SI8011754A8 - Process for obtaining morpholine derivatives - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
F.HOFFMANN-LA ROCHE & CO.
AKTIENGESELLSCHAFT POSTUPAK 2A PROIZVODNJU DERIVATA MORFOLINA Oblast tehnike
Pronalazak je iz oblasti farmaceutske industrije i proizvodnje fungicida (MKP C 07D 265/30; A 01N 9/00).
Tehnički problem
Tehnički problem koji se rešava ovim pronalaskom je u torne da se pronade efikasan postupak koji bi omogučio proizvodnju novog .derivata morfolina .,koji bi imač prednosti u odnosu na poznata jedinjenja te vrste.
Stanje tehnike S obzirom da je jedinjenje koje se dobija postupkom prema pronalasku novo, potpuno je nov i postupak za njegovu proizvodnju. Najsiičnije jedinjenju koje se dobija po: tupkom prema pronalasku je jedinjenje opisano u nemačkom objavljenom spisu br.27 52 096 . Medutim tu se radi o cis-jedinjenju koje ima oko 10 puta slabije anti-mikotično dejstvo u odnosu na jedinjenja proizvedena postupkom prema pronalasku.
Opis rešenja tehničkog problema sa primerima izvodenja
Navedeni tehnički problem se rešava novim postupkom za proizvodnju derivata morfolina opšte formule - 2 -
u kojoj R označava etil ili fenil, kao i soli i N-oksida tih jedinjenja, koji se postupak od poznatih postupaka te vrste razlikuje po torne što jedinjenje opšte formule
reaguje sa jedinjenjem koje odaje karbonijum jon opšte formule R ®
VI H3C^C_CH3 u kojoj R ima gornje značenje ili što se radi dobijanja N-oksida jedinjenje formule I treti ra vodonikperoksidom ili perkiseli nama ili se baza formule I sa kiselinom prevodi u so. Alkilovanje jedinjenja opšte formule V se vrši u prisustvu tzv.Friedel-Kraft kata-lizatora kao što je aluminijumhlorid.hlorid gvožda,cinkhlorid,bortrifluorid,kalajni hlor fluorvodonik,sumporna kiselina i fosforna kiselina.Posebno je pogodna sumporna kiselina. Upotreba inertnog organskog rastvarača nije neophodna, ali je pogodna. Kao rastvarači su pogodni alkani kao heksan, cikloheksan; hlorirani ugljovodonici kao hloroform, etilen-, dihlorid i metilenhlorid, pri čemu je metilen- hlorid posebno pogodan· Temperature reakcije alkilovenja ni j· kritična ali leSi po pravilu iamedju 0»50°0» prvenstveno lene« dju 18 - 20°C.
Prvenstveno 1 posebno u slučaju upotrebe eunpome klseline posle zavrfietka reakcije dobijeni proizvod se ekatrahuj« a obliku soli s» inertnim organski» rastvaračaa, kao na pr· metllenhlorid·
Xf slučaju da je potrebno noše slobodni aain da se dobijo sa pogo» dnom basom« kao natri jumhidrokaid« kalijuahidroksid « soda« potafia lil Icalcijufflhidrokaid.
Pogodna j «dinj en ja« ko j a od a ju karbon! jun j ona opšte lomni e VI su odgov&rajuči teroijarni alkoholi« kao 2-a»etil-2-butanol ili terc. hloridi, kao 2-hlor-2-»et il~butan. 8 svrhu proizvodnje N-oksida jadinjenja formule X obradjuje ee jedinjenje formule X sa vodonikperokoidom ili perkleelinom.
Kao rastvarač služe« u slučaju upotrebe vodonikperoksida kao okai-daoionog sredstva« alkohola kao metanola« etanola ili isopropanola« pri čemu poslednji ima prednost· Pogodne reakeione temperature leie izmed ju o 1 50°C, posebno pogodno pri 40°C* Kao perkiseline mogu da ee upotrebe na primer persirčetna kiselina« perbensoeva kiselina« metablorperbensoeva kiselina« peradipineka kieelina·
Kao rastvarač sa perklssllns aluŽe prvenstveno halogenovani ugljovodonioi« kao metilenhlorid« kloroform ili etilenhlorid·
Kao reakciona temperature pogodne eu iste« kao pbethodno za rea-kciju sa vodonikperoksidoa ito je opisano·
Zedinjenja formule X grade soli sa organskim i neorganskim ki» solinama· Kao soli za jadinjenja formule 1 dolaze u obzir posebno soli sa fiziološki podnofiljive klseline· Ovde pripadaju prvenstveno halogenvodonlčna kieelina« kao na primer hlorovodonična kieelina i bromovodonlčna kiselina« dalje fosforna kieelina« asotnu kise» lina oaim toga nono 1 bifunkcionalne karbonske kiseline 1 hidro» karbonske kisoline, k&o na pr· sirčetna kiselina, maleinska ki« sslina, čilibarna kiselina, fonoma kiselina, vinska kiselina· llmunska kiselina, aaliellna kiaallna· eorbinoka kiselina 1 mlečna kiselina i naj sad sulfonake kiselina· kao 1,5-naftalin» disulfoneka kiselina· Proizvodnja takvih soli vrči ae na po sebi posnet način.
