SI8810229A8 - Process for preparation of tetrahydronaphtalene derivatives - Google Patents
Process for preparation of tetrahydronaphtalene derivatives Download PDFInfo
- Publication number
- SI8810229A8 SI8810229A8 SI8810229A SI8810229A SI8810229A8 SI 8810229 A8 SI8810229 A8 SI 8810229A8 SI 8810229 A SI8810229 A SI 8810229A SI 8810229 A SI8810229 A SI 8810229A SI 8810229 A8 SI8810229 A8 SI 8810229A8
- Authority
- SI
- Slovenia
- Prior art keywords
- ethyl
- methylamino
- isopropyl
- fluoro
- tetrahydro
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
POSTUPAK ZA DOBIVANJE DERIVATA TETRAHIDRONAFTALINAPROCEDURE FOR OBTAINING TETRAHYDRONAFTALINE DERIVATIVES
1. Oblast tehnike u koju spada pronalazak1. FIELD OF THE INVENTION
Pronalazak spada u oblast hemije odn. farmacije, a odnosi se na postupak za dobivanje derivata tetrahidronaftalina, opšte formule z\:The invention falls within the field of chemistry or. Pharmaceuticals, a process for the preparation of a tetrahydronaphthalene derivative of the general formula z:
• · ·I II l\ z \ • · 9 ·• · · I II l \ z \ • · 9 ·
niloksi ili nizi alkoksi-nižialkilkarboniloksi, X označava C^-C^g-alkilen, koji u datom slučaju može oizi prekinut sa 1,4-fenilenom ili prekinut ili produžen sa 1 , 4-cikloheksilenom, A označava di- ili tri-supstituisan, nreko etilenske grupe vezan 2-imidazolil ili u datom slučaju supstituisan benzimidazoli1, benzimidaztolonil, imidazo|4,5-c|piridinil, imidazo|4,5-c|piridinonil, benztiazolil, benzodiazepin-2,5-dion-1-ilnyloxy or lower alkoxy-loweralkylcarbonyloxy, X denotes C 1 -C 4 -g-alkylene, which in this case may be terminated with 1,4-phenylene or terminated or extended with 1,4-cyclohexylene, A denotes di- or tri-substituted , an ethylene group bound by 2-imidazolyl or optionally substituted benzimidazolyl, benzimidazolonyl, imidazo | 4,5-c | pyridinyl, imidazo | 4,5-c | pyridinonyl, benztiazolyl, benzodiazepine-2,5-dione-1-yl
2.2.
ili pirolo|2,1-c||1,4|-benzodiazepin-5,11-dion-10-il i n predstavlja broj 0 ili 1, u obliku racemata i optičkih antipoda, kao i N-oksida i na farmaceutski primenljive kiselinske adicione soli ovih derivata.or pyrrolo | 2,1-c || 1,4 | -benzodiazepine-5,11-dione-10-yl in represents the number 0 or 1, in the form of racemates and optical antipodes, as well as N-oxides, and to pharmaceutically acceptable acids addition salts of these derivatives.
Ova jedinjenja su nova i odlikuju se dragocenim farmakodinamičkim osobinama.These compounds are novel and have valuable pharmacodynamic properties.
2. Tehnički problem2. Technical problem
Tehniški problem koji se rešava predmetnim pronalaskom sastoji se u torne da se ostvari postupak za dobivanje novih derivata tetrahidronaftalina, koji se odlikuju dragocenim farmakodinamičkim osobinama.The technical problem to be solved by the present invention is to provide a process for the preparation of new tetrahydronaphthalene derivatives, which have valuable pharmacodynamic properties.
3. Stanje tehnike3. State of the art
U Evropskoj patentnoj publikaciji br. 0.177.960 opisani su derivati tetrahidronaftalina, ali koji imaju umesto heterocikličnog ostatka A jedan po izboru supstituisani ostatak fenila. Takodje su opisana kalcijum-antagonistička svojstva pomenutih jedinjenja.In European Patent Publication no. 0.177.960 discloses tetrahydronaphthalene derivatives but having, instead of the heterocyclic residue A, an optionally substituted phenyl residue. The calcium-antagonistic properties of the compounds are also described.
4. Opis rešenja tehničkog problema sa primerima izvodjenja4. Description of a solution to a technical problem with examples of execution
Predmet ovog pronalaska su jedinjenja opšte formule I,The subject of the present invention are compounds of general formula I,
3.3.
