SE178032C1

SE178032C1 -

Info

Publication number: SE178032C1
Authority: SE
Publication date: 1961-01-01

Description

Uppfinnare: B Alhede Prioritet begtird freuz den 12 augusti 1958 (Danmark) Det är kant, att foreningar, vilka aro verksamma som bronkodilaterande medel och ha formeln: /CH, \)—CH—CH,NHCH/ \CH, OH Cl kunna framstallas darigenom, att man substituerar metylgruppen i kloracetofenon med brom, omsatter den bildade kloracetofenylbromiden med isopropylamin och redncerar den erhallna tertifira aminens ketogrupp med alumindumisopropylat. Man kan aven genomfora reduktionen med aluminiumisopropylat pa kloracetofenylbromiden och darefter be- handlaisopropylamin Dessa forfaranden aro emellertid komplicerade och ge relativt datigt utbyte. Inventor: B Alhede Priority begtird freuz 12 August 1958 (Denmark) It is true that compounds which are active as bronchodilators and have the formula: / CH, \) - CH — CH, NHCH / \ CH, OH Cl can be prepared thereby substituting the methyl group of chloroacetophenone for bromine, reacting the chloroacetophenyl bromide formed with isopropylamine and reducing the keto group of the resulting tertiary amine with aluminum diisopropylate. The reduction with aluminum isopropylate on the chloroacetophenyl bromide can also be carried out and then treated with isopropylamine. However, these processes are complicated and give a relatively yield yield.

Det är likaledes Rant, att man genom omsattning av p-oxifeny1-2-amino-1-propanol med aceton under samtidig katalytisk hydrering kan erhalla ett derivat, som ar substituerat med isopropyl i aminogruppen, men utgangsmaterialet är icke lattillgangligt. Dessutom är den motsvarande proeessen icke kand for utgangsmaterial, som aro substituerade med klor i fenylgruppen. It is also Rant that by reacting p-oxyphenyl-2-amino-1-propanol with acetone during simultaneous catalytic hydrogenation, a derivative which is substituted with isopropyl in the amino group can be obtained, but the starting material is not readily available. In addition, the corresponding process is not known for starting materials which are substituted with chlorine in the phenyl group.

Fareliggande uppfinning avser ett forfarande for framstallning av 1-(klorfeny1)-2-isopropylaminoetanolforeningar, vid vilket Oliallnamnda olagenheter undanrojas och forfarandet kannetecknas darav, att en klorfenylnitroetanol omsattes med aceton under katalytisk hydrering. Darvid intrader samtidigt en reduktion av nitrogruppen och ketogruppen samt bildning av den avsedda foreningen under vattenavspaltning. Utbytet är Mgt och klorgruppen farblir helt opaverkad under normala reaktionsbetingelser. Bruttoreaktionen kan skrivas Da den som utgangsmaterial anvanda klorfenylnitroetanolen med latthet, oeh likaledes med gott utbyte, erhalles pa. det fran framstallningen av fenylnitroetanol kanda sattet, namligen genom ,omsattning av klorbensaldehyd och nitrometan i narvaro av ett kondensationsmedel t. ex. natriumalkoholat enligt faljande reaktionsformel: \—CHO CH,NO, Na-alkoholat CIX/ Na.,0 X ClOH kan den onskade foreningen pa detta satt uppnas ur ytterst enkla utgangsmaterial med far-re reaktionssteg och i battre -atbyte an vid kanda fkfaranden. The present invention relates to a process for the preparation of 1- (chlorophenyl) -2-isopropylaminoethanol compounds, in which the above-mentioned illegal units are eliminated and the process can be characterized in that a chlorophenyl nitroethanol is reacted with acetone during catalytic hydrogenation. At the same time, a reduction of the nitro group and the keto group and the formation of the intended compound during water cleavage occurs. The yield is Mgt and the chlorine group remains completely unaffected under normal reaction conditions. The gross reaction can be written as the chlorophenyl nitroethanol used as starting material with ease, and also with good yield, is obtained on. from the preparation of phenylnitroethanol the process, namely by reacting chlorobenzaldehyde and nitromethane in the presence of a condensing agent, e.g. sodium alcoholate according to the following reaction formula: CHO CH, NO, Na-alcoholate CIX / Na.

