SI8010046A8 - Process for obtaining new (piperidinyl-alkyl-quinazoline derivatives - Google Patents

Description

FIELD OF THE INVENTION

The invention is in the field of Synthesis of Heterocyclic Compounds and relates to a process for the production of new grits (piperidinylalkyl quinazolics. (International Petenst classification: C07D 401/06

Technical problem

A technical problem solved in the present invention is the expansion of the range of currently available drugs that are serotonin antagonists. This technical problem has been solved by providing a process for the preparation of novel (piperidine alkyl) -quinazoline derivatives of general formula (I) (as explained in greater detail below) which are potent serotonin antagonists. is new and original and the Applicant is not aware of any prior art techniques that can be directly compared to the process of the present invention.

The state of the art

The most relevant references in the prior art known to the Applicant are the following ^:

A number of pharmacologically active quinazollnones which are substituted in the heterocyclic ring with a piperidinylalkyl side chain are known in the art. Such compounds may be lacquered in the following references:

U.S. Patents 3,322,766; 3,528,982; 3,635,976; 3,812,257;

3,865,827; 4,096,144; and 4,099,002;

French Pat. 1,431,815; i

J. Med. Chem., Q, 807 (1965).

The compounds obtained by the process of the present invention differ from the foregoing substantially in the presence of certain substituent groups on the piperidine ring of the piperidinyl-alkyl side chain.

't

In the U.S. No. 4,033,369 discloses a series of 1- (benzazolylalkyl) 4-substituted piperidines, of which the compounds provided by the process of the present invention differ substantially by replacing the benzazole group with a quinazoline group.

Description of a solution to a technical problem with examples of execution

The present invention provides a process for obtaining new derivatives of the general formula:

Q-Alk-N} - Z (I) as well as their pharmaceutically acceptable acid addition salts, wherein in formula (I) above: is an alkylene alkylene sequence having from 1 to 4 carbon atoms;

Q <is a quinazolinyl radical of the formula:

(iv) (v) (vi)

(vii) (viii)

where s Ϊ O or S; . .

r ^ is hydrogen methyl, ίphenyl or phenylmethyl;

r is hydrogen or nitro;

· R is hydrogen, pyridyl or phenyl optionally substituted by methoxy;

r is hydrogen, methyl, phenyl, and is optionally substituted by fluoro, chloro, p-ethyl or methoxy, pyrides Inyl and phenylmethyl;

r ⁵ is hydrogen, methyl or phenyl which is optionally substituted with methyl; i.

6 7 ⁴ are each independently alkyl;

R is a member selected from the group consisting of hydrogen, hydro si and el. i

Z is a member selected from the group consisting of the radical 1 formula:

-Χ-Ar; and the formula radical:

where is:

An aryl radical; · \ S x

X is a member selected from the group consisting of ^ C = O, ^ CHOH, CH-OCR _a ,> 2 ' ^C ^ ₀ > ^CH 2> q ¹ 'θΝ-OH;

wherein said R &lt; 1 &gt; is alkyl and said q is integer 2; ig

R is a member voted from groups obtained containing vodorik, halo, lower alkyl with 1 to 4 carbon atoms and C ^ _ ₄ alkyloxy arrays;

wherein said aryl is as used in the definition of the parent Ar., and said Q member is selected from the group consisting of phenyl substituted phenyl, thienyl and pyridinyl, wherein said sani phenyl substituent has from 1 to 3 substituents independently selected from the group that contains halo, lower alkyl, lower alkyloxy, trifluoromethyl and amino.

According to the process of the present invention, the above compounds of formula (I) are prepared by the reaction of the compounds of the general formula:

Q-Alk-W '(II) wherein Q and Alk are as previously defined and W is a halogen or sulfonyloxy radical, having the compound of the general formula:

HN \ 2— ^z (III) in which R and Z are as previously defined. '

The previous reaction can be carried out according to standard pc columns for N-alkylation. The reaction is preferably carried out in some other reaction-inert organic solvent such as, for example, some lower alkanol, e.g., methanol, ethanol, propanol, 1 ethanol and similar alkanols; aromatic hydrocarbons, e.g., benzene, methylbenzene, dimethylbenzene and the like; some ether, e.g., 1,4-dioxar 1,1′-oxybispropane and the like; some ketone, e.g., 4-meta1-2-pentanor N, N-dimethylformamide; nitrobenzene; and the like.

For the collection of the acid released during the reaction by N-alkyl, some suitable base may be added to the reaction mixture, for example, some alkaline or alkaline earth metal carb or sodium or bicarbonate. Preferably as a base

Also, there may be precipitated metal iodide in the reaction mixture, e.g., so that the reaction is accelerated.

uses sodium kai x> nat.

add small amounts of a-sodium or potassium a-iodide,

Some elevated temperatures are also used to enhance the reaction rates and preferably the reaction is carried out at reflux temperature of the reaction mixture.

When the reaction is complete, the desired compound of formula (I can be isolated from the reaction mixture by conventional means) as with extraction with a water-immiscible solvent, cystalization, column chromatography and the like.

Starting materials for the process of the invention / compound. is of formula (II) and formula (III) / are iii known compound iii s <can be made by methods known in the literature. P) The occurrence of starting materials not previously described in the literary are described in detail in Examples 1-22. ,

The invention includes a process for obtaining and farmaceu ^ s analogue-addition spli with acid compounds <i _pribv? K (D. 2- vM

The wretches of the formula (I) have basat eaablna, Sbog κ maga sa convert to their therapeutic acts »4 aatok» Uta »klssliasks edioleae jokes ttratlreajea m odgoi apajodlt kiaeilotM, such as» these are, as priaa », Bsergaaake fla * classUas, for example, chlorovcdAMiCaa, ^ roas * · hydrogen, and the like, and bundles, asotic, phosphcraa> 1 al Jaa acids _t lli organic acids ·, such as 5e, for example, alr4ekna, pr »biafMik *, 9 ~ ki «9tfe * lp ^ i

Meeltn «, (MleMrin>, '* o» «adUtUellne, (.: -2-buttudlxi« * ll.ne, (ii) -2-but <o <li> tU «la». 2bidrokaibutandiUeelina, 2, Wihi4roksibut and ikiaalln, 2Udrekei-l, 2 _t 5-prapantrlksrbeeic acid, btnsee,> fanU-a-praptnova ».-hydretal-baaselelrfieta», aetaas Sauce «ethansulf oneka, beneol sulfene identical, b-aetllbenael mlfonsk, tiklehtenecht, tibeclehtht, 4-anino -.) - hydroke Ibeaseeva and «personal kieellne. Obrauto ao s« can be converted to al <»ed bass form of treatment» aa aiJRellja · «*

Compound foreule (X) ->. 'M' their iarmeeeuteki »kti>» kieelinek · ediiien * eoli iaa ju drs.jooene taraekole Ae eeebine · ua «ci wlu ee» Bel • otegoeietiel pm. Mtel eUu and keo such «ee« uf fUealU in ledeft raeliditib «bleaching» «*» jU · j · * preevl td ju juleg _u tnadaja olebeden sere onine '' ··. '·' H / i * L ·, ·

J ^ SJn »pr« U ».tnlh M ·» a «·« «! ·» Ut »P * - · M« · »· bIdu J. ¢ 21,1 ^ 0 pec ·» · »·» «« ai »· *! * · 4eM» »» i »» 'j

t. »tovla. ek »4H» i «l» p. «» »» · «rtu« »« * »« hW 4 · »1 · 4 ·» 4 · U) «·· ** ·» ·· ?? · ** ** ♦ / ... ^; 24 'f; ,? <». . · · _> J ίΛ V »... '

Ztftf, 1 "ABtageaietiiko de ji" ve no effect of seritonin eietpan rheteria of the rat in the theta eu of the used tail artery of the iepoidea: h euijeke bands (210-235 g). from each ertetle eu obtained · d ^ e epireli «tape« duilae 5-6 ea and width »2 en and perpendicular lertical in the orgehekee cupet of 100 e L which eedrfti kietonl & nl Kitkeneaeeieit's r« etvor. single-stranded contradictions of artesian bands eu Add up and add a single dot of serotonin * (40 ng / sl) to an organic bath during week 2 and in a 10-nun interval. Aplituda kmtrakoij »wasna pr« and 5 olnutb poele added foreign drugs · \> ala beautiful plowing »goniat was re-added three times to ee vid» lo de H j «contracelles again uepoetaven yen and nomalie's« e «? Rv» column tab ·! © 1 peke is not worth the »ti Εΰ ^ θ in ng / alts iaveatan number of compounds of formulas · (1), which ·» t obtained © in the upper® teat, In veli s «soil needs to be paid d« © vradnoati ^{? J} 50 ^{eit The} principal conoeatrea of drug addicts oli • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

·

Test fj «Effects in teatovia® ieluda & no injury. .>: * ·. · «*.

o '>

·· laureate (ealade) laeavata JodinJenjete 48 / (3>

Compound 48/60 (ββοίο © lifooere of obtained l ead © nta © 14oa 4-aetokei-H-oatylbanaolateeaaine and formaldacl and ©) j · Stal ₄ '* -' ··. ? ί. jy ¹ ,,, - A .. -. ·

Qal »hMilM'VM0 * fcUBik <·» «* ·« M at © R, M prlna », kUttti ^> © Β? Ώΐ · 8 J · lnekaljoa dat © compound» 8/80, pakaetU «kc iftlateatt ©

And the prostate flow »of blood in raallllBia vaekulamlo al) J« via * l © ijanaat limb and © katratltata, My w notni after 5 Umit · pat! © In jocal Jo of this compound t> eoavi uain of «4 tre (lac ·) t for 50 minutes · S © k, which counter-strike, aode ae swans © 8 © in these peoovl previously trained a «classic and BX aatagoK niatiko», f edjutie, otiaullJuchl © facts on Sol idacnl then niau pctianutl such that n peoovl third Ireni © aa © dia4ait4 © e 48/8 () and "ected from" aekls H 1 antagonal 4Jco arc | naga repent ave atakava duties l ©! td © lt © lX © t8 ©. ^ © ttt ..

