimethylamino-α-methylphenethylamine dihydrochloride (method a) 12.5 g of N, N-dimethyl-3-methyl-4- (2-nitropropenyl) aniline in 150 ml of dry ether is added to a stirred mixture of 9.1 g of lithium aluminum hydride in 200 ml of dry ether at such a rate that the solvent is boiled slightly under reflux without external heating. The mixture is stirred and refluxed for 5 hours. 50 ml of saturated sodium sulfate solution is added dropwise with vigorous stirring and cooling in ice water. The mixture is filtered and the ether solution is dried over anhydrous sodium sulfate. The dihydrochloride is precipitated from the solution by the addition of ether saturated with hydrogen chloride. The crude salt is purified by recrystallization from ethanol / isopropyl ether. Yield 12.6 g, m.p. 205-207 ° C. Another recrystallization from the same solvent gives 11.0 g of the compound with m.p.

208-209 ° C.

Example 8. 4-Ethylamino-α-methylphenethylamine dihydrochloride (method b) 11.0 g of 4- (2-nitropropenyl) acetanilide dissolved in 150 ml of dry teterahydrofuran is added dropwise to a stirring mixture of 11.0 g of lithium aluminum hydride. 200 ml dry ether. After the addition, the reaction mixture is boiled under stirring and reflux for 4 hours. Carefully add 60 ml of saturated sodium sulfate with stirring and cooling. The mixture is filtered and the ether solution is evaporated. The residue is dissolved in dilute hydrochloric acid and the solution is shaken with ether.

The acidic layer is alkalized with sodium hydroxide and the solution is extracted with ether. After drying over solid sodium hydroxide, the extract is evaporated. The residue is distilled to give 4.7 g of the free base boiling at 97-100 ° C / 0.03 mmHg.

The free amine is converted to the dihydrochloride by dissolving the base in ether and treating the solution with an excess of dry hydrogen chloride. Recrystallization of the precipitate obtained gives 4.8 g of the pure salt which melts at 184-185 ° C.

Example 9. 2-Chloro-4-dimethylamino-α-methylphenethylamine dihydrochloride (Method a)

A solution of 12.0 g of N, N-dimethyl-3-chloro-4- (2-nitropropenyl) aniline in 150 ml of dry teterahydrofuran is added dropwise with stirring to 8.0 g of lithium aluminum hydride in 200 ml of dry ether. After the addition, the reaction mixture is refluxed for 5 hours. 40 ml of saturated sodium sulfate solution are added portionwise and the mixture is filtered. The filtrate is dried with anhydrous sodium sulfate and simmered with hydrogen chloride in ether. The precipitate is removed by filtration and recrystallized from ethanol / isopropyl ether. Yield 9.3 g, m.p. 187-191 ° C. Another recrystallization from the same solvent gives 1.8 g of the pure compound with m.p. 193-195 ° C.

Example 10. 2,6-Dichloro-4-dimethylamino-α-methylphenethylamine-dihydrochloride (Method a)

A solution of 13.7 g of N, N-dimethyl-3,5-dichloro-4- (2-nitropropenyl) aniline in 150 ml of dry tetrahydrofuran is added dropwise with stirring to 8.0 g of lithium aluminum hydride in 200 ml of dry ether. Then the mixture is refluxed for 4 hours.

40 ml of saturated sodium sulfate solution are added dropwise and the mixture is filtered. The filtrate is dried over anhydrous sodium sulfate and sieved with hydrogen chloride. The precipitated salt is filtered off and washed with ether. Yield 15.2 g, m.p. 195-197 ° C. The product is recrystallized from aqueous ethanol / isopropyl ether. Yield 11.9 g, m.p. 199-200 ° C.

Example 11. 6- (2-Aminopropyl) -1-methyl-1,2,3,4-tetrahydroquinoline dihydrochloride (Method a)

A solution of 11.6 g of crude N-methyl-6- (2-nitropropenyl) -1,2,3,4-tetrahydroquinoline in 150 ml dry ether is added dropwise to stir 8.0 g of lithium aluminum hydride in 150 ml ether . The reaction mixture is refluxed for 4 hours.

40 ml of saturated sodium sulfate solution is added dropwise and the mixture is filtered. The filtrate is simulated with hydrogen chloride in ether. Dissolve syrupy product is dissolved in 250 ml of water and alkalized with sodium hydroxide. The solution is extracted with ether and the extract is dried over anhydrous sodium sulfate. The solvent is evaporated and the residual oil is distilled off.

Yield 3.3 g, b.p. 135-137 ° C / 0.07 mmHg. The base is dissolved in ether and the dihydrochloride is precipitated from the solution by the addition of an excess of hydrogen chloride in ether. The precipitated salt is recrystallized from ethanol / isopropyl ether. Yield 3 »3 g, m.p. 221-222 ° C.

Example 12. 2-Bromo-4-dimethylamino-α-methylphenethylamine dihydrochloride (Method a)

A solution of 10.0 g of N, N-dimethyl-3-bromo-4- (2-nitropropenyl) aniline in 100 ml of dry tetrahydrofuran is added dropwise with stirring to 8.0 g of lithium aluminum hydride in 200 ml of dry ether. After the addition, the reaction mixture is refluxed for 4 hours. Then 40 ml of saturated sodium sulfate solution is added portionwise and the mixture is filtered. The filtrate is acidified with hydrogen chloride in ether. The precipitated syrupy product dissolves in water. The solution is washed with ether and alkalized with sodium hydrochloride. The precipitated oil is extracted with ether and the ether extract dried over anhydrous sodium sulfate. The solution is acidified with hydrogen chloride in ether and the semi-solid precipitate is filtered off and recrystallized from ethanol / isopropyl ether.

Yield 8.2 g, m.p. 195-196 ° C.

The table below shows data for some intermediates according to the invention incl. those described in Examples 1-6. The products in this table not exemplified above are made by analogy. The oily nitro intermediates are used directly without further purification.

145571 13 m ν Ί R6

Table | CH = O-NQo '--Λ' * ^ Ύ "\

V

H1 R2 R / f R6 Mp. ° C Described 1 Example # 3-CH3 H CH2 CH5 CH ^ 75-76 1 (b) 2- CH3 H CH3 CH3 CH3 Oil Η II CH3 C2H3 CH3 Oil Η H C6H5CH2 C6H5CH2 CH3 011 3- C1 H CH3 CH3 CH3 95-94 2 3-C1 5-C1 CH3 CH3 CII3 113-114 3 (c) 3-Br H · CH3 CH3 CH3 * 102-103 5 (b) 3-C1 H CH3 CH3 C2H5 90-91 6 ch3 '.

CH = £ -NO2 4 (c)% gh3-