DK146280B - PHENYLA ETHYLAMINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES - Google Patents
PHENYLA ETHYLAMINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES Download PDFInfo
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- DK146280B DK146280B DK346981A DK346981A DK146280B DK 146280 B DK146280 B DK 146280B DK 346981 A DK346981 A DK 346981A DK 346981 A DK346981 A DK 346981A DK 146280 B DK146280 B DK 146280B
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- DK
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- derivatives
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- aminoamphetamine
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- phenyla
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Description
(¾ (19) DANMARK VE3(¾ (19) DENMARK VE3
(12) FREMLÆGGELSESSKRIFT on 146280 B(12) PUBLICATION ON 146280 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Patentansøgning nr.: 3469/81 (51) !nt.CI.3: C 07 C 103/44 (22) Indleveringsdag: 04 aug 1981 (24) Løbedag: 03 sep 1974 (41) Aim. tilgængelig: 04 aug 1981 (44) Fremlagt: 22 aug 1983 (86) International ansøgning nr.: -(62) Stamansøgning nr.: 0041/76 (30) Prioritet: 04 sep 1973 SE 7312002 (71) Ansøger: *ASTRA LAEKEMEDEL AB; Soedertaelje, SE.(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) Opfinder: Goesta Lennart 'Florvali; SE, Svante Bertil *Ross; SE, Sven-Ove "Oegren; SE.(72) Inventor: Goesta Lennart 'Florvali; SE, Svante Bertil * Ross; SE, Sven-Ove "Oegren; SE.
(74) Fuldmægtig: Kontor for Industriel Eneret (54) Fenylætylaminderivater til anvendelse som mellemprodukter ved fremstilling af 4-amino-amfetaminderivater(74) Plenipotentiary: Office of Industrial Energetic (54) Phenylethylamine derivatives for use as intermediates in the manufacture of 4-amino-amphetamine derivatives
Den foreliggende opfindelse angår et mellemprodukt til anvendelse ved fremstilling af hidtil ukendte 4-amino-amfetaminderivater af den i DK fremlæggelsesskrift nr 139.716 omhandlede art.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.
tøj Mellemproduktet ifølge opfindelsen er ejendommeligt ø ved at det har den almene formelclothing The intermediate product of the invention is peculiar in that it has the general formula
OOISLAND ISLAND
CMCM
COCO
* □ 146280 2 R6* □ 146280 2 R6
JH„-C-NH-ZJH "-C-NH-Z
V’V '
/V/ V
1 2 eller et salt deraf hvor R og R , der er ens eller forskellige, hver er et hydrogenatom, en alkylgruppe med 1-5 kul- 3 stofatomer eller et halogenatom, R er en alkylgruppe med 4 1-5 kulstofatomer eller en benzylgruppe, R er et hydrogenatom, en alkylgruppe med 1-5 kulstofatomer, en benzylgruppe eller en CH2CH2CH2-bro bundet til fenylringen i ortostil-ling i forhold til N-substituenten, R~* er et hydrogenatom /Γ eller en metylgruppe, R er en alkylgruppe med 1-5 kulstof- atomer og Z er en gruppe med formlen -CO-R, hvor R er et hydrogenatom eller en alkylgruppe med 1-4 kulstofatomer, 1 2 med det forbehold at R og/eller R er en alkylgruppe med 3 1-5 kulstofatomer eller et halogenatom når R er en metyl-4 5 gruppe, R er en metylgruppe og R er et hydrogenatom.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.