Polami nat eri j ali forsule VI eu poznate jedinjenja.
Jedinjanja opSte formule V mogu da se dobiju tako da se jedi« njenje opšte formule
CH
meša aa 0i8«2«6»dimetilmorfolinom 1 katalltičldU. hidrira.
Kao rsatvarač se prvenstveno upotrebl java organski raatvarač · kao na primer alkohol· kao metanol· Temperatura ni j e kritična· ali po pravilu leži iamedju 0 - 50°0·
Kod katalitičkog hi dr ir trnja sluz e uobičajeni katalisatorl hidriranja, kao na pr. platina« Raney-nikl ili paladijum, pri Čemu 5% paladijumugljenika posebno pogodno deluje·
Jadinjanja prema pronalaBku sadrže u morfolinekom oatatku aa P.subatituriranim fenilnim ostatkom vezujuče propilenske lanoe asimetrični O-atom 1 o tud a mogu da se jave u obllku raoemata i u obllku optičkih antipoda« Poslednji mogu da ee dobiju ia nastalih raoemata šepanjem sa optički aktivnih kiselina« na primert aa A/»kamfomom kiselinom« /+/»kamfor-10-sulfon.skom kiselinom« 0,0*»dibensoilvinakoa /L» ili IMJblik/, LA/«vinakom kiselinom· - 5 - S/-/-*iaskom kiselinom, L/+/»gltttaminake kiseline~4~-sulfonatom, X/-/ -j abuSno» kiselinom Hi DA/"*j*bužaoa kiselinon· Ovo eefrpanje može da e« Trdi uobi&ajemlm metodama eepanja·
Jedinjanja prtu proaalaaku imaju fungididno dejstvo 1 prema torne mogu da nadju primerni a borbi ee gljivioama ti poljopri-vredi 1 povrtaratvu. Jedinjenja eu podogna poaebno aa borbu ea pravim gl j Ivicama brafina* kao na primer, Kryeiphe graainla, Podo-spheroa leucotrična /plesan jabuke/, Bphaerotheca pannoea bolesti rdje /, Oldiua tuckerl /prava bra&navioa vinove lose/ bolesti rdje keo na primer one la rodova Puccinia, Uroayces 1 hemileia posebno Puccinia graminis /orna rdja Site/ Puooi&la coronata /rdja ovsa_, Puccinia eorghi /rdja kukuruia/, Puccinia atriiformia /čuta rdja Sita/, Puooinla reocndita /mrka rdja Sita/, Uroayoea fabas la appensloulatus /rdja Sbunaatog pasulja/ kao 1 ea Heallela viatatrim /rdja kafe/ 1 Pragmidiua anoronatum /rdja ru5e/.
Dalje delu ju ova j «dinj anj a i prit iv sledečih fitopatogenih gljivicat tfstilago avenae /glavnica/, Venturig inaegualia /jabučne kra-ate/ Oercospora arachidioole /bolest arija lista kikirikija/ Opbi-abolua gr amini a /bolest etabljike Sita/, Septoria nomorua /mrka boja lista Sita i pleve/ ili ftarsonina rosse /zvezdasti gar ruže/. Pojedine substance is ove klase jedlnjonja imaju istaknuta spore» dna dejstva protiv raziliitih vrsto sledečih rodova:
Hhlsootonls, Tilletia, Helminthosporium kao 1 doli&ično protiv različitih vrsta peranospora, Ooniophora, Lan&ltes, Corticium Tboilaviopaic i Fuaarium.