• drown! Pokeeuj · superimposed Malus on atnsmalnin aadriein and large «hollow orven spots» by • lueokoti »koJ · correspond to surfaces ·» · raapednu i'e »d ·, _ηΛ « etan number of pointsfclh »nfcaSdnistlka eerotonins leso dtpin , for example ^ «atilaergld» kiproheptodin * oiacinserln _t «lent arin, pipfttaporon _tl spipapavon« picotifan and »etertfcliu, completely" permeate "oijanoau into the vent and ecetrenltata as well as injuries to the smooth surfaces of laluea and ·!» di »· 1« «1 *. '- ib · loatupak. · *

Pao's »uijaoi Zlatar d« a6ag »·] ·, melt 23 & Οµ? $ 0 g / cross« eyes au ironed at aaau and «J> vod · was on reepolageine • d llbitua« gluedIvan · compound and aa given ordlno kno raetver iii as auapensia u vod mo j aredlni «control paaov i« tlenje *> aesr <ea alepu jiabt> MdadUA f ^ lnpiti ··· & - · · ▼ • no jttdinjaaja # Jadan daa kaaai | e avla> aawi * a Jtdat n to »i of '2.5 ag / ke 5-O- (dif »uli« itil) * l ~ pipara «lailaetilj» l-notil-i;.' benei »idieol-2-« eteno. and subcutaneously. Two d «·· keenies, ie» poal · aroln <«of giving lapitlvan One Jed.j ·. i given Jo intr> v «xoanoa injakoijoa ovi» paaoviaa ₉ oei »pao's · which alul · as alej proba (tklank ^N ) (ae doaoa of 1 Compounds 48 _z Sc (aval« dissolved in water at a concentration of »e / ni). Pat «laute paale av · injakoija j;« & lne, purpurao-pH »© <$ coloring (eljanoae) ex« tresii tete jo o «started» as 0 (oleuatvo coloring) _t ♦ (nrodnj · coloring) ill ♦ + (Strong swelling). Four Chees poal · intravenous ^ infill injections of compound 48/80 pao's aa uaardani and ieluai au la removed. Hours »au avl ialuot beautiful tyrants n« tictansiiu 1 on plaster »(blood _t fluid, greyhound * no ) and peiljiv ^ jspreni * heroekepsko 0 '·

Id vt ^ ian from 0 to - »· ♦♦, at * erau <· 'of ^ over» potpw α odeuetvu vid / Ivih sweeten a ru ^ greater value than / this orvenlo / rubim pe ^ ue who? ®, blame » more than half flat # ^1? * - '', ί - ** · ™ I '* - - - - t. l · *

Other columns * 'tables · 1 stories' and 'a fair number of eating formulas (i) reach (in ng / kg bodyweight) at which the wholly distal ieluee are disturbed and due to the smooth surfaces of the lelue' ai * iepitivunib dogs (SD ^ garden tests) »',

,. v

The third columns of Table I show * t «the greater number of meals LP & jo, of formula (i) doee (in" g / kg body weight) at which there is a complete oduction of the ejnoeee of the ear and extraaletsets $ 0 of iepitive peo value).

drowning a child in tubell l are not a child in order to «bite the veil of this proneleekg as lote anymore eluoe eomo keo prlner k <'summer forsekolophic deete's compounds of d« these <orwul <i (X)

• .s \ f \ w <”ri'i? T * r ·.

% h

c £

M S < • o. • H O '° cr in . 0.31 « 0.16 r. " C w α · <; n H «3 ε ~ · O • «Λ 0 Q W 0.31 2.5 0.16 ....... ....... 1 * * e «k c β Φ s ft-P u φ H c β 3 vO O • · · · · o m o Ar V V Φ X X X Ά * β Ό υ υ υ ι (a k Im (m and a a * * W X. 1 1 f O 0 0 υ υ υ 1 1 1 d 1 1 1 Alk - ^Z ( ^Z HO) - -Vho); - ^Z ( ^Z HD) - > * 0 0 O I v 1 m X χ χ υ __c • M ci. 1 1 1

/

N-Alk-N VC-Ar

ο = υ

Oh

M λ y S ^- * S e Ό • H · O om Q W 0.08 0.63 60. * • 2 E o «-4 '- ⁶ O ^S u «<* \ O Ό • · o o « n © -P a i d) 60 n c Λ 0) k > o . 1 Oh Ar J * * K X> o 7 «? (m k, • · * 'T Alk (M (M ?? in Ά o Pi ΜΊ v> X X s £> υ υ ^ _c £ . ϋ « 'ώ

ί «&} S« «J • o · Ή o o m Q W > o «- 6 'st S' * · 0 M ¹¹ S • o U 5 »Q H »·. o., 1 .. · / '' b © P a §3 & ·· ·? f • o Alk ^ P4 x ^N U, «Λ & X 9 Λ X «L Pi X P! ** ✓ 1

it

Cold examples of latu with the aim of getting Ril into the thorns of this invention, but not in any "case of n" o ^ r "personal, otherwise oil" other nuglaaano avi to give parts in the mass, and ava teapo "tours given in etepenise Calaljuae.

i. Beblv.njl »lo« i> ra »41Jw,«; _; * ¹ _b · \ · '''

- -. «- '·'. ·; / 'i' z - v * '\ ΰ 5 parts »aegneaijuaia adds« · 2 «1ΰ parts» l, 2 * dit * t ^ td ^^''·' i fat amount of iodine to aa iaieie »reakoi * Zeti« .ee pkapa ^ · * ¹ '*'. . 'J''► 1 J' ta Ja »adds a rotor of 28 parts 4 ~ chlorine-l7« ethyl ^ ip «vices _r in 18C parts tetrahydrofuran * doc a« asala spirava'ne? Ϋ ^β 0. After shade Jan I. added i> a drops «raetvorodltdelavs 5-« etllbeasoaitrlla u $ o dal tetrahydrofurana «-jPodi · ' _$ aavrčka addition continue aa a» plant ntqku X <a · at teaparaturl refluka «Itakoiona ssefta aa obloui and sipa 75 -chloride in water «

The product aa was extracted with 2,2'-octibiepropone "Ktatrakt aa lepa water", refined, filtered and evaporated, yielding 35 dal (3-aetiphenyl) ~ (l-aetyl - * - piperylinyl) M & etaaone in the form < the rest.

by the lotto «method 1 entering the equivalent amount of the corresponding aupatituary bentonitrile and k * chlorine * l * satylpiperidine obtained au>

«

I (4-bro, Tif «;, il) - (1- <satyl-4-piperidinyl) -aetBn« n as a residue, t (2-chlorofeuii) - (l-iaethyl ~ 4-piperidinyl) - «ietane <n as uljeat ostatftkk »·. * <

j i '> 5' i.,, <

. κ C σ 7 parts «» a, inesi jua «liquefaction» i add roatver of $ 0 parts l-bromo - ^ - aetllbensole mi 140 dol «1, l> -okaibloofcaaa teke d« is »honey reflakaevel« · Colekupaa ro «columns »Aaoft»>

• * -'i · * ', refluxed »for 15 ainutes, Grinjarv kzaplak jt oblodjoft,, *' · · * · ·.

but 10 ° 0 1 added dropwise a solution of $ 0 dol »« atil) -4-piperidlakarbeaitrila tt 70 dol »* 1 | l ^t -oMoikioot« · »· ';

k; ··, <'b

After the addition, the administration of tott4 continued

- ^: 8 j '* • A

5 «» »at room teaporet & l« Htakoiona aaeJU still displaced «raatvoro of 4C works asonijua-hlorld» in 4C) down »platoon · Where the organics» feese, ousona, filtered »i! uperoaa, giving SE part (2-a> ethylphenyl) -Cl- (feullaetll) -4 ~ pi peridlailj ~ aetenona as ul lobster astetk »«> rimar 3

The .and aoivn solution of 35 parts (J-ethylphenyl) · 'l-wetyl ~ 4 ~ piperides nyl) ~ methenoau, 1 «-'p sodium carbonate and 22i parts of limethylbenzene was added dropwise 22 to ethyl-urbonochloeidate at a temperature of of 2G * G. coconut shrimp added to them

And j? »Ea ae & is» for 6 Chao at refluxing temperatures · The tacotene e «· ή s is evaporated, yielding 12 parts of ethll-4- ($ -aetylbenzoyl) * - l-pip« ridincarbokeilet «as oil; oatetke.

