DE1445134A1 - Process for the preparation of trifluoromethyl-1,4-benzodiazepine derivatives - Google Patents

Description

The ärtindwoa affects new »

old valuable pharaokodynjuaieohen.

The new compounds of the invention; have goose epexially ilirkaamkeit on dae central Nerreneyatea dee animal Organlaaua and are particularly valuable as "ataractics" and antiaapreseioaealttel and Beruhlguoaeaittel · Aujieerdesa beaitseo. these connections antiJconvuleIre and miakeient »i> aö.nen new iirksaakelt ·

The ürfindun ^ also relates to new trifluoroethyl acbe in the Herovellun ^ ά · τ therapeutically »irJc

mouth ^ enzodioxepine of this invention mean ^ eTull Mind

the irifluomethyl-1 _t 4-l? en * oai «4tepindei ⁱ lv * t8 dleaer iarf indunii» eroen by the £ ol & m.dQ 3truJcturfor «el wieiergabi

809805/1073

St. ₄

Here in

Alkenyl »

eis tfseeerate £ fa £ es ₉ a t & lsiaxe JUJgrl-,

WmmmmxmtmttmUm. od «r» iae

«La i» * a «r * tciftota» _t »is. Hfelagtaatea, * iu * fri «

fluor »· thy I-,

oil*

at farm »! f let eia fteeeerataffa to «, a Qltlezfttc«? or

809S05 / 107S

Jauss become the precautionary compounds of this invention represented by the following atrocture form *

yprael j

NH-nlöderes

A compound of this invention of particularly preferred and advantageous calming air fresheners is 2--ethyl "Liao - ^ - - phenyl-7-trif luaraethjl-3H-1 ₉ 4 ~ b" a £ <"di * sepla-4-oxide,

The Begelohrrang "lower" alk / lgxuppe ¹ · _r "lower A-Lkenyl ^ ruppe ^M and" lower Alkojqrgruppe "suffered here alone or in Koaioln &tl'jn with other Bexaichnungea. Groups with 1 to 4 »Yorsu ^ e« eiee 1 to 2 zCoiu ens to iTf at oaen genwint ·

The irflnaunti refers, al oh also s, to phaxaaxoutiiich aanehaüare SuuresAditionsseJ.se aer the above defined ίΛββη, which old non-toxic "organic vsad anor ^ aniaohen." J & uren ei "oil a et" eruea. l> ermrti (£ e -Alae know slightly btJcaanten methods made "ground · I / ie ßase either the calculated old Meo ^ e an organic or inorganic acid in an old" ater axsohbftren LööUBga "itt" l _t "ie Example A" Ice acetone or ethanol "must be set", where the old is isolated by cooling and cooling, or a clean build of the acid becomes old in an otherwise immiscible solution, as for example Ethyl ether or chloroform * obei iiich daa wünnte 5alx direct abacheitiet. ^ Ei cner or ^ auia ^ her balse ainc such & lt Makeln-, r ^ uaar-, ii * nxoe- _t

-, S * «cia-, isiaaathjxaaaalio / l-,

R Π Q R Π -, '1 Π 7 C;

-> _s £ & @ ig «·» ® Proplon · »* wsin-p salicylic lemons ·» alue © »- ₈ jdilch« ·, apple, maati * l- _e CisuMuaia, cltracon »,

the

ait

4iiiwi solo & s old C

is

Z & lp &% ®T9 & ss £ ® & » dl · ·· Saiae

Si ©

diaaer

CF ₉

809805/1073

% f &> ^u

Herein H ^ «R ₂ and R .. dl« given meaning and λ «divides a Halogenatoa represents» vorsugeweiee «in chlorine» or

Oeafc ·· the scheme given above is “la trifluoraethjleubetituiertee o-Amino ben * ο phenol alt Ejdro ^ laainhydro” - ealorld in a lower alcohol ale I £ «iaeamlit & l» «1 · beiepieleweiee nethaaol,« ethanol or IaopropaaoX »TO? iee In igenemrt an orgeaiech · ^ έ ** ·, wi * »eieyielaiwiee pyridine or lutidine, toeheaadelt _t ia · ent * prefthiea <A« BeßtefpJieaonoxia au form · lairoh Ao / liemng the ··· Oxia «üUAtt-fe Behassälueg with a v-Reloaojlohloria lying in wait for elnve »iurebinding means» tel · · »ie einea illcaliaatallfer & fosyd» s * B »Kmtri ^ K» or ialiuehydrojgrd »eiro a tririiM> ra« thjlsub «titled« 8 »« CX-HAleacyl-ettino) -bensopbenoaoxia erhcLLten _v "elehes dureb. fletewaiiig old einea mmxrmn denjdratieieread Mitt «l» wi $ beispi «! ·« ·! ·· chlorine »retoXf or .Sehvefeleäore,« yklleierS «i ^ d * other ·«! X » da · OxIa auok aeylates wta aykiielext we * · deu _v by the reaction la 8e« l ^) i * r «J.8atmg slis ^ s Z '& a & ta « in ·· eaurebinüeadea ttittele durflo ^ fuhTt «ir4 * l> aa «ztialten · ormethjrl ~ 2- (q« tial oallryl) Ά -p ^ enylehin Aaaoniak or aa primary AmIa b * i ana inert IBexneMltiwl »vl · Taa« er _s