Osim toga delu ju jodinjenja formule 1 1 pritiv fitopatohoaih bakterija kao na pr· Xynthomonas vesioatoria, Kanthomonas orysae i druge žanthomon&de9 kao i protiv različitJUb vrsta Erminia tracheiphil« 6
Pre svega su aktiva· materije prosa proaalasku »bog njihovog fungistat 1č kog i fungicidnog dejstva pogodna za borbu prot iv infekcija ko j e se imamivaju gljlvlc&aa i kvaeoima« na primer Genera Candida« Tricgophjrte ili Hiatoplasaa. On· ea posebno aktiva· prema Candida-vrst aoa« kao Candida albioans i pogodne su prvenstveno ta lokala« terapije površinskih infekcija kož· i slusokože« posebno gonitalnog trakta« na primer Vaiinitis, epeoljalno lzasvanog ea Candida· Oblik primene imbora j· lokalen tako da aktivni preparati u oblika masti« čepova, supomitorija, ovula ili drugih pogodnih oblika moga da dodju u primerni·
Froievodnja farmaoeutskih preparata može da a· vrši na po sebi posnet način« moSanjea aktivnih materija ea uobičajenim organskim ili neorganskim inertnim nosečim materljalima i/ili po» močnim materijalima« kao voda« želatin« mlečni Seč er, škrob« grus« msgnesijumetesrat« talk« biljna ulja« polielkilenglikoli« vame-lin« sredstva ea konzerviranje« stubilisovanje, umrsžavanje ili emulgo vanje, soli ea promenu osmotskog pritiska ili puferi«
Poziranje se vr3i prema individualnim sahtevima« ali bi pri» mena od dnevno 1-2 tablete« ko je s odri e 50-100 mg aktivne materije ea vreme od nekoliko dana predstavljala pogodno dosiranje·
Kasti s&drže svrishodrto O« 5*5 % prvenstveno 0,5-2 % posebno pogodno 0,5-1 % aktivne materije· sledeče obavečtenje o probama i rezultati dati na tabeli daju str očnjaku tak od j e potrebnu in-foroaeiju o doziranju aktivne materije·
Jedinjenja prema pronalaeku i spi ti vena su na njihovu delotvo-most prema Candida albioans u Vagin&l-Candidlaels-testu na paeovi-ma opisanem u Path.Kiorobiol. 23i62-68 /1960/, pri čemu bu dobljeni sledeči rezultati t
Jedinjenje
: Keric^ntrocij-a u% pri ko jo j je nastupilo "ED 50" dejstvo cis-4-/3-(p-terc.Amyl-fenil)-2-metilfenil/- 2,6-dimetil-morfolin 0,01 cis-4-/3-/p-<^,o6· dimetil-benzil)-fenil/-2-metil- propil/-2,6-dimetil-morfolin 0,01
Primer 1 U 1223 g cis-4-(2-metil-3-fenil-propil)^2,6-dimetilmorfolina u 4 1 metilenhlorida na 5°C u toku 45 minuta ukapava se 4941 g koncentrisam sumporne kiseline , a zatim u toku 60 minuta 520 g 2-metil-2-butanola. Reakcioni rastvor se uz hladjenje ledom tretira sa vodom i vodena faza vise puta ekstrahuje sa metilenhloridom. Organski ekstrakti se tretiraju sa natrijumhidroksidom i na kraju isperu vodom,osuŠe , upare i uljni cis-4-/3-(p-terc.-amil-fenil)-2-metilpropil/-2,6-dimetilmorfolii se destiluje u vakuumu, tačka kljuČanja 120*0/0,1 Torr.
Analognim putem dobija se reakcijom cis-4-(2-metil-3-fenil-propil)-2,6, dimetilmorfolina sa 2-metil-3-fenil-2-propanolom cis -4-/3-/p-(</,«: -dimetil-benzil)-fenil/-2-metil-propil/-2,6-dimetilmorfolin sa tačkom kljuČanja od 162°C/0,04 Torr.
Eksperimetalno je utvrdjeno da se gornja reakcija može izvesti na tempe raturi od 0°C do 50°C.
Gore navedena polazna ntaterijn dobija se ovako: 1000 g °^-metil-cimetaldehida, 10 1 metanola i 789 g cis-2,6-dimeti1-mor folina tretira. se u azotn03 atmosferi sa 50 g 5% paladijum-uglja. Zatim se uz hladjenje vodom pri 30°C hidrira do kraja primanja vodonika, odfiltrira od katalizatora, metanol &
Oddestiliše pod saanjenim pritiskom i tada destiliSe sirovi proizvod ključa pri !09°0/0*055 Torra.
Primer 2 266 s 0ie<JU/3-/p-toro*»aail-f«ail/-2-«etil-propil/-St6-dieitil-faaorfolin so raofcvori u 500 ml absolntnog etanola i pri sobnoj temperaturi 5CC ml 2B% HCL-etanolnog raotvora ukapava u to · Homogeni rastvor se^ na rotacionom uparivaču upari do euva i oatatak se prekristalifie iz 100 ml vode· Kristalizat se lepere sa vodom i oouSi u suš niči pod vakuumom na 55°0· Dobijo oo hldrohlorid od cis-^-./5-/P“tor.-amil-fonil/*-2-metil-propil/-2l6-dimetil-morfo-lin kao boli, laki hidroskop&ki kristali sa tačkom topljenja 204-206°C.