> ο1βϋβό! of the corresponding feuyl- (l- «ethyl- or l-leniiaethyl-4-piperidiniD-aethanone and workers in a« personal way, obtained also ethyl ~ 4- (broieben »oil)« - l-piperidinyl boxy lat xo residue, • til-4 - (2-tilorb «nzoii) -lTpip« rid>: ikarbo4u »ilftt as oil» et i · residue i, · i '· ethyl-4- (2-aetylbea »oil) 4l-piperldinylcarbok« ilet as ul £ * «T '' b ¹ i '' oststak, \ i / '. -' ^Γ ΛΛ '· .-'

ŽIiSl £ _l j '/ ·' i X '·: ·:

& tfefts.od 12 works • til-t ^^ 5-swtUbensoil) -l ^^ e «idiiik« i ^ aUlata and $ 22 down «solution · ιζ <β% -sog solution) bronavodAhic ** acid» e ib na js 1 rofluxovens on flow 5 Honor? tfsakcises

- 'V ^: -, · ¹ smsis jo upsrens 1 residue jo kristallsan is ^ propanold, yield 7.5 parts · (5-ethylethyl) - (t ~ piperidiall) - «iOtaM» · * λ; <

hydrebronide · * '.

/

Keds ^ and according to this year's hydro-las process were obtained «(4-brothfen 1) - (4-plporidinyl) -a · thion hydrochloride, (2A ^ lorfanii ;-( 4-piperidinyl) -« et «Jvoa- bidrobro «id, t * t« 200 * 0 i S '' (4-aet ii f enyl) - (4-piperidinyl) -aet «> non-hydrobnM» id · f

ί

And from <5 del this 2-chlorpropour.it rilo, 61 di o (4-fluirf «uil) (4« plporldlnll) -i »otanoa-hydrochloride ·, 6? down «inside ju * i-teorfeouota and 16C down« ootaaltrile jo ao & eae ir flukoovauo overnight at liX) ° 8, Hoakoiouo oood «, jt cool« dodst · _t «water and eloi are separated * Watery fesi jo osotrol« veno d- notilk-peatenonas · Compound «organic photo eu oettAei.o« fitriitUO and persistent «· Oofcetek j« pro41i6 «n hiu ^ atogrophs, o« no kd-Otti silic & bare uc prtnean «eofto trihltveotsne, hksens iu« tenole _; ($ 0 | 49il) koc oluonto * Pure friction «u oota loot« i Oluoat jo io platform · 5 kinds of ostotsk j «kriotalieon io. ^ · Μ> 4β1ΐ4ορ »« £ «& ·.

• '.η, rpodukt j «odfiltrlrea, and ooufton cojuci l? d> lavo 4 * (<if-fiuor * ii '/ š bensoll) «a-aotll * l * pipprlAln-« eotc>& 4rtril », it» 126,7 ¹ ^, -X όΜά «of 32 below 4 ~ ( 4-fluorfeonsoil) ~ u-aotiX-: «piperl ^ Uk-seotoI aitrilo 1 400 down notonols, souls eaonjokon, bidrogonlsed into a rovrevo abutment at 2J? ° C us p isohu 5 down« ionoy nickel as cotioliooro «l o & t o jo opoor * ovona is * e <Injured amount of hydrogen, as filtrate filter it «and the filtrate persists · The remainder is added to the notilhoncol and again ioperon. Ootetefc to the rootvorou in 2,2'-okeihiapropoau and the solution filtered until it was hi ^ tor · Reotvaro upren, giving 3 ^ down «(100 #) [l- (2-eaino-l-aotilotyl) * 4piperidinyl! - (4-fluorophenyl) -a «ten <« ie as oily oatko · 'i- *;

Sao5e of 4,5 dol.ove l "chlor-p, 5-diotokaiprop * tte, 12,15 d" i "v", Fir (4-fiuorf «nll) - (4-pip" ridinyl) - "ethanone- hydrochloride,

10.6 parts of the afttriJua-uarchonet and 120 parts of the <-ια $ ί1 · 2 * pentanone of the match e «ireflukjojo overnight. Roakoion> amoeba 'is cooled down, water is added, and the layers are separated. organic fez b «.. heals, filters 1 steam. The residue a «purifies the hroaat jjgrefi« Joa a «column« llikagel «with the example of briblor« «taas and ttetaflualt (95» 5 «sapr») as eluent. Qe> up «s« pure fraction and «laeni • a iapari. CetataR aa crystals # «ia aaeče setilb« a «ile i • t ..

2 ^ 2'-okaibspropane, with "« gets 9 parts (55>) *

(1- (3t5-diethoxypropyl) -4-piperidinyl3 - (4-fluorophenyl) oatunone.

m * 9f, 7 meia of% down »2-aaino-» 3 »5 ~ dichlorobene« oeve acidic and 240 parts of ethanol is saturated «a gaaovitl« chlorevodonisea. C «Xa buys a hat» It is echons and refluxed for 10 deea / a · Keeloion a ^ ous is an ost «viana de aa cooled and rinsed with a sack. Cvretoi? oatatku I added «water and sodium-hidr Jfceid.

The etched product was filtered off and dried, breast-fed 2; works et i1-2 - «.% 1no-3,5“ di hiorb es zoo ta ·

J cwianu is mixed with 25 parts ethyl -; ~ «:! Iao-3,5 ~ dlhlor Muaoet« and 160 parts «diraetilb« acole liquefaction «e is added by delava ethyl-kerbonohlortdat«. Addon hacking hack, n same «<

- 20 - '. '»E M & m i ng during β 5 e» this at ue ^ pereturi ref port? / Anja, Usaitaiou · geeaa »a pair and eetatnk kriatalila la peteel-et» * · Product »· odfiltrlre and dry * dn ^ learn.jo works et (lYY? t £ · dichlor-2 ~ (ethoxycarbonylleino) -btinaoeta · ££ kaO ^j '<

t ', · fteeia From 46 dol »ethyl-4-Jxlor- [> tokeikerb <mil) * aniwri * <· <t ·. · «'Tenaoate and 10 parts 2 ~ ealaoetan> le ja aefteaaiatel · * · *« ne 160-170 * 0 avedok oil odeotlLovaae o «loififtj ^' 1 ^ 4t4i» · • tnroreaog ethanol · Foale aa & ancho in the course of about j «ohledj «» 1 added »j · 2 ~ ρΜφΜ4ΐ. Come on, £? (· Μ4) Μ * ϊ '&ν' ··· λ'Γ ^; '''»Aa and oeušea' giving 25 gave (64 £) 7 * dlor» ^ (2 * 4liM? • teBl '*'. Et11) * 2,4 (IH3R) -hinaaoliodloB «· .t. '

·. '· »,>

Order by the latent process of the alkali and the corlate ^ l aktIvelaeta «quantities» · appropriately «upatulaulen 2 ~ ((etokaikejrt> <aklX) *: etainoj -beaaoeta and 2-aninoatanol obtained in tetoftdjM and

5- (2 hldrokaietll) -l ~ i & atH «-2» 4 (lH _and 5H) —hinaaolinAion, 6 ~ hl © r-5- (2-hydrokaethyl) -2 »4 (U _t 5H) ~ dlnaaollndi4m _w 6. a-dichloro-5 "(2'hydrocaiyl til) -2 _l 4 <m _t 5H) -hlnaaoll | 3Kle 1 5- (2-uldroccietyl) -6-c.atyl-2 _f 4 (l H» 55) -hinoaolindiim.

l '' ^J /;

h £ iii £ _2 of 14 parts «6-chler-5» e ~ dlhidro-5 * (2-hldrokei <til) *** iftnll-2 (lH) -binesollnone, 5 dol «natriuneoetet and 200 parts« aetenole j «Hidreeenisovaaa at normal« prttlaku, and «oboo jt« aporeturiux prlaenu 2 part «10 ^ -aog pai <41ju * eu« ugl ju keo ketallzetore. Since j is "absorbed ie" 4uaete quantities of "hydrogen", k «t« lix »tor is filtered off 1 fllre persisted» Oet «t« k is eešaa e 2 _t 2 * -okelbiapropen · Čvfj «t ΊΡ» · *

L. > '·.

duct filtered 1 uee & en into 300 parts «water» Fe »<« 4 ·?