«Dreary > * Q In

or a lower alkyl alcohol, ie methano

ο «gate

Iaopropamol "treats" thereby the
phenyl <-3U «> 1» 4-benxoAiaaepin «4 * ox / d · die eer« earth ·

Ilia ml m inagMfly «i ^ r ^ '« » fc4nuhm tr

■ ubetltuated o-> amlnobensopnemon · be

th / X «

'809805/1073

Rs

fcwei is already there

• irtfiucrÄ © thyliaatlß, will sit brosid la an Ath # rI8 »mg _f

or XetrsbydTOfturaaXustasg * feel

mi® hmlmptmlmmt »® « i & er ÄthjrX

Μ ©

öioxisä®ls with

sit esuse & lioaeas & ä «?

809805/107

trlert and dissolved in wasarigea Satriissnydroxya · The alkaline ~ 4 »and« old hydrochloric acid is retained and filtered » whereby the J-l ^ enjrl-ij-trifluoromethyldi oxindole is cooled

Its solution of 29.5 g of -. ~ Lienyl-5-trifluoro * ethyldloxindole in diluted «watery» satiluahydroxyd becomes at 0 ° C »it

al a 3 1-i ^ en Wasserstoffperox / dlSming treated · oils mixture vklrd J hours »stirred thereafter ait hydrochloric acid acidified una filtered · In" product is dissolved in Saseer "old an excess of a KatriumcarbonatlSsung and extracted old ether · Bach narrowing 2-Aaino -> - trifluoraethylbencojphenun is obtained from the extract "

Bine Mi fichuo "; consisting of 26 »5 £ 2-aaino-5-trifluoros; ethylbenzophenone, 27 »0 g Hyüroxylani nhyarochlorid» 150 ml Ethanol and 5u al pyridine were refluxed for 1d hours heated and then concentrated in the vacuum treated with water and extracted with ether * The ethereal solution wiru old Weser washed and diluted with Fetrolather · Hach Let stand overnight 'the crystals are filtered off and aue Xtbanol uakrlstallleiert »whereby 2-Aaino-5-trifluoromethylbenzophenonoxia is received "

Chloraoetylchlorld (11 »2 g) is alternated with 4» 0 g of sodium hydroxide in a bucket of LSsuag from k '? Left to stand at room temperature, then acidified with hydrochloric acid and diluted with water and ether. The ethereal chloride is separated off, dried and concentrated, which gives 2-chloroacetamido-5-trifluoriaethylbenzo-phenonoxia as the carbonate 200 ml of acetic acid are suisegebea »and the resulting mixture is saturated with hydrogen chloride. According to Vd. υ hours is ^d at 4ü to 50, the mixture iia Yakuum concentrated »give 2-chloroethyl-4-pheayl-6 * trlfluormethylohlnazolln" i "obtained OJsyd" ird "

lln _t > -oxide and 150 el ice-cold 30 jt-igea methanollschea methyl

8 0 9 8 0 5/1079

asoLu tseraen flattened ναιά 16 hours at chewing temperature leached «i) the crystalline * product is filtered off and removed from · ethanol \ jakriatalliei» rt, «© by 2 ^ © tajrlaaln - $ * p3iettyl * 7 <"'

is obtained.