Primer 5 TJ 21 g cis-4-/3-/p«*terc-aail-renil/-2-aetil-propil/-2*6-dimetil-morfolin ukapava se uz aceton-ouvi led-hladjonje ukapava ea ra-atvor od 60 ml 50¾ vodonikperoksida u 60 ml anhidrida airčetno kiseline da reakclona temperatura n© prodje 5Q°C i zatim se pusti da dalje reagtije 16 časova na oobnoj temper ..turi· Elog oe proverava poaoču tankoelojne kromatografije /hekson-etar Iti/· Radi razlaganja suvi&nog peroksida re&kcioni rastvor se ohladi na - 10°C i trctira sa 200 ml 40 % kalijhidrokaidcu Posle 20.ča-sovnog mešanja razblaii so sa 500 ml vode i ekstruhuje sa hloro-formon. SJedinJeni ekstrakti hloroforma noutralnc se isporu« osuže i upare. PrckristalisanJ cm ostatka iz ICO ml pentans dobije ee širiti cie-4-/3-/p-terc.-aDil-fonil/-2-metil-propil/--2,6-di»etil-iaorfolin-h-okeid· -9 -
Sledmi primeri opiauju proiavodnju fasmaceutekih preparata* Primer 4
Proievedeni eu na uobičajen način vaginalne tablete Bledečeg aaatavai 50 mg 400 ag 261 «g 100 ag 25 ag 9 ag 64? as 0is*4~/3~/P*~t; ere ♦ *amll-f enil/-2-a©t il-propil/~2 , 6dime-til-aorfolin Oek*kalcijum£oefat 2 H20 Direktno preeujuče debljlne 2ΪΑ-ΗΧ 1500
Kleini iečer /euden raeprflivanjem/
Polivinilpirolidon Linuneka kieelina
Hagaeeiju&atearat i
Primer 5
Proizvedena je mast elededeg eaetava i ci g-A-./3~/a · a-dijnetil-ben*il/-feiail/2- netil-propil/«-2,6-diaetil-ttorfolin 0,7 g
Cetilalkohol 5,6 g
Vuneka mast 9 »C g
Vaaelin, beo 79»3 g
Parafinsko ulje *s 100,0 g 10
VtiΛ9Τ β
Proiavaden J* to*«® slsddog itetavtit ere · -aadl-fenil/-2-«etil· -propil/-2,6-dieetil~aorfolin 0*7 e» Poliokaietilen&tearat 3,3 g Gosto paralinako ul$s 8,0 g Va*ali&,b*o 10,0 g Karbokaivinilpolimer CA2BOPOL 934 Fh 0,3 g KaOH, najČistili 0,C?g Voda, demineraliKovana ad 100,0 g
F.HOFFMANN-LA ROCHE & CO.
AKTIENGESELLSCHAFT PROCEDURE 2A PRODUCTION OF MORPHOLINE DERIVATIVES Field of Engineering
The invention is from the field of pharmaceutical industry and the production of fungicides (MKP C 07D 265/30; A 01N 9/00).
Technical problem
A technical problem solved by this invention is in friction to find an efficient process that would permit the production of a new morpholine moiety, which would have the advantage over known compounds of this kind.
State of the art Since the compound obtained by the process according to the invention is new, it is a completely new process for its production. The most pervasive compound obtained by: the impediment of the invention is the compound described in the German published file No. 27 52 096. However, it is a cis compound having about 10 times less anti-mycotic effect than the compounds produced by the method according to the invention.
A description of the technical problem solution with examples of performance
Said technical problem is solved by a novel process for the production of morpholine derivatives of the general formula - 2 -
in which R is ethyl or phenyl, as well as salts and N-oxides of these compounds, which process of known methods of this kind differs by friction which compound of general formula
reacts with a compound that yields the carbonyl ion of the general formula R ®
VI is H3C ^ C-CH3 in which R has the above meaning or, for the preparation of the N-oxide, the compound of formula I is treated with hydrogen peroxide or perisislates, or the base of formula I with an acid is converted into a salt. Alkylation of the compounds of the general formula V is carried out in the presence of the so-called Friedel-Kraft catalyst such as aluminum chloride, chloride iron, zinc chloride, bortrifluoride, chlorine chlorine fluoride, sulfuric acid and phosphoric acid. Particularly suitable sulfuric acid. The use of an inert organic solvent is not necessary, but it is suitable. As solvents, alkanes such as hexane, cyclohexane are suitable; chlorinated hydrocarbons such as chloroform, ethylene, dichloride and methylene chloride, where the methylene chloride is particularly suitable. · The alkylation reaction temperatures are not critical, or as a rule, for example 0 ° 50 ° 0, preferably lene 18 - 20 ° C.