• ^- <* ^1. ··. LJ ',' filtered and oau & en »daodl 11> 2 down (91 JO 3» e-dkldre * ·

3- (2-bidrokeethyl) ~ 4-f <»iI-« 2 (lM) * bin »eollae» e »t« tj 1 * 1 * 0 «« i · '·;' _t tf;'; /. · I £ i £ 3 £ _l £ sseS «of 25 share 7-chloro-5- (2 ~ hldrokeietil) -2» 4 (lH _t 5 Ij-hine · »i

soladion «, 52 parts thionylchloids and 150 parts * trick .omethen«

j «mixed 1 reflux« ram during 0 0aaa »Kefkolone clamp is then cooled« · lateloi product is filtered off »uiprene trichloroethano and petroletroe» «ati» quenched at Sen ee gets 22 parts (68 '7-chloro-5- (2 '-U.oratil) * 2 _l 4 (lii, &) * hinatolln-dlone · h «or'« n aačia ad also obtained t

5- (_Miloret 11) -yl-aae til-2 ₁ 4 (1 h, 3H) -hinaaolindione,

3- (2-hioretil) -5,4-dihydro-e-phenyl ~ 2 (LM) -hina "oliac" _t tet "

179 »5 * 0, ^ hior-5- (2 ~ iiior # til) -5» 4-4lhl4ro-4-ftnll-2 (lH) -hin <solinon »

6 ~ $ 1 or-J- (2-chloroatl) »k, k (IH _t JH) -hinesoliadlon,

6,8-11ηΐθΓ -? -> (2-ηΐθΓ ^ 11) -2,4 (ΐΗ,?: 0-Ηίη «κο11η <11οη,« »t * Zfffa 1 * 41

5- (2 ~ hlo «efcil) -6-uet; il - 2 _f * (lH, jH) ~ hinetolindiou» / · ι irir.or 11

Onefio from $ 13.6 «2-oainebease & id * t down« i »broo» J-lUorpropon », 21 d« o notrijun-corboneta 1 200 part «o ofcOMlf jo worn 1 roflukeoveno over the weekend« «heofcoieae« by «jo jsotie filtered «and filtrate« paren · Uljeof oststak j »umoftaa

Iu »ethylbonsol · Holds off filtration« while no pootol on biotre and sotigc j «uaperoa ra« forming · 01j »from the rest is still pro <personal bronatography on the column alllfcagol« us prinon oso »o trifelor» »ethane and nethanol ($ 9 i5 «Sopr«) as the solvent "Ci" 'o the frequency was collected and the oluont still persisted ·, you'sfe will remain «: oo ua ^ sha in 2,2'-okelbiapropan, The product i filtered: oeuion, giving 7 down" ( 3?%) 2- £ (3-chloropropyl) -e »lnol-» bon nald ·,

«.«. 4lu <j * c.

1-tlHr 12

·)

Jnosa ol 1C dolov «<-C (3-chloropropyl) -« a.ino1 -benason; to, 16 dalts; c-propanone, 1 part k - & «tllb« aisol «ul f same ki Milno 1

I

4 ύ dolo ethoole still «« and refluote over no4 · hook * eion «oaofte jo persisted and oiled oetatok assisted to 2,3 * - oxlbisproponoa« Product morefiltrlran and onuoa, di & & 10 dol «l- (3-chloropropyl) - 2,3-diMidro - ?, 2-di »0« il - * (l Qbinasolinen «·

In the street t ice. »Chilled (lodging bath) solution of 27» 5 parts. -brouetenaridn-hydrobroids in 200 dol «water added <

Is reefcvoi · of 28.9 parts 4— siatokai-2 * -nitrob «nzoll-lllorid ·. in 65 del «) benzene b at 5-10 * C. With anal ooianjo, a liquefied solution of 10.3 parts of netride-bidrokeld M S $ O dol · water at 5 * »10 ° C« heken sev & otki

Λ Inheritance, n®att> ow © oe oLofienjeing $ during 2 da >a> at this fractional tempere ture of the "but but" thesis Is odokoatm "and the oil flow at the same time it is puffed into 2-propanol, Product of & lt *? * ran i oeufion, de Judi 27.5 d <love (63 ά) t- (2 ~ brometll) «- 6 · * oetokai-2 ~ nitrobeasaaid ·, t.t * 135.8 * 0, / frpiaep 14»

I

U »eian and ohledjeaua eaeeu of 25 parts 2-easiaoetenOla 1 19! of parts of iretylbenzene was added dropwise a solution of 29 parts of 4-fluoro-2 ~ nitrobasoyl chloride in ethylbenzene. After the addition was continued, continued continued for 90 minutes at room temperature. The precipitated product was filtered off with water and taken 4 minutes in water. -aetll ~ 2-peutsnanoau. the boil was dried ^, filtered and evaporated, deJudi 28 parts (G4 O u-ilor -: ;-( 2-chloroiroethyl) -J-nitrobeazamide as a residue.

of 28 parts 4-fluor-E- (J ^ hydrokaiatii) -2- »itr akenseaide 4c dal tionllhiorlde 1 1%) parts t fish or ie tene j» found and rofluxed during 2 Chaas. of the cooling filtrate "dfiltrieaa, the precipitated product 1 was then dried, d ^ jul 24,> partitioned (83 fl- (2-chloroethyl) -4-fluoro" 2-nitrobone "id.

' ^! > * ££ LSS £ J £ *

baa ed 14,4 gave N »(3-broapropyl) -2'-aitrob insaiaid ·, * 12, ^ part» (4 * fluerfeail) - (4-piparidinyl) -Betenonw «ktdrofcl OPlda, parts of sodium carbonate 1 200 parts 4 * wbil ~ 2 »pe & fcaaaa * jf nešaaa and ref onion owl» · e te 3 Tea ua tfru & enu etc0 | eša

J of water. kaakoiena sae & a i mastered, you add j> 'added and $ 8 to the child and in a separate, organic fez was dried «, filtered and epajrane« oil oatatek was purified by chromatography «w keleei elUka *

I gel us priaenu e »eda triblormetene 1 methanol (^ OilO, sape») k «o eluent«. the fractions au were collected and the tluent was directed, giving 18 parts (87 X <) K- (3 ~ t'4- (4-f jucrbent> yl) -l ~ t iperidiai) J propyl] -2-phtrobeneeide as oily residue and »V

Thinning according to the method 1, the use of equivalent equivalents of tin constitutes (4-fluerfeail) - (4-piperidialX) ~ aetenea * i> idro4Uel4e l edgevav »jute supstlfulaeaag 2-« ltrebeaseaid4, takedi 86 | n de * r ki venil t

h-t2- £ 4- (4 ~ f luorb «ft« © il) -l-piperidiaUl-ethyl] ~ 2 ~ aitiebe «** eid *.». XSO * C,

4-fluorophenyl-4- (4-fluoro-benzoyl) - | -piperidinyl-N-til-3-nitrobonoothyl, t-io3,5 ° 0 and n-C 2 - [4- (4-fluoro-benzoyl) -1-pi ^ oridinill -etiij-4- «« to) ol ~ 2 ~ nitroban »» mid, tt »-134 ^O C ·

In 1 dou solution of 2 dolphins in 40 dol · ofc. about dodo J · 18 dol · N ~ E3- [4 ~ {4-fluorobonioyl) -l-piperidlnilb prapill »2-nltroboaoanldo 1 200 dol · aotaaoio» Oolokuftae ea »I» 4 * hydrogoaioovoaa pol aoraol & oo attachment 1 oob to »p »Raturi uo priaonu 2. Part 5 λ-βο <plot ao on coal as Tent Metals» and because it obsserbovea · ioraduaota the amount of water andM «« M »tollooto» j- ·, liltrate 1 filtrate jo slow · Oljaet ototok j «praČiddoe hrouot & gr & f & f & f & f otlikogole columns ut priaeau ouaod «trlchlor» • ton 1 »ethanol (90 <10, top» ·) koo oluoate. chiofe Jraoklje ou collected 1 eluent still persisted. Uljaofc oatutok jo 1 riotelia • an io 2-prppnnolo. the product jo odliltriron 1 ooueoa _f ley

$ 7.5 · (45>) 2nd «iao-M-C5 * C4- (4-fluurbeaBoil)» l'piporidioyl! -propyl 1 -beasealie, t> t. 115,2®C.

*

f.ethical lug j «persisted, giving a second frakeia of 6 de] of this (56 2-ethtino-N-t? -C4 -> (4 ~ fluorobenzoyl) -l ~ piperidinylI-propyl IJ-boron- aaide as an oily residue.

Rodool is also getting the hirogenation just getting there.

<i-onir.o-U-i2 ~ (4- (4- / 1uorbea «oil) -l-piperidir ill-ethyl« · ben »« ®id, mp 142.5 ° G.

2 - »(3, ino-4-fluur-bL ^ - [4- (4-fluoroben» oil) -li iperldiniU otil] -benzoeiid, fc «t» 124.1 ° C 1 xi-e »ino-H - (2 (4 - (^ - / 1uorbonaoyl) -i-piperidyr yl-otlll * '

4- «ethocaiben» aaid, tt 168 _t l®c.