An «ethanol! ε »α« Lt5 © ung shown in the produced Bas "is, old eisutrn ifeereohsss & th" rlaoh "a

b «h« adelt _t «odi ^ cli nmoh Filtration, txad Uaau» feto & lisnol 2 »M®th ^ l« sim «&-> sh« ^ fl-7 ^M trifluor *

-1 ₉ 4 «b« & sodia £ eplnt4 ^v ®xy <ä ^ <ürocshlorld # ^ iialt «n« aird,

A Mieekung b # st «h ^ id with * 2® _$ bg 2-Nitro * 4 <» trlfluor->

? o Ml Chl ^ fmacArstsffeaur * imd 40 si * Ä »*« r will

on dO g E ^ rstaa ^ enta El »| pgel» e & «^ sit 6.0 g at 0 to 5 ° Q b * h ^ iaa $ lt · 1) 1 «asha !,» «,«

wlra! «Agiss ^ ss su." aiiier m-is »rlg« ii Löeim ^ Ten Cuproyanid (berä; · - by Behsnälim ^ ταα i5 t> K ^ X ^ reulJTat old

50 Mlsut @ & lan ^ to 50 feie 6ü ° C «r>

Dme firm

imi iPiitxmti ^^ <ä @ r extracts will

jon 1t _t 4 g 4 «r im & 0 el

the lower © Mj ^ g «®« it si ($ ä®M «a Ath # r nod Slad« japfan te «fird ^ - Amino ^^ t ^ ifXiaiirsss ^ grlbaii ^ oiiltril« rhaltea

To miner Atherl ^ sroo ^ Yoa 1O ₉ O g Phenyl aagnaeluabroaid 9 · 9 β 2 ~ i

i8chus7 ^ * ira 3 hours 1mm ** lA ^ kf1.o »·« rhitst, «oramf üls uzid 50 al kona« n trier te Ohlorwaseereäof feäui »sugagaben« Uar! «'© Btsfoff wii-d filtered off and with helaaea waaaer Gewaaohen »uroaurcb 2-Aaino-4-trlfly ^ or2iethylb © aÄOpheaon is obtained

PAD 80980 5/1079

this 2-Xmino ^ ~ triflu0rm <»1 ^ 1beasophs & .9a mlrd with Hydroxylaain hydrochloride, yridine and ethanol for 24 hours "A kitchen flua is heated and worked up" as described in Example 1, whereby 2 »Aaiao-4 * tririux> raetJbtyloeiiSdph9 & yoiiOxitt obtained will·

Its mixture consists of 14 »g of the oxime in Ίου ιοί Slsesaig is treated with 11 ₁ 2 g of chloroechoyl chloride at 50 ° C , and the mixture obtained is at Timm. temperature stirred for 16 hours · The precipitate consists of 2-chlorite th ^ l-4-phenyl »7-trifluorometh / lohiaamolln, jJ-oxydh / droohlorid ·

; tethylaaiin (IpJ iüa #insr 25 ^ -i ^ en methanolleohen solution) «lrd au K ', ü g 2-Cüioraeth / l-4-phenyl-» 7 "trifluoraethjrlchinasolint ^ -ox / d' - 'given the hydrochloride often The resulting miso slope was stirred at iauateaperatur for 24 hours. Naoh kbt 11 stepped ion of the re-production and recirculation of the lower base layer as well as ethanol becomes 2-üeth / laaino - ^ -> phen7l * a «trifludrmeth7l» &-> 1 _> 4 * ben £ odlasepin ₉ 4 * ozyd received «

“There will be an athanolla-like solution to this baee with a Covered with ethereal chlorine water treated »» o vird dae hyüroohlorid received "

üeieplel 3

4-trifluoromethylisatin (21.5 $) in 100 ml 'D furan su a Atherlösun τοη ^ 27 # 0 g P ^ e ^ up _T and the resultant mixture for 40 minutes at exivitct hüoJcflusa xma and then cooled to Eieimee ^ r and co-centered 3ohweiele * ure βsieben. ΰ * τ Hledereohlsg wlxu filtered off and in a Batriuahydr <uqrdlo * »UK £ gelSat * iMrch acidifying and filtering the resulting SledersehXagea ^ -r ^ enyl-4 * trifloormethyldioxindole is obtained.

., ine .uosuog uleao * l> iozinaole in vsra 'nr.i * m "ftscrigem Katrlumhydrox / d is Tdt 1Uu ml 3 ^ -ig # a waa ^ erstoffperoxid at ü ° C treated 1, it is λμά i-Aaino-6-triiUuoraethylbenÄQpiienoG ·