Especially 1 especially in the case of the use of euphoric acid after the completion of the reaction, the resulting product is exaggerated in the form of a salt with an inert organic solvent such as sodium methochloride
In the event that it is necessary to have a pair of free aain to obtain a "bottom bass" sodium hydroxide "potassium hydroxide" soda potafia lil Icalciufflhydrocaid.
Suitable for "dinj en ja" who have a carbon! June, the general breakdown of VI is answered & tertiary alcohols " 2-a " ethyl-2-butanol or tert. chlorides, such as 2-chloro-2-ethyl-butane. 8, the object of producing the N-oxide boiling of formula X is treating its compound of formula X with hydrogen peroxide or perkleline.
As a solvent, they "serve in the case of the use of hydrogen peroxide as an okai-daoion agent" of alcohol as methanol "ethanol or isopropanol", the latter having the advantage of: Suitable reaction temperatures are between 1 ° C and 50 ° C, especially suitable at 40 ° C. for example, for percutaneous acid «perbenzoic acid« metablorperbenzoic acid «peradipineka kieelina ·
As a solvent with perklssllns allues preferably halogenated hydrocarbons such as methylene chloride chloroform or ethylene chloride
As the reaction temperatures suitable for eu of the same as for the reaction with hydrogen peroxide, it is described ·
Compounds of Formula X are composed of salts with organic and inorganic salts. Salts for boiling of Formula 1 take into account especially salts with physiologically unsaturated clays. These include preferably a halogenated hydrogen cell, such as, for example, hydrochloric acid and hydrobromic acid, further phosphorus kielin, asotne kisse »Lina oaimoj nono 1 bifunctional carboxylic acids 1 hydrocarbonic acids, k & amines on acetic acid, maleic acid« sslina, acetic acid, phonoma acid, tartaric acid • lactic acid, aaliell kiaallna · eorbinoic acid 1 lactic acid and lactic acid now sulfonic acid · like 1,5-naphthalene »disulfonic acid · Production of such salts of mugs in a self-enumeration manner.
Polamine natrium or forsule VI is a known compound.
Compounds of the formula V can be obtained by eating the general formula
CH
mixing aa 0? 8? 2? 6? dimethylmorpholine 1 catall. hydrates.
As a feeder, a primary organic solvent was used, such as alcohol, such as methanol. The temperature is not critical. But, as a rule, it is lying 0 - 50 ° 0.
In the catalytic and chemical state, mucus is a conventional catalyst hydride, e.g. platinum «Raney-nickel or palladium, in which 5% of palladium-carriers work particularly well ·
The attenuation according to the invention contains in the morpholine oatatka aa P.subatatrified phenyl residue associated with the propylene lanoe asymmetric O-atom 1 on the other can occur in the form of a racemic and in the form of optical antipodes "The last can also obtain the resulting raometes by deleting with optically active acids" for example, an A / A camphor of acid "/ +/color 10 -sulfonic acid" 0.0 * "dibenzoylvinaco [L]" or IMBblic /, LA / "vinic acid" - 5 - S / - / - * acidic acid, L / + / »glttamine acids ~ 4 ~ -sulfonate, X / - / abiline acid« Hi DA / »* j * acidic acid · This extraction can be 'Hard to get by eepening methods'
The compounds of the proaalaqua have a fungicidal effect, 1 towards the fringe, they can find the right one, and the battle with its mushrooms will give you a field-value. Compounds of eu bind a special fight to the eye of Ivica braffin *, for example, Kryeiphe graainla, Podo-spheroa leucotri / dancing apples /, Bphaerotheca pannea disease rdje /, Oldiua tuckerl / right bra & one of the genera Puccinia, Uroayces 1 hemileia in particular Puccinia graminis / orna rdja Site / Puooi & coronata / rdja ovsa_, Puccinia eorghi / rdja kukuruia /, Puccinia atriiformia / sensuous red Seita /, Puooinla reocndita / red red Seita /, Uroayoea fabas la appensloulatus / red Swine bean / as 1 ea Heallela viatatrim / rdja kafe / 1 Pragmidiua anoronatum / rdja ru5e /.
Further work is carried out on the following types of phytopathogenic fungi: tfstilago avenae / principal /, Venturig inaegualia / apple carotene / Oercospora arachidioole / disease arya leaf kernel / Opbi-abolua gr amini a / Diabetes sieve /, septoria nomorua / brown color Sheets and weeds / or ftarsonina rosse / star gar rose. Some substances of this class of syllables have prominent spores of action against the various types of the following genera:
Hhlsootonls, Tilletia, Helminthosporium as 1 < / RTI >& versus various types of peranospora, Ooniophora, Lan & ltes, Corticium Tboilaviopaic and Fuaarium.