Mellemproduktet ifølge opfindelsen er nyttigt som udgangsmateriale ved fremstillingen af hidtil ukendte 4-aminoam-fetaminderivater, der som det fremgår af DK-fremlæggelsesskrift nr 139.716 har en overraskende farmakologisk profil som antyder potentiel værdi som antidepressanter og også som en ny type anxiolytter. Disse i DK-fremlæggelsesskrift nr 139.716 omhandlede 4-aminoamfetaminderivater har den almene formel R6 1 CEL-C-NH0 ,v/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---IR2 --- I
Y'\ /Nr'Y '\ / Nr'
R RR R
3 146280 eller er farmaceutisk acceptable salte deraf, i hvilken 1 2 formel R og R , der kan være ens eller forskellige, hver er et hydrogenatom, en alkylgruppe med 1-5 kulstofatomer 3 eller et halogenatom, R er en alkylgruppe med 1-5 kulstof- 4 atomer eller en benzylgruppe, R er et hydrogenatora, en alkylgruppe med 1-5 kulstofatomer, en benzylgruppe eller en Cl^C^C^-bro forbundet med fenylringen i orto-stil-lingen i forhold til N-substituenten, R5 er et hydrogen- i atom eller en metylgruppe og R er en alkylgruppe med 1-5 kulstofatomer, med den betingelse at R og/eller R er en alkylgruppe med 1-5 kulstofatomer eller et halogenatom .3 4 5 nar R er en metylgruppe, R er en metylgruppe og R er et hydrogenatom.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 eksempler på grupper indbefattet i de ovenfor angivne definitioner er alkylgruppe med 1-5 kulstofatomer: metyl, ætyl, n-propyl og isopropyl, halogenatom: klor, brom,jod og fluor.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.
Forbindelserne med den almene formel I kan fremstilles ud fra mellemproduktet ifølge opfindelsen ved hydrolysering.The compounds of general formula I can be prepared from the intermediate of the invention by hydrolyzing.
Hydrolyseringen kan gennemføres med en stærk mineralsyre.The hydrolysis can be carried out with a strong mineral acid.
illustrative eksempler på gruppen Z er formyl, acetyl, propionyl, butyryl, isobutyl og valeryl.illustrative examples of the group Z are formyl, acetyl, propionyl, butyryl, isobutyl and valeryl.
Forbindelserne med formel II kan som vist i efterfølgende reaktionsskema, hvor R1, R2, R3, R^, R3, R^ og Z har de tidligere angivne betydninger og X er en bromid-, klorid- eller jodidion, fremstilles ved omsætning af forbindelserne III eller IV med et alkalimetalcyanid eller en C^-C^-nitril i nærværelse af en stærk syre, fx svovlsyre.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-R54 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 alkalimetal- ___^ cyanid eller ' + I ’ nitril I 2) H2or h i ; -r ,/V / v “ i6 V IV yRi 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
CH2-C-NH-ZCH 2 -C-NH-Z
-¾° I-¾ ° I
hCT i * * 'N·hCT i * * 'N ·
R6 /N\ JR6 / N \ J
CH=C-R5 R3' VCH = C-R5 R3 'V
Ε3>^ R -J— |J alkalimetal- ^ cyanid eller J nitril__Ε3> ^ R -J- | J alkali metal- ^ cyanide or J nitrile__
RJ RRJ R
IIIIII
Udgangsforbindelsen III kan fremstilles ved fraspalt-ning af vand fra forbindelsen IV, som kan fremstilles ud fra et aldehyd med formlen V ved omsætning med en Grignard forbindelse.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.
Aldehydet med formlen V fremstilles i et trin der indebærer formylering af det substituerede anilin ifølge Vilsmeyer-Haack-reaktionen: 5 146280The aldehyde of formula V is prepared in a step involving the formylation of the substituted aniline according to the Vilsmeyer-Haack reaction:
CHOCHO
P0C1, f\'''rS^NP0C1, f \ '' 'rS ^ N
R—DKF > R_CJ^ X; X}R-DKF> R_CJ 2 X; X}
R3 r'1 r3 VR3 r'1 r3 V
Formyleringen gennemføres ved anvendelse af en blanding af dimetylformamid og fosforoxyklorid. Fremstillingen kan også gennemføres ved anvendelse af en blanding af fosfortribromid og dimetylformamid (Acta Pharm. Suecica 7, 87, 1970).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).
Andre forbindelser end dimetylformamid der kan tjene som formyleringsmidler er fx N-metylformanilid eller formamid. Som katalysatorer udover fosforoxyklorid og fosfortribromid kan anvendes fx tionylklorid, fosgen eller aluminiumklorid.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 6146280 6
Opfindelsen belyses nærmere i det følgende.The invention will be further elucidated in the following.
