NO742946L - - Google Patents

Description

"Analogous method for the preparation of 1-(ra-acyloxyl)-1-hydroxy-2-BT-alkylamino-.

:Athens."

This invention relates to an analogous process for the preparation of 1-(α-acyloxy£enyl)°1-hydroquin-2HSf-alkylamino*-ethaneQr with the

. general formal

where R means an alkyl group with 3 to 19 carbon atoms, and &2 means methyl or ethyl, and acid addition salts thereof.

The compounds of formula I have an asymmetric carbonator and can therefore exist in the form of racemic radicals or in the form of optically active compounds.

The new compounds are prepared in accordance with the invention by reduction of corresponding acetophenone derivatives with formalin

where R. and or as indicated above, and means hydrogen or an optionally substituted benzyl residue. The benzyl residue can e.g. be substituted with alkyl--ellar alkoxy groups or a halogenator, in particular a chlorine atom. The editors understand by catalytic hydrogenation atad kjønto hydrogenation catalysts, oom f.oke. Pd, Pt, Mi or mad komplox metal hydrides have little reducing power, as f.oko. sodium borohydride. If reoton £1^^©tyr a benzyl residue, it is simultaneously removed foycirogonolytiok vod don catalytic hydrogen-er ing. If the reduction 0:10:1 of the koto group is carried out against complex metal hydrides, the benzyl group is then removed by catalytic hydrogenation. 1 The starting compounds rcsd the general ©formal II which is used in the first method are prepared by the aylation of m-hydroxy-acetophenones with formalin3 where R2 and R3 have the meanings given above, with an acid chloride with formalin

where R^ has the meaning stated above, and possibly subsequent

selective hydrogenolysis of the Itenzyl group. Racemates of compounds of formula Z are optionally cleaved in the usual way in the antipodes.

The new compounds of formula I are bases and can be transferred in the usual way to the physiologically compatible acid addition salts.

Acids that are suitable for salt formation are e.g. mineral acids so

such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid or organic acids such

such as acetic acid, propionic acid, butyric acid, caproic acid, capric acid, valerian acid, oxalic acid, malonic acid, ravoyre, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, benzo2syra, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid , 8-chlorotheophylline or the like.

The new compounds of the general formula I and their acid addition agents are distinguished by valuable therapeutic properties. They are particularly suitable as active substances in heart and circulatory agents, and can therefore be used in the treatment of heart failure or circulatory disorders.

The compounds of the general formula 1 and deree eyreaddisjonsoalter can be used enterally or parenterally. They are used in doses of 5 to 100 mg. The preparations with formal I and their acid addition salts can also be used together with active substances of other types.

Suitable galenic infusion forms are e.g. tablets, capsules, suppositories, solutions, omulions, aerosols or powders, and for the production of these you can use the usual galenic auxiliaries, beremidlor, explosives or lubricants or substances which give a depot effect. Preparation of such galenic preparation forms is carried out in the usual way according to known preparation methods.

The following examples shall serve to further illustrate the invention.

Example 1

1-(m- stearvlocayphenvl)-1-hydroxy-2HK-ethglamino-ethanehy<irochloride.

a) ' m- Btearylokflv- torffi- atylaminoraTO . ■...

Ell a solution of 53.0 g (0.25 mol) of rhophyroxy-c^-ethylamine- /.

nrratofenone»Hci;i ICO es?, trifluoreddifcriyro oattoo dropwise uiicloar ... ; stirring vad 30 C 94.5 (j,(0.312. mol)', stoaryl chloride.. perafter hol-. Cfå,roaksjonjøfLandiAg&i for 5 minutes. vad•'. §DQC and : stir in without cooling, in .i: lit$r otylacatat.. DarVoi" okjor crystallization of the compound., KrystP.IA^sis eveugoaog vfce&oo sæad etylacatat... '.Yield: .id8 'g, .8S,C;\; dat theoret:lr£c?L. Caolte point: 195°c Xox»'»?: ciÆcryotailis.-.\rjj'osi-ffrai etandl).