In addition, the part of the iodization of formula 1 1 closes the fitopatohoa bacteria as per pr Xynthomonas vesioatoria, Kanthomonas orysae and other gentomon & de9 as well as against different types of Erminia tracheiphil 6
First of all, active substances are proaalasca ", the god of their fungicide, and fungicidal effect, suitable for the fight against infectious infections that have been infected with glycol and ampia, such as the Genera Candida" Tricgophyrte "or" Hiatoplas ". On special features · according to Candida-like species as Candida albioans, and preferably suitable for the treatment of skin infections of the skin, and the occurrence of a "particularly gonital tract", for example Vaiinitis, euphorically cured ea Candida. that the active preparations in the form of fat «plugs, suppositories, ovules or other suitable forms can come in suitable ·
Fertilization of the pharmaeutic preparations may carry out, in its own way, the moisture of active substances in conventional organic or inorganic inert pregnant materials and / or by "strong materials" such as water "gelatin" milk secheer, starch "grus" msgnesiumetetrate "talk" vegetable oils «polylkyleneglycols» vame-lin «preservatives» stubilization, syringe or emulsifying, salt in the change of osmotic pressure or buffer «
Posing is carried out according to individual sautées ", but in case of" a meal of 1 to 2 tablets a day ", 50-100 mg of active ingredient was present at the time of a few days for a convenient dosage
Kasti s & holder is made of O 5 * 5%, preferably 0.5-2%, especially suitable 0.5-1% of the active substance. The following test report and the results given in the table are given to the strata, such as the required in-foroaiju about dosing active substances ·
Compounds according to the invention and sphythmous veins are at their work-bridge according to the Candida albioans in the Vagin & Candidlaels test on paws described in Path.Kiorobiol. 23i62-68 / 1960 /, whereby the following results are obtained t
Compound
: Keric ^ ntrocium in% in which the " ED 50 " the effect of cis-4- [3- (p-tert.-amyl-phenyl) -2-methylphenyl] -2,6-dimethylmorpholine 0,01 cis-4- [3- (p- -benzyl) -phenyl] -2-methyl-propyl] -2,6-dimethyl-morpholine 0.01
EXAMPLE 1 In 1223 g of cis-4- (2-methyl-3-phenyl-propyl) -2,6-dimethylmorpholine in 4 l of methylene chloride at 5 [deg.] C. for 45 minutes, 4941 g sulfuric acid concentrations were added, 60 minutes 520 g of 2-methyl-2-butanol. The reaction solution is treated with ice with ice cooling and the aqueous phase is extracted several times with methylene chloride. The organic extracts were treated with sodium hydroxide and finally washed with water, dried, evaporated and oil cis-4- [3- (p-tert-amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine was distilled in vacuo, key point 120 * 0 / 0,1 Torr.
Analogously, it is prepared by reacting cis-4- (2-methyl-3-phenyl-propyl) -2,6, dimethylmorpholine with 2-methyl-3-phenyl-2-propanol cis -4- [3- [ ;, ": -Dimethyl-benzyl) -phenyl] -2-methyl-propyl] -2,6-dimethylmorpholine with a point of 162 [deg.] C / 0.04 Torr.
Experimentally it has been determined that the above reaction can be carried out at temperatures ranging from 0 ° C to 50 ° C.
The above starting material is obtained as follows: 1000 g of ^ -methyl-cimetaldehyde, 10 1 methanol and 789 g of cis-2,6-dimethyl-1-ol folin treated. in a nitrogen atmosphere with 50 g of 5% palladium-carbon. Then, while cooling with water at 30 ° C, it is hydrated to the end of receiving hydrogen, it filters off the catalyst, methanol &
They were deprived under a deep pressure and then distilled the raw product key at 09 ° 0/0 * 055 Torr.
EXAMPLE 2 266 with OIE < 3 > 3- (p-toro * " aryl-phenyl) -2-ethyl-propyl] -St6-dieityl-pha-phoroline with reflux in 500 ml of abscess ethanol and at room temperature 5 C, % Of the HCL-ethanol solution is added to it. The homogeneous solution is evaporated on a rotary evaporator to evacuate, and the residue is recrystallized from 100 ml of water. Crystallize the paste with water and oouSi in dryness under vacuum at 55 ° 0. Obtain the hydrochloride of cis - N- (5-tert-amyl-phenyl) -2-methyl-propyl] -2 H -dimethyl-morpholine as paints, light hydroxyl crystals with a melting point of 204-206 ° C.