Fremstilling af mellemproduktet ifølge opfindelsen Eksempel 1.Preparation of the intermediate of the invention Example 1.
N-[α,a-dimetyl-β-(4-dimetylaminofenyl)-ætyl]-acetamid 9,2 ml acetonitril sættes dråbevis ved stuetemperatur til en under omrøring værende opløsning af 18,5 ml koncentreret svovlsyre i 140 ml eddikesyre. Derpå tilsættes 30,6 g N,N-dimetyl-p-2'^'rdimetylvinylanilin og blandingen opvarmes og omrøres i en time ved 70°C. Væsken udhældes i knust is og blandingen neutraliseres med natriumhydroxyd (pH 6). Den rå forbindelse der udgør 29,8 g filtreres fra og renses ved omkrystallisation fra ætanol/ligroin. Udbytte 17,0 g, smp. 156-157°C.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.
Beregnet for ci4H22N20: C 71,25 H 9,46 N 11,96 O 6,83 Fundet: C 71,4 H 9,4 N 12,0 06,9%.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%.
Anvendelse af mellemproduktet ifølge opfindelsen til fremstilling af 4-aminoamfetaminderivater med formel IUse of the intermediate of the invention for the preparation of 4-aminoamphetamine derivatives of formula I
Eksempel 2 4-Dimetylamino-g,q-dimetylfenætylamin-dihydrokloridExample 2 4-Dimethylamino-g, q-dimethylphenethylamine dihydrochloride
En opløsning af 3,5 g N-[a,a-dimetyl-β-(4-dimetylaminofenyl) -ætyl] -acetamid i en blanding af 25 ml vand og 25 ml koncentreret saltsyre koges under tilbagesvaling i 16 timer. Derpå inddampes opløsningen under nedsat tryk og remanensen omkrystalliseres 2 gange fra metanol/isopropylæter. Udbytte 1,1 g, smp. 239,5-240,5°C.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.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE7312002 | 1973-09-04 | ||
SE7312001A SE382047B (en) | 1973-09-04 | 1973-09-04 | PROCEDURE FOR THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES |
DK464774 | 1974-09-03 | ||
DK464774AA DK139716B (en) | 1973-09-04 | 1974-09-03 | Analogous process for the preparation of 4-aminoamphetamine derivatives. |
DK4176 | 1976-01-07 | ||
DK4176A DK145571C (en) | 1973-09-04 | 1976-01-07 | BETA NITROSTYRENE DERIVATIVE USED AS INTERMEDIATE IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES |
Publications (3)
Publication Number | Publication Date |
---|---|
DK346981A DK346981A (en) | 1981-08-04 |
DK146280B true DK146280B (en) | 1983-08-22 |
DK146280C DK146280C (en) | 1984-01-30 |
Family
ID=27220352
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK4176A DK145571C (en) | 1973-09-04 | 1976-01-07 | BETA NITROSTYRENE DERIVATIVE USED AS INTERMEDIATE IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES |
DK346981A DK146280C (en) | 1973-09-04 | 1981-08-04 | PHENYLA ETHYLAMINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK4176A DK145571C (en) | 1973-09-04 | 1976-01-07 | BETA NITROSTYRENE DERIVATIVE USED AS INTERMEDIATE IN THE PREPARATION OF 4-AMINOAMPHETAMINE DERIVATIVES |
Country Status (1)
Country | Link |
---|---|
DK (2) | DK145571C (en) |
-
1976
- 1976-01-07 DK DK4176A patent/DK145571C/en not_active IP Right Cessation
-
1981
- 1981-08-04 DK DK346981A patent/DK146280C/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
DK4176A (en) | 1976-01-07 |
DK146280C (en) | 1984-01-30 |
DK145571B (en) | 1982-12-13 |
DK346981A (en) | 1981-08-04 |
DK145571C (en) | 1983-05-09 |
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