-J) 1 - ( m- Btøarvlokev£e:.;.v::.) " 1- hvdrokPV-^. - IT^ tvlaTiino- QtanhvdgoIilpirid.

■<:.><...>" ■• . """ " ■'.. 72 g/(0.15 mol) s of ( lon in step h ej&olfviy*.£orbindeloé i i;44.iifcer'. " /Atanol and 5"g 5&risT vÆiafiiiaa-^ 'åtaoejÆsæar cg 66C, ' Sfter' rtvfclwh'.:.>fc\hy3^ k&t&ly&ratoron, t>gisrøtanol^n -v" ^rafcillosæs." Yte/ c. ^rystailinoka ' raaltfuvni atr^es with acetonit^i"'. rtg-uvsugG. yield 69 g''.* 95,^. 1 r v £ot tøoreiirTo.' :.' Melting point: ■. 113°C £2c sfcanol). * ■

• Voi frpnigåhgBEiåtQn' L-' :?;'.^') cvonsfe-Aoncta'^?';r:o^3Sl;Erombtillos £r» ££lg-■■ Q^ido of the connection....'

??orbindelBer ;imed gQir-^.'' A tea of Ir-y-irra^o Kidsinat

l-( m- stearylbksvfanvlS -^V^vrlrokBy "2-H-^tvlayiino-otanhvdrochlorride.' ■

A) m»stearvl6kov^ i>- W^ tylQaiÆO' <x! Ot6j:oaon»

22 g m^hydroxy-o>* (53^thyl ^-benzyl-ani.:o)-acot<p>phenone hydrochloride

() ,.065$. mol) bppløoos'£ 157 ml 1 n caustic soda, and while stirring

at 20 C /add 22 g (0.0725 mol) stoaryl chloride dropwise. after'- 20 minutes, the acylation product; ± ether is taken up, and then .

shaken: dehiorganic phase first red 1 n.nafcrbnlut bg thenftér ..-with water. The dried ct.^rfaDo iimdc^osusYpg the residue hydrogen-aros^mad .390 .ml S6^-ig rr.Jtanol, soa contains the calculated'vasng-de\hydrogen chloride, Sat. a?, ;jalle^iua-kloi:;i.d "and 1 g of coal under pressure vdd;60°C. bebenjsylorinc;;ia ar'avclutfcev.©£t<sr 5.minutes,* and the hydrogenation stands. ■ Katnlyoiitoron of<3t>.g;is.i.hot state, and xxari^ Lt^ B^^ ^^ o^ Xl- y^^& a don desired connection by cooling- "" ing,.."' ilets' *avsugtt5.nc,,.J;^' wrecks kry£iteI?.-'.%io ' ;oad' acotoriitril,: .■ ,. ■'' VK&yttø:- 22 -g" * -SO^ST.' tear it-“theoretically?/. V-- -:' '. ftcii^sgnuftt-t 195°^ (ov<*,->2y8tåiXioesjca- -Crn ethanol).

■£) IM CT^ téarvlokoyforåy 7.) - -1 • -^T/jlrr glt sv-; * ::?- - ethylamino - ethanehvdrofclo. ride.

....- ■<.>.<.>Vett .catalytic chy&rogsivsring of 19 g t0,0395 mbl) of deia i,fcr.inn ... A ■ .^ifchplcjte^if.p^rbihdslscs in 400ral asafcahol i. ifcaryar - ov .0-/5-g pia^ista'*-olsréyd at.nbrmaitsyklo oi?^0°C, feir «nr^' .g 96,5# of'it t,ep- . r^hÅakp^.Bv slu£t&ro£t-røfi tr^Ifeov^t' 113°C (oakryétåll.invo-jon Ssr. ptaabl) "mslbg- ;fréfnbtilloo' l --.viyrylokoyffrjiH-./■.:.) • •i*;hydroxys'y-2-S'~3t^l-. r^isrø^t^n-hydroclu:.* ;!^. wja£$'teptuik^i' 139 v .(6v--?:**'/c.cfr.llic3ao'io3i ><:>rr.- icoprepanol).. ■' - V :"■ ■."*■» ■ » .... ■ ■ *..■'..