Av de tre mojliga i fenylgruppen monoklorsubstituerade fareningarna ar den, som har kloren i o-stallning, att foredraga genom att den har den storsta terapeutiska verkan, men forfarandet kan aven anvandas for framstallning av m- och p-foreningarna. Of the three possible compounds in the phenyl group monochloro-substituted compounds, the one having the chlorine in the o-form is preferable in that it has the greatest therapeutic effect, but the process can also be used for the preparation of the m- and p-compounds.

Vid hydreringen kan man anvanda en adelmetallkatalysator sasom platina, men omsattningen forloper lika bra med Raney-nickel som katalysator. 2— — Reaktionstemperaturen bor ligga under c:a 110° C, varigenom man. helt undviker, att klorsubstituenten paverkas och undviker, att OH-gruppen i 1-stallning reduceras bort. Reaktionstemperaturer av 50-90° C, fOretradesvis 70-80° C, ha visat sig lampliga. In the hydrogenation, a noble metal catalyst such as platinum can be used, but the reaction proceeds as well with Raney nickel as catalyst. 2— - The reaction temperature should be below about 110 ° C, whereby one. completely avoids that the chlorine substituent is affected and avoids that the OH group in the 1-position is reduced away. Reaction temperatures of 50-90 ° C, preferably 70-80 ° C, have been found to be suitable.

Utgangsmaterialet behover icke isoleras utan kan anvandas i den form, i vilken det erhalles vid omsattningen mellan klorbensaldehyd och nitrometan och eventuell efterfOljande uthallning i attiksyrahaltigt isvatten, separering av vattenfasen och torkning. The starting material does not need to be isolated but can be used in the form in which it is obtained in the reaction between chlorobenzaldehyde and nitromethane and any subsequent precipitation in acetic acid-containing ice water, separation of the aqueous phase and drying.

Forfarandet askidliggores med foljande utforingsexempel. The procedure is illustrated by the following working examples.

Exempel I en hydreringsautoklav pa 2 1 anbringas 50 g o-klorfenylnitroetanol, 500 g aceton och 0,5 g platinaoxid. Darefter pafylles vate till ett tryek av 60 atm vid 20° C, Autoklaven varmes till 80-90° C, vid vilken temp eratur hydreringen genomfores. Hydreringen avbrytes, nar trycket sjunkit till ett vdrde motsvarande c:a 15 atm vid 20° C, vilket drojer c:a 2 tim. Efter avkylningen avfiltreras katalysatorn och filtratet indunstas i vakuum, varvid en olja erhalles som rest. Denna loses upp i en blandning air lika delar aceton och eter och hydrokloriden Mlles med en losning av klorvate i alkohol. Den omkristalliseras ur metyletylketon och smatter darefter vid 165167° C. Utbytet utgor 36 g. Example In a 2 L hydrogenation autoclave are charged 50 g of o-chlorophenyl nitroethanol, 500 g of acetone and 0.5 g of platinum oxide. Then hydrogen is filled to a pressure of 60 atm at 20 ° C, the autoclave is heated to 80-90 ° C, at which temperature the hydrogenation is carried out. The hydrogenation is stopped when the pressure has dropped to a value corresponding to about 15 atm at 20 ° C, which takes about 2 hours. After cooling, the catalyst is filtered off and the filtrate is evaporated in vacuo to give an oil as a residue. This is dissolved in a mixture of two equal parts of acetone and ether and the hydrochloride is mixed with a solution of chlorine in alcohol. It is recrystallized from methyl ethyl ketone and then slaps at 165167 ° C. The yield is 36 g.

Onskar man direkt framstalla acetatet istaIlet for hydrokloriden kan man igenomfora hydreringen i narvaro ay 1 mol attiksyra, marvid acetatet utkristalliserar vid indunstndngen. Pa motsvarande satt framstalles m- och p-foreningarna. If it is desired to directly produce the acetate instead of the hydrochloride, the hydrogenation can be carried out in the presence of 1 mole of acetic acid, in which case the acetate crystallizes out on evaporation. Correspondingly, the m- and p-associations are presented.

Claims

Patent claim:

A method of producing aminoethanol compounds with bronchodilating action, characterized in that a chlorophenyl nitroethanol is reacted with acetone during catalytic hydrogenation and at a temperature below about 110 ° C, after which the corresponding 1- (chlorophenyl) -2-isopropylaminoethanol is recovered. Request publications: Patent Papers treat U. S. A. 2 414 031. Stockholm 196

2. liungl. Bair. P. A. IsTorstedt & SiMer. 020089