DK146280B - PHENYLA ETHYLAMINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES - Google Patents

Description

(¾ (19) DENMARK VE3

(12) PUBLICATION ON 146280 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No: 3469/81 (51) Nt.CI.3: C 07 C 103/44 (22) Filing Date: 04 Aug 1981 (24) Running Date: 03 Sep 1974 (41) Aim. available: 04 Aug 1981 (44) Submitted: 22 Aug 1983 (86) International Application No: - (62) Stock Application No .: 0041/76 (30) Priority: 04 Sep 1973 SE 7312002 (71) Applicant: * ASTRA MEDICINAL AB; Soedertaelje, SE.

(72) Inventor: Goesta Lennart 'Florvali; SE, Svante Bertil * Ross; SE, Sven-Ove "Oegren; SE.

(74) Plenipotentiary: Office of Industrial Energetic (54) Phenylethylamine derivatives for use as intermediates in the manufacture of 4-amino-amphetamine derivatives

The present invention relates to an intermediate for use in the preparation of novel 4-amino-amphetamine derivatives of the kind disclosed in DK Publication No. 139,716.

clothing The intermediate product of the invention is peculiar in that it has the general formula

ISLAND ISLAND

CM

CO

* □ 146280 2 R6

JH "-C-NH-Z

V '

/ V

Or a salt thereof, 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 halogen atom, R is an alkyl group having 4 1-5 carbon atoms or a benzyl group, R is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a benzyl group or a CH 2 CH 2 CH 2 bridge bonded to the phenyl ring in ortho position with respect to the N substituent, R 1 is a hydrogen atom / / or a methyl group, with 1-5 carbon atoms and Z is a group of the formula -CO-R wherein R is a hydrogen atom or an alkyl group of 1-4 carbon atoms, with the proviso that R and / or R is an alkyl group of 3 1 5 is a carbon atom or a halogen atom when R is a methyl group, R is a methyl group and R is a hydrogen atom.

The intermediate of the invention is useful as a starting material in the preparation of novel 4-aminoametamine derivatives which, as can be seen from DK disclosure no. These 4-amino amphetamine derivatives disclosed in DK Publication No. 139,716 have the general formula R6 1 CEL-C-NH0, v /

R2 --- I

Y '\ / Nr'

R R

Or are pharmaceutically acceptable salts thereof, wherein 1 2 formulas R and R, which may be the same or different, are each a hydrogen atom, an alkyl group having 1-5 carbon atoms 3 or a 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 from 1 to 5 carbon atoms, a benzyl group or a C1-C3-C6 bridge connected to the phenyl ring in the ortho position relative to the N substituent, R is a hydrogen atom or a methyl group and R is an alkyl group having 1-5 carbon atoms, provided 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.

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.

The compounds of general formula I can be prepared from the intermediate of the invention by hydrolyzing.

The hydrolysis can be carried out with a strong mineral acid.

illustrative examples of the group Z are formyl, acetyl, propionyl, butyryl, isobutyl and valeryl.

The compounds of formula II, as shown in the following reaction scheme, wherein R 1, R 2, R 3, R 3, R 3, R 3 and Z have the previously indicated meanings and X is a bromide, chloride or iodide ion, can be prepared by reacting compounds III or IV with an alkali metal cyanide or a C 1 -C 4 nitrile in the presence of a strong acid, e.g., sulfuric acid.

4 146288 OH R6 1 I 5 CHO, CH-CH-R5

Ri I e6 \ R \ J \ U 'j ^ HMgX p |] R2 I | J r5 ^ R ^ “Η" H alkali metal- ___ ^ cyanide or' + I 'nitrile I 2) H2or hi; -r, / V / v “i6 V IV y

CH 2 -C-NH-Z

-¾ ° I

hCT i * * 'N ·

R6 / N \ J

CH = C-R5 R3 'V

Ε3> ^ R -J- | J alkali metal- ^ cyanide or J nitrile__

RJ R

III

The starting compound III can be prepared by decomposing water from compound IV, which can be prepared from an aldehyde of formula V by reaction with a Grignard compound.

The aldehyde of formula V is prepared in a step involving the formylation of the substituted aniline according to the Vilsmeyer-Haack reaction:

CHO

P0C1, f \ '' 'rS ^ N

R-DKF> R_CJ 2 X; X}

R3 r'1 r3 V

The formylation is carried out using a mixture of dimethylformamide and phosphorus oxychloride. The preparation can also be carried out using a mixture of phosphorus 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.

146280 6

The invention will be further elucidated in the following.

Preparation of the intermediate of the invention Example 1.

N- [α, α-Dimethyl-β- (4-dimethylaminophenyl) -ethyl] -acetamide 9.2 ml of acetonitrile is added dropwise at room temperature to a stirred solution of 18.5 ml of concentrated sulfuric acid in 140 ml of acetic acid. Then 30.6 g of N, N-dimethyl-p-2'-dimethylvinylaniline are added and the mixture is heated and stirred for one hour at 70 ° C. The liquid is poured into crushed ice and the mixture is neutralized with sodium hydroxide (pH 6). The crude compound constituting 29.8 g is filtered off and purified by recrystallization from ethanol / ligroin. Yield 17.0 g, m.p. 156-157 ° C.

Calcd for C 14 H 22 N 2 O: C 71.25 H 9.46 N 11.96 O 6.83 Found: C 71.4 H 9.4 N 12.0 06.9%.

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

Example 2 4-Dimethylamino-g, q-dimethylphenethylamine dihydrochloride

A solution of 3.5 g of N- [α, α-dimethyl-β- (4-dimethylaminophenyl) -ethyl] -acetamide in a mixture of 25 ml of water and 25 ml of concentrated hydrochloric acid is refluxed for 16 hours. Then the solution is evaporated under reduced pressure and the residue is recrystallized twice from methanol / isopropyl ether. Yield 1.1 g, m.p. 239.5 to 240.5 ° C.