1 - ( nt- rstéarvioksyf.- a^ ivli - fry^ roksv"?, v& • '^'^^ ivvgini^ etan- Sivdroklprici!..'

30.55 g; JtfO, 1 mol) in-hydroxy-tjr(K-eii^.- &-bangy1 -amino)-aeetpranon-åhydrohybrid, dissolved in 250 ml of 1 n nafcroalufc, reacted at rora--, temperature'rawsd 33";5 r (-r>,ll mol) nte«:ty^kl.prid to m-stearyloxy-, c^(K^tyl-lff-bahByl-0'vli.-:o)-acetophenone-W^rofchloride. Bfter !20 minutes" f bre is taken. utetr ing, and die .esganisko. phase" is shaken- with X »■ natroniu£ pg dored:-:'jred water. The iJtiirfaa is dried with hatriiAråsul barrel, and solutionBiaid^Glet avdeotilla^;ic.. The residue' is dissolved in G00, ml of methanol,YiøtrF»*-' loaros msd. notösioliok hydrochloric acid and subjected to .hydrogenation ommøn mod Slanoy-Cii?il;el.. Hydrogeneringdn sK;.\ ox under, -pressfe. and .vad<:>-€0°C. Hydroconopptagelson answers,il ; 2 equivalents of hydrogen after removal of the catalyst

the methanol is deethylated in vacuum, and the residue is isolated, the _ iswiked compound...... ':• "; Ptbytté -35. g. 72.5?S r\v c?et theoretical.... t»p.3ltapunkt 113°C (c.^ystalioaoion f.ira ethanol).'

Example. 7 ■■■_.*.;'.<1>ti" . l^ rm- f n- nekBvlkarbonvlcc^ av) - fenvl ' 1 ~ l~ Iwc tr:okBv-- 2- l! ?-^ tvl- ^ mlno-- etan--Iwdrbkiprid.^

<f>to.a solution cv 2,*>.V g (0.Ol mol) iMn-hecoylcarbohyloxy)

.<o»^/^tylamino;yacetoisasi.;:.i.. ECl.i SO ml -jstanol is added under, jom-raring at o :til .- écC 0.5 g of sodium boron liydride. Sfter 5<:>:'minutes

'iias&Btilles pH.of 5*__-5 ir.addik, and .nbfcasiolen."abdastiller3o i

volume; The residue epplcH/iu in water: and crjøros cvak alkaline wad to-- .. uation of; arambhiuifi^yili/cilxyd. The released base '.of • endof orhind-plncåft is taken up, in ethylac. dry rose riir.d n^tariuiasulphate and indavæas.Ss:ca the residue in ethylfia.si.r^-. tttkryatalli:jor.:j.*u the hydrochloride of for-Mwdalson-iaed;'etheric ^:'.\Uavre... Unused 2.7Å';'g rv the theoretical-i.-E^lfcepoint"in 120° 9 (o-■', .■..-..vTJtalliiao^on ethylacetati).

• *. ■ ■ - . ■'..-*.■■'

Claims (2)

1. Arialogy process for the preparation of therapeutically active 1-(m-acyloxyphenyl)'' 1-hydroxy-2-5'-alkylaniino-ethanes of the general formula where means an alkyl residue with 3 to 19 carbon atoms, and R2 means methyl or ethyl, in the form of racemates or the pure optically active forms, and acid addition salts thereof, characterized in that an acetophenone with the formula: where R, °9 R2 is as indicated above, dg R means hydrogen or an optionally substituted benzyl residue, is reduced, an N-benzyl residue which is possibly present in the reduction product is cleaved off, racemates of formula I are optionally split in the optical antipodes, and/or primarily obtained acid addition salts are transferred to free bases or salts with other acids, or primarily obtained bases are transferred to desired acid addition salts. 2. Process as set forth in claim 1, characterized in that a starting material of formula II is used where R 1 means heptadecyl and R 2 means ethyl.