- i ¹ ':? · - B '; 1

7.2 dolls * 2-C (4 ~ hlaj? .- l-0i <60bUtil) '© ftinol »b« wi »mi. <·» •> ·>. 'j ·' · «. 'you' * £ '' ·

7.5 dol * (4-fiuorf * nil) - (4-piperidinll2- «i'tbaw * H4drehl <MPid · 10.1 dol * ki-dietllotaaonins 10.2C dol © ^^ tonitr ^ soi · © Sport jo i refkooveno within 24 days * loekaloas ftiOSa »OB $ 0V & 1 water was added to the boil * Oil ·! product is still etched trichlor» ethene .Jetrekt jo oauion, filtered and up iron, gave $ 10 · (81 /) # - (2- (oaiaokarboall) -phonyls -4 • (^ - fluorboaaoll) · 'l-piperidine-butanemide keo oetetka »v ¹ ' hrlapr 18 a, In soynn eoo & u from 250 dol · 'pyridine 1 59 parts · fc-fluer * lh-iadol 42 dolecalecylarlides were added at the command with a tttoporotura of 22 ° C * h windows «evHotka doc« Vanja, i set t

jo a "cunj" in tbk 2 Caaa but room temperature »Bookeioaa eweu * j« v »» blessed conduits, and 2 P roatvor klomVods »nil kl & ellne added. žrodukv j «ekatrabovan iva times os 550 gave v s» X, 1 * - 'Oksibl »et one * bpojoui ekatri kti au ooulani,

- Zi filtered and matched. ooetec is purified by brooietogreiioor not column eili & ageie in * priaenu era «already trichlorraetene and« ethanol (95i5, »6pr.) keo eluents. the same fractions were collected and the oluent was evaporated, yielding 95 parts of "] -ban" 0il-4 ~ (6 * fluoro-ld ~ xndol * 3-yl) -1,4-dihydropyridine Jtep ul Lobster residues · f

b. 3raeSe of 95 works lb <naoil-4- (6-fluor-lii-iadel -> - il) * lt # * ^s dihydrepyrldine 1 54C parts £ t, u-dlmetileoete «ide is didrogeaiaavans in .arr-ονοβ apparatus aa 5 part of the catalog - 10 palladium South at the corner of the South. Fo Curtains apeerbated iaradu * lattic amount of hydrogen, catalyst i filtered through tjrflo and filtrate I typed aa water in mixing, 'at t <we at extracted oils · Upper liquid f ** · still offset and aseataip oil is marl water® «Ul i at product is traclot trichlot '* aeteno »· Extract i oeu & ea, filtered and evaporated · The rest i washed aokoeively aa eneftou patroller and 2,2 * ~ Qksibig ~ r' propane, suppresses 2 λ of hydrochloric acid solution and naJzftd water, the fetot is dissolved in trichloresetene and the resulting solution washed with 1 h solution of n &lt; 3 &gt; trihydrocaida and water, then dried, filtered and evaporated. The residue was heated in &quot; an amount of N, N-diethylethoateaide at 60 < 0 > over the weekend · Solid product edfiltered »n, washed with anecho® water and resin atoms, dried in vacuo at 8O * C to give 25 parts of this L-benzoyl-A— (6-fi 'sor-lii * indole ~ 3 ~ il) * piparidii t. t · · o · The compound of F4 part l ~ b <naoil - << - (6-fluoro-ia * indol-3-yl) -piperidine> in parts> 11 urea hydroxide, 495 parts 1,2 -ethanediol and SO parts of water still 1 tefluKaovens within 6 hours · beek «oj one ssnaAo have been cooled and $ 00 d · of water has been added to our find. Jstalotaa produst J · odfiltrirsn, washed with water * 1 patroiatrO ^, satire dried in vacuo at i> 0 ° 0, yielding 16 parts 6-nuor-9 ~ (4-piperidiriii) * lH-ind.ola,. t «t» 2 £ A * C · l, d «taada of 7» 5 parts 3- (2-chloroethyl) -2,4 (18,5H) ~ hiaajMlln ~ d ions, 6,8 parts 6-fluorine ~ 3 * (4-piperidinyl) r <H-iudal, parts of 'sodium-carbonate, 0.1 part of potassium''of iodide, and 260 dal of 4-sotii-2-pentaoone I aei & ne 1 raf lnkaavana-n tefctt nights. More water was added and separate water ethers separated from the ethereum. Organe ** faaa is dried «filtered l persistent« ♦ ivrat aatatek ja kuvea in ^ -pfccfpanol »The product is filtered and oeuien, giving the first fr * Jcoi it of d part

5- (2- (4- ^ 6-11nor-JlH-yudyl-3 "* 11) -1-piperidinyl-methyl ** 2,6" (1H, 5H) -quinolin-dione.

and la vodtn «fese (see above) filtered a quarter aatatak and cooked & n in 2-propanol · iroduct i filtered and oaufian, barking irufou a fraction of 5 dal? '(2- (4— (6« fluor «lH» indel5-il ) -1- ,, iperidinyl-ethyl) -.2,4 (lh _t 3li) ~ hinesolindioaa, tt «5C0,0 ^e C.

a. ζοοίχΐχψα ^ ioeonifc is missed by Krna tse * «nu eaeftu pd 6 parts« 5- (2- (4 «(6-fJuor-lH-indol -> - il) -l-piperidixiill-etlij« ;, <(1ίι, 5 i) «ainasollndione and 1-./0 parts of acetic kiaeline <

Ion oil lobby clear raetvor. Z «; tis added 200 delava iai4njsa>_c> ice »and loe deli · water and vaalkaliaane raatvaran n? .tri,> uns-kidrok« goes. The product was extracted with trichloromethane and the amount of ethanol · skatr ^ kt was boiled, filtered and evaporated, yielding 2.3 parts of £ ^ C2- [1- (2- (1,4-dihydro-2 ^ dioUao ~ $ ( <a ') ~ hinuBoli> il) ~ «ti3 J ~ 4 ~ pipexldlnilkert> onlll -3» fluorfonii-foruaeida as Oetetko «friaw M>' i '' · .. v,.

M. > '>

A Laeda of 13.5 parts l- (2-eddLnof onicone mono) 12.1 parts H, N-diethyleth «n» 9lne and 72 parts benaol xje «edena-l monitored not 5 ~ 1G ° O» Zati «Buried added raetvOr From 24d «2> trichloroethell-chloride in M parts · beaaole in« maintenance toapo »rature at 1-10 * 0. Haken aavrietka added the swollen joe at that temperature for 30 ainuts Sankajo »· '.. in' f '* · * / j' '· ** ϊ V'? 'and aae & e was filtered, the fllter cake was washed X the filtrate was evaporated · solid residue Was cooked in «ethanol» jtoole cooling, the product was filtered 1 dried, dayddl 19 parts (6ό ..s) r.-f2-ec - tilphenyl ) -2,2, *> - trichloroaoetaeid », tt« 112,7 * 0 »dtaeut» of ΐχ.) Parts u- (2-acetylphenyl) -2,2,2-trihlort> eetefflid «, parts 2-» iai & oethanol and 200 parts of ethanol · is «(given first during 5.5 Chua ur reflux and aetis over ncdi at room temperature. The calf created is filtered off. irodnkt Ja iapraa a« 2.2 * - <3 (kaibiepropanoa 1 oeulon uVekurn. dftjudl 4 \. · parts «(59» 2,2,2-trichloro-H-C2-Cl-C (2-Wdroko3otU> * i & luoj- «tlli-feailj-eoetaeldo, tt · 102 ° C« t

The first K, 2 parts were added to 135 parts of ^ K-diibethylforaenld

2,2, £ '-trihl © r -:; - C2 ~ [l-L (2-hydroxyethyl) -i®ia «I-ethyl I-phenyl - 3C aoethanide e satyr. in portions "5.7 parts" of sodium in ^ * b "hydride" (with no eggs), with the occurrence of racial reexia. Some of the Brush addition brushes continued with overnight swelling at room weight. Keokelone eaaefto is poured in water 1 product is e <atrehovon trichior »« tenom. The extract is 0 «uj5en, filtered and evaporated · Gstetek purified chromatogrefijoca» about the knee sbHkegel «« with prlaehu e «ech trichler« t «ne 1» et »· * nole (9GslO, sopr ·) fceo eluento · pure frequency« « u "eats" · blueut is vaporized, acting 8.5 parts · 3,4-dihydro-3 * (2 * hydroxyethyl) -4-eetiI-2 (Ul) -hiaesoliae ^ l »o fivrstog eetatfce« o «els of 8 parts · 5,4-dlhydro-3- (2-hydroc «letX) * 4 * pptll * 2 (lH) -quinaselin« no, 8 parts »thionylhlorlde 1 90 parts« trlhlemetene is «eiens i refluxed in week 1. 5 <0 ·· Ke «k • ion» sae & e is upperene · Thursday is too early hrosstografijos ne kneji «lllkegel» u «prieenu« sede ferihl distracted · 1 «otenol f

(9515, "apr") k "o eluent" · the pure fins! Are fused and the elunet is still paired · The residue is j «selenium in 2,2 * -oxib» pro ^ sau · The product is filtered off and dried, yielding t, 6 parts «5 ** (2 ~ Uoret 11) -3,4dihydro ~ 4 ~« iet31-2 (lK) -fcinesQllnen », tet · 126,4 °; · v

rrlaer 20 se nseuenu limit from IG parts mvtil -? - C (2-hydrocsieti i) -etniaej · bensoet »and catching of the" ircetric acid "liquefaction is a dodsvt solution of 4.5 parts of potassium oijonst in 25 parts of" veda "flanks »Aavpdetkft of addition, continued the present via hail at room temperature · eu <eion & a» eh »j« ueprese · C spindle oststel «one» a vo io ©. ; roiuxt It is filtered off, with a fine week and also with ethanol, with »tifi oaucen, giving 5 parts (48?,) 3- (2hydro * tii.®u ll) -2,4 (lii, 3′u) -hinesolitidionw, m.p. 273 »6 ° 0 · l

3®e of 3.6 parts «, l - (? - bidroiceiatyl) ~ 2.4 (lH, 3H) -h; lnasollndiona 1 4o parts · thionyl chloride e j · added · 1 ratlu * e> vatoe U'td nights. Jeaksloas with »eSa. — Is it left to cool n« seb «u & tone?