EXAMPLE 5 TJ 21 g of cis-4- [3- (pyrrolidin-2-ethyl-propyl] -2-dimethyl-morpholine was added dropwise to acetone ice- atrood of 60 ml of 50¾ of hydrogen peroxide in 60 ml of anhydrous anhydride to react with a temperature of 5 ° C and then further reaction of 16 hours on the oblique temperate is allowed to continue. · Elog is checked for the thin film chromatography / hexon ether Iti / To dissolve the dry peroxide, the reaction solution is cooled to -10 [deg.] C. and treated with 200 ml of 40% potassium hydroxide. After 20 hours stirring, dilute with 500 ml of water and extrude with chloroform. Nitrogen extracts of chloroform are neutralized by the "solution and evaporates. The precipitated cm of the residue from ICO ml of pentane yields cy-4- [3- (pyrrolidin-2-yl) -phenyl] -2-methylpropyl] -2,6-diethyloxypholin-h-okeide -9 -
The following examples describe the development of the pharmaceutical preparations * Example 4
Examined eu in the usual way of the vaginal tablet Fading aaatavai 50 mg 400 ag 261 «g 100 ag 25 ag 9 ag 64? as 0is * 4 ~ / 3 ~ / P * ~ t; ere ♦ * amll-f enyl] -2-aryl-propyl] -2,6-dimethyl-aryloline OE * calcium ether 2 H2O Directly-oriented thick 2μΑ-ΗΧ 1500
Kleini ucer / euden raeprflivanjem /
Polyvinylpyrrolidone Linuneka kieelina
Hagaeei & amateurs and
Example 5
The fat of elededeg eaetava and ci gA-...... 3 a / a-di-methyl-benzyl} -phenyl / 2-naphthyl-propyl-2,6-diaethylttorpholine is 0.7 g
Cetyl alcohol 5.6 g
Vineyard grease 9 »C g
Vahelin, beo 79 »3 g
Paraffin oil * with 100.0 g 10
VtiΛ9Τ β
Proiavaden J * to * «® slsddog itetavtit ere · -additional phenyl / -2-« ethyl · -propyl] -2,6-dimethyl-arylolin 0 * 7 e »Polioacetylene & tearate 3.3 g. 8.0 g Va * or & b * o 10.0 g Karbokaivinylpolymer CA2BOPOL 934 Fh 0.3 g of KaOH, the most purified 0, Cg Water, demineralized 100.0 g
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH756079A CH644113A5 (en) | 1979-08-17 | 1979-08-17 | N-substituted 2,6-dimethylmorpholine compounds |
| CH418780 | 1980-05-29 | ||
| YU1754/80A YU43475B (en) | 1979-08-17 | 1980-07-08 | Process for producing morpholine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI8011754A8 true SI8011754A8 (en) | 1997-06-30 |
Family
ID=25694874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI8011754A SI8011754A8 (en) | 1979-08-17 | 1980-07-08 | Process for obtaining morpholine derivatives |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0024334B1 (en) |
| AR (1) | AR225318A1 (en) |
| AT (1) | ATE4206T1 (en) |
| AU (1) | AU530398B2 (en) |
| BG (1) | BG60798B2 (en) |
| CA (1) | CA1128943A (en) |
| CS (1) | CS402091A3 (en) |
| CU (1) | CU35298A (en) |
| DE (3) | DE19375077I2 (en) |
| DK (1) | DK150509C (en) |
| ES (2) | ES494314A0 (en) |
| FI (1) | FI69455C (en) |
| FR (1) | FR2463767B1 (en) |
| GB (1) | GB2056454B (en) |
| HR (1) | HRP930340B1 (en) |
| HU (1) | HU182189B (en) |
| IE (1) | IE52642B1 (en) |
| IL (1) | IL60813A (en) |
| IT (1) | IT1220970B (en) |
| LU (1) | LU82713A1 (en) |
| MC (1) | MC1345A1 (en) |
| MY (1) | MY8500272A (en) |
| NL (1) | NL8004537A (en) |
| NO (1) | NO153176C (en) |
| NZ (1) | NZ194628A (en) |
| PH (1) | PH15480A (en) |
| PT (1) | PT71708B (en) |
| SE (1) | SE447730B (en) |
| SI (1) | SI8011754A8 (en) |
| YU (1) | YU43475B (en) |
| ZW (1) | ZW15780A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3421810A1 (en) * | 1984-06-12 | 1985-12-12 | Basf Ag, 6700 Ludwigshafen | PHENYLALKYLAMINE - BIOREGULATORS |
| CA2008775C (en) * | 1989-02-24 | 1998-12-22 | Alberto Ferro | Nail lacquer |
| EP0446585A1 (en) * | 1990-03-12 | 1991-09-18 | F. Hoffmann-La Roche Ag | Control of fungal infections in aquaculture |
| EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