N-oksidi i farmaceutski primenljive kiselinske adicione soli ovih jedinjenja kao takvi i za primenu kao terapeutske aktivne materije, zatim dobivanje ovih jedinjenja, dalje lekovi koji ih sadrže i dobivanje takvih lekova, kao i primena jedinjenja opšte formule I, N-oksida i njihovih farmaceutski primenljivih kiselinskih adicionih soli pri suzbijanju odnosno sprečavanju oboljenja odnosno pri oporavljanju zdravi ja, naročito pri su.zbijanju odnosno sprečavanju angine pektoris, ishemije, aritmija, visokog krvnog pritiska i insuficijencije srca.N-oxides and the pharmaceutically acceptable acid addition salts of these compounds as such and for use as therapeutic active substances, the preparation of these compounds, further the drugs containing them and the preparation of such drugs, and the administration of the compounds of general formula I, N-oxides and their pharmaceutical applicable acid addition salts in the control or prevention of disease or in the recovery of health, especially in the suppression and prevention of angina, ischemia, arrhythmias, high blood pressure and heart failure.
U ovom opisu primenjen izraz niži alkil - sam ili u kombinaciji - označava prevolančane i račvaste, zasičene ugljo vodonične ostatke sa 1-6, pogodno 1-4 atoma ugljenika, kao što su metil, etil, n-propil, izopropil, n-butil, izobutil, sek-butil, terc-butil, 1 torne slično. Izraz C^-C^2-alkil” na slican način se odnosi na alkil-grupe, u kojima alkil-os tatak ima 1-12 atoma ugljenika. Izraz niži alkoksi označava niže alkiletarske grupe u kojima izraz niži alkilThe term lower alkyl used herein, alone or in combination, refers to the branched and branched, saturated carbon-hydrogen residues of 1-6, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, 1 torn alike. The term C 1 -C 4 -alkyl "similarly refers to alkyl groups, in which the alkyl axis has 1-12 carbon atoms. The term lower alkoxy means lower alkyl ether groups in which the term lower alkyl
Ima gore dato značenje. Izraz halogen obuhvata četiri atoma halogena fluor, hlor, brom i jod. Izraz C^-C^g-alkilen označava pravolančane ili račvaste zasičene ostatke sa 1-18 atoma ugljenika, kao što su metilen, etilen, propilen, metiletilen, butilen, 1,1-dimetilpropilen, pentametilen,It has the meaning given above. The term halogen includes four halogen atoms fluorine, chlorine, bromine and iodine. The term C 1 -C 4 -alkylene denotes straight or branched saturated residues of 1-18 carbon atoms, such as methylene, ethylene, propylene, methylethylene, butylene, 1,1-dimethylpropylene, pentamethylene.
1-metilpentilen, 1-metilpentametilen, heksametilen, heptametilen, undekametilen i torne slično. Izraz aril označava u datom slučaju halogenom trifluormetilom, nižim alkilom, nižim alkoksi, nitro- ili amino-grupom jedan ili više puta supstituisan fenil. Primeri za u datom slučaju supstituisan benziimidazoli, benzilmidazolonll, imidazo|4,5-c|piridinil, imidazo|4,5-c|piridinonil, benztiazolil, benzodiazepin-2,5dion-1-il ili pirolo|2,1-c||1,4|benzodiazepin-5,11-dion-104.1-methylpentylene, 1-methylpentamethylene, hexamethylene, heptamethylene, undecamethylene and friction alike. The term aryl denotes, optionally, by halogen trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group one or more substituted phenyl. Examples of optionally substituted benzimidazoles, benzylmidazolonyl, imidazo | 4,5-c | pyridinyl, imidazo | 4,5-c | pyridinonyl, benzthiazolyl, benzodiazepin-2,5-dione-1-yl or pyrrolo | 2,1-c | | 1,4 | Benzodiazepine-5,11-dione-104.