¹ raturu. latalolan product Jo filtered, washed «eo 2 * 2 * -efcei blspropaoo ·, dried, breast-fed 3.4 work (86» l- (2-hl «rehil) -2 | (lU, 3H) -hlnssolladlo» o, tt , 215,3%

According to "procedure 1," the equivalent of the quantity l "of the corresponding starting points is still equivalent to that obtained" <

[1- (3-hydroxypropyl) ~ 3, * {12,38) -quinazoliadiee », m.p. i

1 ~ (3-bloropropyl) -2,4 (1H, 5H) -hine * oliedioa, mp 187.1¾.

f t

In a 16-fold ratio, the 2-phonyl-4 (3H) -hlneeoliaene 1 225 dal of H, Β-diaethyl-phoreaide in poroiota added 3.2 (at room temperature) 3.2 parts of the 6 / - $ ~ euphenyl ester of the hydride ( at the chow reaches sgsotomy reakoy, temperatures * rise to 34 ° 3). pasle savr ^ enoc addition, raacolone en a c ^ a ^ bou »at 10 fetnute after which I vspsvenjee added 12.4 gave 2-broeetahol (weak exoteras of reeckei). 2oal perfect addition continued for 3hours 1 hour at room temperature, "" you "2 hours" at 80¾ and overnight at room temperature. keakolona Brneco I chilled, poured in the genus ic vret produ: t Je lelsem uv «£ uau · /..afafcia Je ij pren vo io ii 2,2 · ~ ο .aibiopropeuoia and bsuueo in centuries at (O ° C, dsjaci 15 down »? - (2-hydrvk« iefcil) -2-f «aiiv4 ^ 3H) ~ ttJoe» Qllnon «, waving»: xte; ju of 15 parts »3- ⁴ (3-hldrok» iethyl) -2-fst leaf 5H) -hine oiln 1 ie 1 375 parts trih.loraetaae ukepm «bJo» edible 24 parts thiooyl chloride at room temperature rl · ioele «done» add »set« is »edsajo in 1 Eye 2 cheed uk rofluxing ·» e «keic ethee is evaporated» «(statics is of added water and .- * aesh · is aeutr« lls »oa r ·« formative sodium carbonate. .product i ecetrohoven trlbloraota & om «Sfcstrefct is washed with water, dried, filtered and evaporated« Ost a tal Jo krletolison H βαβί e 2,2 ^r -oxsibleprop «n« i potrolati-a, Product j «odTlltrireu and dried, yielding 11.6 dol« 3- <2 ~ chloro ~ ethyl) -2-phenyl-4 (5 ^) ~ hina «olioon« · '«eia of 5.5 parts« 5- (2-chloroethyl) -2-f «nil-4 (asolinone, 3.3 parts» 5- (4-pip & rldi nll) -lt (-iAdol », 7 parts« netri Jusksrbcnata,, 1 d «o potassium ^ -Jodida and 2υθ parts« 4 ~ a «11-2 * pentunone Je © ananu and refluxed» during <2 £ »e «. and "" columns "α" ύβ Is filtered "through ©. ^! yfJo- «i filtrate j« upera. Cstefcek prel ioocn croaetp}. refined columns aiiiltagel «in prl & en« and «Ae trlhlonaeteno 1 methanol» (9213,? .epr ·) as eliantoca «tiflta fraction eu redeemed and elunate is upssroa ' ^r « et · tek Je fcr ^; otelis «n from saeue etmol» i 1, l '~ o! c «ibi« et »ae, d yesterday 5 parts« 3- £ 2-44 ~ ilH-indol-3-yl; ~ l-pip «ridinilJ- etilj 2-fsuil4 (3H) -bin "" olinon _"t m.p 191.3 ° is 0.

'' ine & eau ecseil. of sodium sodium fluetocalde and 160 parts • ethanol "eu ko® simo added £ 0 parts" 2-thiof en-ao "tonitrlle e zeti" by hoeing 66 parts l- (phenyl®-ethyl) -4-pipeildlninoaa ioele aurlet for adding the whole enet « is "heated not refluxing 1 ae" during l Chaa heecolon unit cooled 1 paired. Oetetak is deetllovan ne apen · turi t

ae molecular to the deatlelle, yielding 70 parts «~ tl * (P« nylmethyl)

4-piperidinylidene} -2-thiopheneneetonitrile (as boron) ·

The bold "oduu works" ~ tl ~ (feail »etll) -4 ~ piperidinilltdRl -2 * i

thiofeneoetonltrile in 800 parts of methanol is k | dregeiieeveaa at normal pressure and nota temperature ee 10 duels katelleetore - peladini not coal (10 #) · Since epeerbovene is accounted for the amount of hydrogen, the catalyst is filtered off and the filtrate 70 is evaporated, - (phenyl * '• et il) «« -f 2-thienyl) -d-plperidimdaee tonitrlle.

i

In 29.6 parts of 1- (phenylethyl) - «- (2-t« #yl) -4piperidineoetonitrile in fcOO parts of dimethylethoxide, <60% of dieperel sodium sodium hydride was added in the lead. Starting off with a napkin, adding nothing to the night Hedselen

L misted the poured n water. Metallic product Is iflieee not vacuum and ectrehoven with trichornethene. Extract j «oeulen, filtered and evaporated · Ojeet j« krlataliaen le P, 2 '- * ok.eibiepro> «ee» dsjull 10 parts (55 t) (l- (phenyl methyl) -d ^ lperldluUj ~ (2-tienll ) -methane », tt 100.5 ° 0« ··! »· 1« ηυ «ajoou of 15 iel [l« (. foni tu; avi.l) ~ 4 ~ pipjri iinill ~ L ^ -ti.enil) -wot «aoina ul? 0 al bn» ola uxopi-, venjew jt added ϋ parts «ethyl-carbonO'hioridates *. The point of a "tip del" vene, the entire rackelon βαβό m Je ^ arrevan "ux refluxing 1 ftteoon during 6 Chap" at reflukfbvc «is ·

Keakoien "mix cooled", filtered 1 paired ", people *

gave this ethyl 4- (2-thienylcarbonyl) - 1 -piperidine pipeline (as a residue).

The a pte 2d portion of ethyl-4- (2-thienylcarbonyl) -1 H -benzyl ether and 120 parts of the 48-membered bromovidonic acid acid is r, ethane and refluxed for 3 hours. Riefcelone is "not cooled" and the petroleum product is filtrated "lapran is 2-propanolone and ~ dried, giving 1? parts «(85 (4-piperidinyl) -φ-tieail) -aetenoaa-hydrobroids ·

I ·· Bridging Compounds of 4.5-Compound Compounds * 5- (2-chloroethyl) -2,4 (ld, 5H) -hina: olin-dioa *

4.9 parts of (4-fluorophenyl) - (4 ~ piperldinyl) - tetanone-i idrochloride d parts of sodium-carbonatb and At parts of ^ -ethyl-2-i entenone in the esune is overnight reflux "aeakoioaa smei a is cooler »xia there her Add it? red, airborne product is filtered off i kriatalieaa ir. '> -10til -? - peutenoma «<ayushi» after »learning,?,? works of (2? λ) 5-C2 ~ [4- (4 ~ ilorben: oil) -lpiperidinyl] -ethyl] -2,4- (lU, 5H) -hiaa «oiindic» «« t »t 227-255 ^ .e

Smoking on a lotus, then using the equivalent quantities of suitable backs. matter obtained au and »/

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Fr Ό ι friner it wields 6 Dales 3- (2-chloroethyl) -1-phenyl * 2,4 (18,3U) quinoline dione, 8,3 parts (4-fluoroXyl) - (a-piparidiayl) * Reading 1 48 parts of ethanol jeoeieaa 1 reflukeovene · At this reflux rate, R, V ~ dimethylforaeald eve down; ee did not elucidate the entire Netteria solids · Throwing, and continued overnight with reflux · Keakelooe ioiede paired · Oetotsk crossed two suffering zhroeetogrets, flying the columns «iiikegele whereby the eluent was first sapled with three ears (9 $ j $, sep *) · setlii esette trichlorraetane 1 aetanel (96i2, e «?? *) · fildte frsfcelje were •• purchased and the eluent was lepa« The etchant is crystals »en ls 2-propeaole, yielding 2. 2 parts (23%) J ~ C2-C4 ~ (4-nu «* easoil) 1-plperldinill-ethyl} -X-feAll-2,4 (lB, 3B) -hinsselladl <es, t« t ·

166, Λ.