| EP1749826A1 (en) | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing bepromoline |
| EP1842848A1 (en) * | 2006-04-03 | 2007-10-10 | Galderma S.A. | Process for producing 3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propionaldehyde and cis-4{3-[4-(1,1-dimethyl-propyl)-phenyl]2-methyl-propyl}-2,6-dimethyl-morpholine (amorolfine) |
| EP1935889A1 (en) * | 2006-12-21 | 2008-06-25 | Galderma S.A. | Process of producing amorolfine |
| ITFI20090032A1 (en) | 2009-02-20 | 2010-08-21 | Synteco S P A Prodotti Di Sintesi Per L Ind | INDUSTRIAL PRODUCTION PROCESS OF CHLORIDATED AMOROLFIN |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT354187B (en) * | 1976-11-22 | 1979-12-27 | Hoffmann La Roche | FUNGICIDE AGENT |
| DE2656747C2 (en) * | 1976-12-15 | 1984-07-05 | Basf Ag, 6700 Ludwigshafen | Morpholine derivatives |
| AU4690979A (en) * | 1978-05-16 | 1979-11-29 | F. Hoffmann-La Roche Ag | Heterocyclic compounds |
| DE2830127A1 (en) * | 1978-07-08 | 1980-01-17 | Basf Ag | N-ARYL PROPYL SUBSTITUTED CYCLIC AMINES |
| DE2830999A1 (en) * | 1978-07-14 | 1980-01-31 | Basf Ag | METHOD FOR PRODUCING STEREOISOMERS N-ARALKYL-2,6-DIMETHYLMORPHOLINES |
| EP0008686B1 (en) * | 1978-08-08 | 1983-04-20 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Synthesis of phenyl-propyl morpholine and piperidine derivatives |
| DE2907614A1 (en) * | 1979-02-27 | 1980-09-04 | Basf Ag | OPTICAL ACTIVE SHAPES OF THE 1- CORNER CLAMP ON 3- (P-TERT.-BUTHYLPHENYL) -2- METHYLPROPYL CORNER CLAMP ON -CIS-3,5- DIMETHYLMORPHOLINS |
-
1980
- 1980-07-07 ZW ZW157/80A patent/ZW15780A1/en unknown
- 1980-07-07 IT IT23283/80A patent/IT1220970B/en active
- 1980-07-08 YU YU1754/80A patent/YU43475B/en unknown
- 1980-07-08 SI SI8011754A patent/SI8011754A8/en unknown
- 1980-07-11 CA CA356,038A patent/CA1128943A/en not_active Expired
- 1980-07-25 AR AR281915A patent/AR225318A1/en active
- 1980-07-30 CU CU8035298A patent/CU35298A/en unknown
- 1980-08-01 FI FI802418A patent/FI69455C/en not_active IP Right Cessation
- 1980-08-05 PH PH24406A patent/PH15480A/en unknown
- 1980-08-07 DE DE1993175077 patent/DE19375077I2/en active Active
- 1980-08-07 EP EP80104656A patent/EP0024334B1/en not_active Expired
- 1980-08-07 DE DE19803029966 patent/DE3029966A1/en not_active Withdrawn
- 1980-08-07 DE DE8080104656T patent/DE3064267D1/en not_active Expired
- 1980-08-07 AT AT80104656T patent/ATE4206T1/en active
- 1980-08-08 NL NL8004537A patent/NL8004537A/en not_active Application Discontinuation
- 1980-08-11 IL IL60813A patent/IL60813A/en unknown
- 1980-08-11 NZ NZ194628A patent/NZ194628A/en unknown
- 1980-08-11 AU AU61321/80A patent/AU530398B2/en not_active Expired
- 1980-08-14 PT PT71708A patent/PT71708B/en unknown
- 1980-08-14 LU LU82713A patent/LU82713A1/en unknown
- 1980-08-14 MC MC801466A patent/MC1345A1/en unknown
- 1980-08-14 FR FR8017977A patent/FR2463767B1/en not_active Expired
- 1980-08-15 HU HU802034A patent/HU182189B/en unknown
- 1980-08-15 SE SE8005784A patent/SE447730B/en not_active IP Right Cessation
- 1980-08-15 DK DK355180A patent/DK150509C/en not_active IP Right Cessation
- 1980-08-15 GB GB8026709A patent/GB2056454B/en not_active Expired
- 1980-08-15 IE IE1729/80A patent/IE52642B1/en not_active IP Right Cessation
- 1980-08-15 NO NO802453A patent/NO153176C/en unknown
- 1980-08-16 ES ES494314A patent/ES494314A0/en active Granted
-
1981
- 1981-03-02 ES ES499957A patent/ES8201563A1/en not_active Expired
-
1985
- 1985-12-30 MY MY272/85A patent/MY8500272A/en unknown
-
1991
- 1991-12-23 CS CS914020A patent/CS402091A3/en unknown
-
1993
- 1993-03-12 HR HRP-1754/80A patent/HRP930340B1/en not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG098580A patent/BG60798B2/en unknown
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