8 Q9 805/1079

% 5 »3 g <S4ae« «

2S> au. Pjsldiia will ^ ex SSirfc nail 10 Stisffld * & Xfiss £

alt 34 fg ms ** But $ X @ M &m> 12 otnaäa & lams, ImX 25 fei «30 C

© as ^

al Äthsmol tSEüä 50 al Fgstä $ M wisA 12 3teä <feas,

öe "Oxia" £ b 100 ml Bealgaäsasf "

at 90 ^@ G @it 12.0 g of C

80 9.80 5/107

the * standing becomes 2-naxolin, > -oxide filtered off

Mea quinaxoline (3.0 g) and 25 al 30 £ »igea äthaaoliaohea Ithylaala vard ^ tS hours tool R« »taapartment gartlhrt · Dar filadaraefalag« ird abfllart uad au acetone uakriatalliaiart, whereby 2 ^ t ^ laa ± iiQ-5- pfaen / l ^ -triflu * rmethjl-3H ~ 1 _# 4 · - benaw> dia * epia _# 4-oxyd receivedo. will·

Lila · Löeuai from 1 »0 above the Ireitn. Baa · in 50 el Athjrlaovtat tdrd alt βία · «molars. XqulTal «at Ualeiasäur * b« h * ad «lt · hmch con * entri" run, i aod cooling is there "Jaleat" rst.

be "t * h * ud au" 21.3 g 5-Trl flixora · thy 1-leatia in letrahyärofuran, becomes "u" iotr Ath. # rlöeiaig ron 32 _e 0 gp ^ hlorphaajrlma & n * eiu "br" tLd sug "born «A · laeb 50 ^ inutea RHoJcriuaaaxhitsuag« ird dia Jiiachua «on JiIs and ko & zo & trlart · ^ ohmifalaüura gagaban · Ifaeh Anfaxb« ltuag _# wi «in Baiapial 3 beachri * b * n _t becomes Jp- ^ hlorphanylora.

Diaa ·· Dioxindole «Ird in« üssrigar Satrluahjdroxjd-XOauBg old 125 as a 3 5t ~ igaa faaaaratoffparoagrdlusung b «l o ° C behead old. Maoh 3 JtuaAaa is diaelnng aagaaäutrt and filtered. Because the «feete product« Ird old alxiaa übaraohuaa rlgen Matriuaoarbonata hairdalt · laeh Sztraktlo & old Äthar uno Sladaapfao dar extracts remains 2-Aaloo »4MJftl9r-5 ~ tri t lao

Mlaohuag beetehend ana 15.0 g dea la described 4ei "e produced benftophettoaa, 13.0 g H / droxjrlnainhydroohlorid, 75 al ethanol and 25 al Pyridia is 12 hours long aa ßUckfluaa received. laeh work-up, «la 1» example 1 aeaohrieben, "ird 2-eel no ■ 4 * -Chlor" 5-trlf luoraethylbenaophanaa, - " get oxia

· Β OxIa becomes 7,0 g 2 «chloropropionylchloria in 50 al Ksalgaäura old treated at> o ° C · i) la obtained

809805/1073

* ii * at R * öut * rr pent door ti S-tu & don. leaf etehm then filtered, "o <S" rch £ "(^ Cfclor * thyl)

will"

Dl «Bahaa & long ¥ cm 1O» O g you »·» Cbiaeftollne old 75 si Kaltea 50
ti ok

•! Skssaa & ii ^ ee ^ ToaauSAiaiSBsaiiisajyAiss ^ S! "S $

«5

«1x4 Sisr ^ k Rttekfl« »jito« i »adiis ^« it Pyriilm vmä. itheaol la eeia oxime

12 _# 0 g

809805/1079

and 125 al Kealgaiiure is left standing for 16 hours » whereby i-chloraethyl ^ i-m-toljrl-o-trifluarmethjrlchinAeolla oxide »Aalten will

This chiaasolin (15.0 g) is treated in moxane oil with 20 g of 2-ethoxyethyl aiA at a temperature of 43 hours. The solution is then absorbed in vacuo. The residue becomes cold chlorine acid · Dissolved »old ether matched» old ffatriuahydroxyd toaeieoh and old ether extracted. 4-ben * odiaitpln, 4-ojyrd is obtained

Kiae Lueung made up of 21.5 sec. In tetrahydrofuran becomes 46.0 g old

Treated in ether. The Uieehasg is then heated for 30 minutes aa iüokXluea "then cooled and added to ia and Jt-centered sulfuric acid and prepared" as in Beieplel 1 eohrieoen "where I-trifluorometh / ldioxindol is obtained · luroh stirring this in water-dioxinaeoliger «.Triuahjrdrox / dl3« ua5 »it Uf al J Tt-igea * aa * eretoffperoxyd for 5 hours with Raimtenperatiir and lufar- • elution,« 1 · Ia Beieplel 1 be »ear rubs _p is 2-A * iao-4'- 5-dltrifluonMthjlbensophanon obtained