6aat of 5.8 parts of 6-chloro-3- (2-chloroethyl) -3,4-dihydro-4-pheoyl s

2 (1Π) -ηΐη «» (Ίΐ »οηο, 7.4 work of (4-fluorfe« il) - (4-pipoildinyl) oetenone and 56 parts of ethanol is nocturnal «and re / lukeovei e overnight · Reaction shot directed «The remnant is crossed by bronze.« T Graphics is a non-columnar alien gel with pri »« atu eneie t fish plaster »not oethanol (95« 5 · «ep« * ·) as eluent »* Cysts

And the sachet «u * akpljeoe 1 eluent was persisted« tfljent © «leaflet of the cucumber» when rubbing ea 2 _e 2 * -okaibiepropaaen «The product was filtered off and dried, yielding 5 parts ($ 7» 6-ηΐθΤ · 3 * Ε ^ -ν4 * (4 ~ fluoroben »ol) -l-plperidinylJ-ethyl) -3,4 ~ dihydr © * 4- phenyl8 (lrj) -hina» oli »one, tt · 1m6 ° G» ha elicaa ne ^ and also au dobiveol «

5 "(2- (4- (4-1 luorbettsoyl) - 1-pyrrolidinyl" ethyl-5 "4-dihydro * 4» ^ enyl-2 (ia) -quinaaoline <» _t tt l? 5» 5 * 0 1

5- (2- (4- (4-fluorobenzyl) -1-piperazolyl-5-yl-5,4-diabrobro-4 • atyl-2 (1H) -quina oline, tt'172 * O · I

ixiaaE_žS_ aoela of 5.6 dol »l- (5-taoefprapU) -2 * 4 (lI _e > a) -Wjoaaolin * diona, 9.03 dal · (4-fluorfeaH) - (WiJwi <UUl) MMtoaaa * ~ hjLdvochlorido. $ 5.7 sodium ua-keafeoaeti, 0.1 dat ^y potassium iodide and $ 120 4-ethyl-2-pentaneb Point and reflux overnight at boiled water # aoekolen ooe obladjona. added velo 1 elejervi au

And separate. organic phase j "dried". filters »· Ϊ conoattrevan · on aalu'aaprenin. Tool · Cooling Concentrate · MetallicMen product is filtered off and crystallized from 2-nozzle, breastfeeding

1.5 gave (18.5 >) 1- (9- (4- (4-iiuerb &apos; nayl) -1-plperldlallI * propyl] -2.4 (ia, 5H) -hinaaoliadione · m.p. 192.9 * 0.

bathtubs per lattice · after 1 flew from 1 ~ (2-chloro «tll) -2,4 (lH.5k hineaelIndiane also fo doblvenit l- (2« (k- (4-fluorobenaoyl) -! - piperiUnil) -et11} «2 _t 4 (18.5R) l hlneaollndlona, mp 219.7 ° 0.

I

Of 5.6 parts of - '(3-chloro-p'opyl) - ?, 3-dihydro-2, i- <ylKetyl ^w 4 (1H) -hiηβεolinone, 4.9 dol · (4-fluorophenyl) - (4- pierldlnll) eethanone hydrochloride, 10 parts · sodium-kerben «ts, 0.1 part potassium iodide and 200 parts 4-aetyl * 2-pentea« is not weekly »and refluxed« via nedl n * prlaonu of the exhaled water «Rookolone saefte cool it · add a line of 1 separate layers · Fez 4-aetyl-2 pontenone jo esulens, filtered i (Starts a solid runoff in the column very well ·· e

gels in «prlneau ono * · trlhloraeteae 1 netaaols (95tl> η · Ρ *>) who eluent. Pure Fractions are "Group 1 Olnone; ·" Platform · /

the double residue is brass with »2,2 * -okeiblapropaaee, Fretdkt filtered off and osue & n, giving 6.6 dol · (78 0) 1 * 0 (4- (4fluorobenzoyl) -l« piperidlnlll-quill * 2 «5-dlhydro * 2, <rdiaotyl4 (lH) -hinft »olinone ·, t» t, 169,9 * 0 * oose of 5.5 parts 3 * (R-chloroethyl) -2-phenyl-4 (58) -hii esllinone. 4 down (4-fluorophenyl) - (4-piperidinyl) -9 ethanoa-hldrol lorddo, downstream carbonate, 0.1 part potassium iodide and 200 parts 4-G «til -? - peftt« none i reflukoovea α α 24 Hours in the presence of freezing water · heekelon »eae & e jo Jiltriron» not hot »The filtrate is persistent · Oetetek is prelhdea hi eaatogm * fijoa n« elllkagele columns with primon οαοϋβ trichiort ethene 1 5 * ethanol (5) »ethanol sep ·) keo eluens “pure fractions” were dissected and the elutoe was evaporated · t / stetek was kristeligiB is

Example 29 of 5 Parts "3- (2-Chlorothio) -2,4 (ia, 3a) -Mieosols" - <ioftO _t 6 dolov «<x ~ (4-fluorophonyl) -4 ~ pperldinl» 0tanol-eeetate (sharp ) hydroallorido, D dolov «natri jusu-carbonate and 280 dolov« 4-4 £ til * 2 ~ t «at« ne * o jo fteisne 1 rottufcoovsaa proko.

kookoiono. rsočo joflltrirsao 1 filtrate jo u | poro · · 'Mljoot ootatok purified hroaotogrefijoe no columns «ilikagol« ua applying trihlormetnne 1 sotonola (95i5 * xapr.) as «lttonsa · Cist« frekoijo «u« «purchased 1 eluons j« The brush is "krlotelloan and 4-motll" 2-pentanone, whisper 2.3 down "1-" (2- (1,4-dihydro-2,4-diocco-3 (2h) -bleosolinyl) - otil - <x- (4-fluoroenyl) -4-pipoidinylsotanol- (oofcro), mp 185.2%.

* rtw 30 tubs according to the procedure described in Example 25 and use the equivalent of the amount of corresponding solids also obtained

3,4-Dihydro -? - C 2 -C 4 - (4-fluorobenzoyl) -1-piperidinyl-ethyl] -2 (1 H) quinosolinone, m.p. 182, l ° 0.

iTAsn.

according to the procedure described in Example 23 1 using an equivalent amount of the corresponding positive ethers also obtained * ·, r, *

Mneeallediee «. t ..

Priaer 32 «i» djelpe peatupfca eplMMM tt | fbtw IM l equivalent quantities · ddgevavajndlb pelaan matter more liquid _in i obtained> ta- t # - (1-4-indol -5-yl) -X-pipevidioil2 ~ etiU «« & » * (18>> 8) ~

6 '^'>'· * ♦, \ un «» »yMU <i * r ^: . «Α, Λί.

η> 4η '. n, '>·!' ... -rtV · * · · _Λ

Example 33

Work according to the 'procedure from. Of Example 23 obtained * in the following example. ? '''? ... _; l, · t.

3- [2- (4- (4-fluorobenzoyl) -1-piperidinyl] ethyl) -N, 3- [1144] -4 (1H) -quinazolinone, m.p. 203.4 ° C, 29% yield.

3- (2-) 4- (4-fluorobenzenyl) -1-piperidinyl] ethyl] -4 (3H) -quinazolinone, m.p. 139.2 ° C, 26% yield. '

3- [3- (4- (4-fluorobenzol)) -1-pyridinyl] pyridin-1 / -4 (3H) quinazolinone (E) -2-butenedioate (1: 1), m.p. 201.1 ° C, 23% yield.

3- (3-) 4- (4fluorobenzol) -1-piperidinyl] propyl] -2,3-dihydro-2-thioxo-4 (1H) -quinazolyl, m.p. 200.2 ° C, 11% yield.

3- '2- / 4- (4-fluorobenzoyl) -1-pyridinyl] ethyl] -2,3-dihydro2-thioxo-4 (1b) -binazolinone, m.p. 225.5 ° C, 13% yield.

»

3- (2-) 4- (4-Fluorobenzoi 1 and - [1 H] -rides nyl / ethyl) -2-methyl4 (3H) -Hisol non ', m.p.] 64.9 ° O, yield 22%.

3- (2-) 4- (2-Amino-4-fluoroberzoyl) -1-piperidinyl] ethyl) 2,4 (1H, 3H) -quinazolinedione, m.p. 269.5 ° 0, yield 17%.

7-fluoro-3- [2- (4- (4-fluorobenzoyl) -1-pyrrolidine] 1 / ethyl 11 / 2,4 (1H, 3b) -quinazolinedione t, t. 248 ° 0, prinof, 20%.

3- (2-) 4- (4-benzoyl) -1-piperidinyl / ethyl) -7-methoxy2,4 (1H, 36) -binazolinedione, m.p. 245.4 ° C, yield 19%.

3- (2- (4- (4-fluorobenzoyl) -1-piperidinyl) ethyl) -3,4-dihydro2 (1H) -quinazolinone, m.p. 182.1 ° C, batch 16%. *;

4-M-chlorophenyl) -3- / 2- / 4- (4τ fluoro obenzoyl) -1-piperidinyl) ethyl] -3,4-dihydro-2 (1H) -quinazolinone, m.p. 191 ° C

18%.

2 '-J 3- [4- (4-fluorobenzoyl) -1-piperidinyl] propyl] -2,3-dihydro-r

4- (1H) -h.inazolinone (E) -2-butanedioate (1: 1), m.p. 188.2 ° C, yield 27 °;>.

^X 3- (2- (4- (4-fluorobenzoyl) -1-piperidinyl) ethyl) -3,4-dihydro-

4- (4-Methylphenyl) -2 H -1-quinazolinone, m.p. 159.1 ° Q, 17% yield.

[1- / 2- / 4- (4-chlorophenyl) -1,4-dihydro-2-thioxo-3 (2H) -quinazolin-1 / ethyl] -4-piperidinyl] (4-fluorophenyl) -methanone monohydrochloride, tt 172.2 ° C, yield? 5>.

3- (2- (4--4-fluorobenzoyl) -4-methyl-1 ~ piperidinyl) ethyl] -2,4 (1H, 3H) -quinazolinedione, m.p. 189.1 ° C, yield 23%.

3- (2-) 4- (3,4-dimethoxyberzoyl) -1-piperidinyl] ethyl] -2,4- (1H, 3H) -quinazolinedione, m.p. 217.8 ° C, 15% yield.

3- (2- (4- (4-fluorobenzoyl) -1-piperidinyl) ethyl) -2- (4-fluorophenyl) -4 (3H) -benzazolinone, m.p. 131, l ° c, yields 41%. jX * i

3- (2-) 4- (4-1 / 1 Fluorobenzoyl) -1-piperidinyl / ethyl / -2- (4-methylphenyl) -4- (31) -quinazolinone, t, t. 143.5 ° 6, yield 3 &% · t

3- (2-) 4- (4-Fluorobenzoyl) -1-pineriinyl] ethyl] -2,3-dihydro-2-yl (3-pyridinyl) -4 (1b) -liirazolinone, m.p. 126.3 ° C, yield 27%.

t.

3- [6- (4- (4-fluoro-benzoyl) -1-pyridinyl) ethyl] -2,3-dihydro-14-methoxyphenyl; -4 <RTI ID = 0.0> 1H </RTI> -hi nazolinone, mp 154.8 ° S, yield t / o. '

3- '2- / 4- in 4-1' fluorobenzoyl) -1-piperidines 1 / ethyl] -2- (4-methoxyphenyl) -4- (3h) -quinazolinone, m.p. 16i, 4 ° C, yield 36> f ».

3- [6- / 4- (2-fluoro-47methoxybenzoyl) -1-piperidinyl] -ethyl] - _s

6.4 (1H, 3H) -Hisolated nedine, m.p. 197.5 ° C, yield ll / o.

2- [4- / 4- (4-fluorobenzoyl) -1-piperidines 1 / butyl] -2, 3-dihydro2-thioxo-4 (1H) -quinazolinone, tft. 174.7 ° 8, yield, 12%,

Example 34 ^ A mixture of 5.8 parts of 3- (2-bromoethyl) -2- (3-chlorophenyl> -4 (3 ·) quinazolinone, 3.6 parts (4-fluorophenes 1) (4-taps _/ pyridine) methanone hydrochloride, 8 parts of sodium carbonate and 120 parts of 4-methyl 2-pentanone was stirred for 1 refluxed overnight koristeči guided separator. ^lL eakci.ona srneea is cooled and water is added. otaloženi product is filtered and the crystals of the 36 functioning 2- of propanol, yielding 3 parts of 2- (3-chlorophenyl) -3 - [S - / 4- (4-fluorobenzoyl) -1-piperidinyl] -ethyl] -4 (3H) -quinazolinone, mp 163.8 ° C.

ha similar n ^ The act also with; obtained:

2- (2-Hydroenyl) -3- / 2 ^L / 4- (4-fluorobenzoyl) -1-piperidinyl / ethyl / -4 < 3 &gt; H) -Hisol non (E) -2-butenediate (1: 1 ), mp 199.2 ^ yield 39? 5? p (4-chlorophenyl) -3- [2- / 4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -4 (3H) -quinaziol iron (E) -2-butenedioate (1: 1), mp, 225.6% yield 4 5%;

3- / 2- / 4- (4-fluorobenzoyl J-1-piperidinyl) ethyl / -2- (phenylmethyl 1) -4 (3h) -quinazole or: (E) -2-but.endioate (1 : 1). Mp 226 ° C yield 51%.

The best way to use prlvredl snagging is known

Applicant

The best application of the invention in the industry is when applied to a process for the preparation of 3- (2- / 4- (4-fluorobenzoyl) -1-piperidinyl / ethyl 2,4 (1H, 3H) -quinazolindione. The production of this compound is already cialisized and is marketed under the name KETANSERIN. The preparation of this compound is described in Example 23 of the description and can be recapitulated as follows : _; 7

A mixture of 4.5 parts of 3- (2-chloroethyl) -2,4 (1H, 3H) -quinazolindione, 4.9 parts of (4-fluorophenyl) (4-piperidinyl) methanone chloride, 8 parts of sodium carbonate and 80 parts of 4- methyl-2 ~ pentanone was stirred and refluxed overnight. The reaction mixture was cooled and water was added. The precipitate was filtered off and crystallized from 4-methyl-2-pentanone to give, after drying, 2.2 parts (27%) of Ketanserin, m.p. Mp 227-235 ° C.

•

In the meantime, the Applicant has improved the above procedure by introducing the following modifications:

i) 2 moles of sodium carbonate per mole of both starting compounds are used;

ii) 1.75 liters of solvent per mole of both products are used; and iii) the reaction is carried out at reflux temperature of the reaction mixture with azeotropic distillation of water formed during the reaction.

In this way, the yield of Ketanserin is increased to 33% and it is isolated from the reaction mixture by simple crystallization.

Claims (1)

the claim A process for the preparation of novel (piperidinylalkyl) quinazoline derivatives of the general formula (I): (λ - Alk - N R -Z (I) as well as their pharmaceutically acceptable acid addition salts, wherein in the above formula (I); Alk · alkylene sequence of 2 to 4 carbon atoms, Q is a quinazoline radical of the formula where, Y represents ό or S, 1 * 1 is a hydrogen, methyl, phenyl or phenylmethyl; p f is hydrogen, chlorine, fluorine, methyl or methoxy; x is hydrogen or phenyl; f * ^- is hydrogen, methyl, phenyl or phenyl substituted at the 4-position with fluorine, methyl or methoxy, or 3-pyridinyl; is hydrogen, methyl or phenyl; z 'ie y and p' are each independently methyl; R is hydrogen or methyl; i Z is a member selected from the group consisting of the radical formple: ^and H 'in which X represents a Member selected from the group containing \ ⁰ \ n CH - υ - C - CH ,, \ h _o i / ³ / ^2s 'C (CH ^) ^ » ^{fide q whole br0} * i M» ⁱ A _R represents a 2-thienyl, 3-pyridinyl, 1H-indol-3-yl, phenyl or phenyl group substituted at the 4-position by the bromine, fluorine, chlorine, methyl and methoxy group, 3-trifluoro methylphenyl, 3-methylphenyl> 2- methylphenyl, 2-chlorophenyl, 2 amino-4-fluorophenyl, 2-fluoro-4-methoxyphenyl or 3,4-dimethoxyphenyl, reacting a compound of the formula: 0¾ - Alk - ji (II) in which Q and Alk are as previously defined, a \! is bronze or chlorine, with a compound of the general formula wherein B and Z are as defined above, in 4-methyl-2pentanone, ethanol, Ν, dim-dimethylforinamide, or their mixture as a solvent, at the reflux temperature of the reaction mixture and in the presence of sodium carbonate as an acid acceptor, after which, if necessary, the resulting compound of formula (I) is converted into its pharmaceutically acceptable acid addition salt <1 ^ 1 JAt / oEi; ilhUd-lACEUTICA N. V., Belgian I Attorney Α (Ι> Μθ k A Tl DRAGOSlWi | ^ .s1tiČ BELGRADE ^ uJncgfa Lazira T Tel. 62CT-662 PROCEDURE FOR OBTAINING NEW DERIVATIVES (PIPERIDINYLalkyl) -HINAZOLINE? Abstract of invention The application describes a process for the preparation of novel (piperidinylalkyl) -quinaaoline derivatives of the general formula: (I) O-Alk-N 'V Z in which Q, Alk, R and Z are as defined in the Claim. According to the process of the invention of the compound of the above formula (I) is obtained by reaction of a compound of the formula: νλ Q-Alk-W (II) in ⁴ wherein Q and Alk are as previously defined and W is halogen, having the formula: (m) wherein R and Z are as previously defined. The reaction is carried out in 4-methyl-2-pentanone, ethanol, or N, N, N-dimethylformamide as a solvent, or in a mixture of these solvents, at the reflux temperature of the reaction mixture and in the presence of sodium carbonate as the acid release agent which is released in the reaction. If necessary, the compound of formula (I) obtained is converted into its pharmaceutically acceptable acid addition salt by treatment with the appropriate acid.