■ »

By KttoJcfluaebehaadlung the ··· Be & eophemon · alt Hydrox / laminiic j £ ^ chloride, Fyrldin and Ethanol idrd da «« ntepreahend · OxIa received «

Chloraoetjrlohlorid (6.0 g) is given * ut # _t 0 g 2 "AAi! Id * 4 **> -üitrifluormeth / it) en" ophenon-oxia and 100 al jSsaigaAure eei 60 ° G for hours at hauavteaperatur «tehen ^ elaasen» then filtered »whereby da · yl-4-i> -trifltto

is obtained

809805/1079

10 g dl "*", "China Soli & s Verdol ait 75 si kfeltes _t saethaaolioshea KettayXaaiix vexaieoht" Hceh Jte en fe &#i; lAua1r "mp" Ravar is filtered diet Misslsang _§ where

obtain

Example "9

ait © iner l'etrshjdrofuraalöeuag

«Iae 40

fXidin wira 16 3timdexi! fts « la Beie ^ lel

will eiae reu A <jui? * l * at citr © a * ß «ffiur« wsa -Abictüiluas dae citrate

"Ird" dar freita base old one

© AD ORIGINAL

80 980 5/10

Example 10

Sine ttleohuag consisting of mm 54 # 4 g 2-5 ~ tri £ ltta »ethjrl & ansQ]? Lieae & (made curan Uaeetmng o-Broaphenjrlmagneeiualsroaid old 5 * Xri * lueraethylisatln tea Behaadlxtag άββ preserved ^» »^ Brcapbsn fp. Indole old W W "R3xy" ä) _f 26.0? 5 al Pyridia and 200 si ethanol is stirred for 24 hours and ea Riiaitfltis btluadelt. Dl »R * akti« m »* le« ii \ asÄ elrd la T »in * -

whereby dm 2-

To · ± ώ »τ MtTJMXi XdffiBig de * iß 4«? fr «» ohrlal »fuin ready« t # a QxXtu (17 * 0 g) la 150 «1 Äia ·» »! ^ w« rd «a 10.0 Ghlormcetylohlerid sufftg * b« a · ¥ »oh 16
becomes dl · a — fcttoBMlaehras la Takuua luniatatrlesrt «aä ier» tjuid au «Bensol uakri» t * l 11 alert, «a

10 £ this · ChlÄMolln * vtrdea alt 125 al 50 ■ • thejiolieohea Metfajrlaala 12 StuxMiea lan «toe! b # hjuadelt # Vaah Flltrsticn turns 5 - & * Broapheaylfi- «tetfeylaadja» -7 ·

To a Mleöhiaf aae 28 ^, 0 β 2

(produced, «ie la Beieplel 1

In 250 al Eleeeaig }% 0 g of 2-ChloiiiexauioyIehIorld b # n. Haea 14 attmden at Haaateaperatur "the Mi * abo YeücuuÄ kona" Ltriert and the Htteketead * ne Beasol grows crystal, whereby 2 - (^ H: hlorp «at / l) ^ - ph4mil ~ 6-trifluorsie1 ^ 1ehia colln, 3 -oxyd received »ird.

Sine l & mmg ran 25 £ dleeee CnlaasollJt · nad $ 0 al Aliylealn in 10) al Metiienol is 36 hours laag $ el Bauatea · perfttiär etehen ^ elaeeen »¥ aoh filtration and Uafcrietmlliaation aue methanol is a-AJI / leAlm ^ i-outyl- ^ 3K -1 ₉ 4-b «n * odi« «i>« in _t 4-oxide obtained ·

809805/1079

BornQ is TS & L ÄiStesffisX

it ©:

809805/1079

MlsebHttg ΐ3 «βΐβ2Μ * ά au® B ₉ Q

is 15 Minatea lau «uf 50 to ia ^v α den, laftg b« l Raiaif aygatag goxfOurt ·

809805/1073

Claims (1)

a t © s. Cf. -V 80980 5/107 2, procedure aach
d & aa dl «-CFy-Sruppe slöfc. ia i-JteHiiag% «fiM @ t msä da *» fl | «In · nl» d «r · Alkjrlgrapp« 1st% st & B «eia. faestmtdffmtom "" in ehlormto * or "in" 3 procedure, 0 the HeeJctlon at $ ΐ * «& 25 Ms 55 ^G C £ m siaa * lmsrteti .i * S- 4 · Method a & öii claim 3 that the inert Loeua ^ ** lttai & ϋβ
or one down «Al & yJ 80 9 805/1079