ili su 2-benzimidazolil, 1-metil-2-benzimidazolil, 1-dodecil2- benzimidazolil, benzimidazolonil, 3-metilbenzimidazolonil,or 2-benzimidazolyl, 1-methyl-2-benzimidazolyl, 1-dodecyl2-benzimidazolyl, benzimidazolonyl, 3-methylbenzimidazolonyl,
3- izopropilbenzimidazolonil, 3-butilbenzimidazolonil, 3-morfoniloetilbenzimidazolonil, 3-benzimidazolonil, 3-benzilbenzimidazolonil, 2-piridilmetilbenzimidazolonil, 2-imidazo|4,5-c| -piridinil, imidazo|4,5-c|piridinonil, 2-benztiazolil,3-isopropylbenzimidazolonyl, 3-butylbenzimidazolonyl, 3-morphonyloethylbenzimidazolonyl, 3-benzimidazolonyl, 3-benzylbenzimidazolonyl, 2-pyridylmethylbenzimidazolonyl, 2-imidazo | 4,5-c | -pyridinyl, imidazo | 4,5-c | pyridinonyl, 2-benzthiazolyl,
2,3,4,5,-tetrahidro-4-metilbenzodiazepin-2,5-dion-1-il,2,3,4,5-tetrahydro-4-methylbenzodiazepine-2,5-dione-1-yl,
6-hlor-2,3,11,11a-tetrahidro-pirolo|2,1-c|1,4|benzodiazepin-5,11-dion-10-il, 5,6-dimetil-2-benzimidazolil i torne slično. Primeri za di- i tri-supstituisan 2-imidazolil, koji je vezan preko etilenske grupe, su 1-metil-4,5-difenil-2-imidazoliletil i 4,5-difenil-2-imidazoliletil i torne slično. Izraz odlazeca grupa'* označava grupe sa halogenom koje su poznate kao odlazece grupe, pogodno hlor ili brom, arilsulfoniloksi, kao na primer, toziloksi, brombenzolsulfoniloksi, benzolsulfoniloksi ili msitilensulfoniloksi, ili alkilsulfonlloksi, kao na primer, meziloksi ili trifluometilsulfoniloksi.6-chloro-2,3,11,11a-tetrahydro-pyrrolo | 2,1-c | 1,4 | benzodiazepin-5,11-dione-10-yl, 5,6-dimethyl-2-benzimidazolyl and thorne-like . Examples of di- and tri-substituted 2-imidazolyl, which is bonded via the ethylene group, are 1-methyl-4,5-diphenyl-2-imidazolylethyl and 4,5-diphenyl-2-imidazolylethyl and thorne alike. The term outgoing group '* means halogen groups known as leaving groups, preferably chlorine or bromine, arylsulfonyloxy, such as tosyloxy, bromobenzenesulfonyloxy, benzenesulfonyloxy or msitylensulfonyloxy, or alkylsulfonyloxy, such as trifluoromethyloxy
Izraz farmaceutski primenljive kiselinske adicione soli obuhvata soli sa anorganskim ili organskim kiselinama, kao što su sona, bromvodonična, azotna, sumporna, fosforna, limunska, mravlja, maleinska, sirčetna, čilibarna, vinska, metansulfonska, p-toluolsulfonska kiselina i torne slične. Takve soli se mogu napraviti sa aspekta stanja tehnike i uz uzimanje u obzir prirode jedinjenja koje se prevodi u jednu so što za jednog stručnjaka u toj oblasti ni u kojem slučaju ne predstavlja problem.The term pharmaceutically acceptable acid addition salts include salts with inorganic or organic acids, such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, maleic, acetic, amber, tartaric, methanesulfonic, p-toluenesulfonic acid and friction-like. Such salts can be made from the aspect of the prior art and taking into account the nature of the compound which is translated into a single salt, which in any case is not a problem for one of skill in the art.
Od prednosti su takva jedinjenja formule I, u kojoj R oznaO čava izopropil, R-5 označava prvenstveno izobutiriloksi ili metoksiacetiloksi, a n označava prvenstveno broj 1. DaljeOf advantage are those compounds of formula I, in which R is isopropyl, R- 5 is preferably isobutyryloxy or methoxyacetyloxy, and is preferably number 1. Further
5.5.
su pogodna takva jedinjenja formule I, u kojima R oznacava fluor. Takodje su pogodna takva jedinjenja formule I, u 2 kojima R oznacava metil. Takodje su pogodna ona jedinjenja formule I, u kojima X oznacava C^-C^-alkilen, naročito pogodno propilen, butilen, pentametilen ili heksametilen, A oznacava prvenstveno 2-benzimidazolil, 2-benztiazolil,are suitable compounds of formula I wherein R is fluoro. Such compounds of formula I, in which R is methyl, are also suitable. Also suitable are those compounds of formula I, in which X is C 1 -C 4 -alkylene, especially preferably propylene, butylene, pentamethylene or hexamethylene, and A is preferably 2-benzimidazolyl, 2-benzthiazolyl.
1-metil-2-benzimidazolil, 1-dcdecil-2-benzimidazolil, benzimidazolonil, 2,3,4,5-tetrahidro-4-metilbenzodiazepin-2,5-dion-1-il, 6-hior-2,3,11,11a-tetrahidropirolo|2,1-čili , 4 |-benzodiazepin-5 ,11-dion-10-il, ili 1-metil-4,5difenil-2-imidazolil, naročito pogodnc 2-benzimidazolil ili 2-benztiazolil.1-methyl-2-benzimidazolyl, 1-dececyl-2-benzimidazolyl, benzimidazolonyl, 2,3,4,5-tetrahydro-4-methylbenzodiazepin-2,5-dione-1-yl, 6-chloro-2,3, 11,11a-tetrahydropyrrolo | 2,1-chili, 4,1-benzodiazepin-5, 11-dione-10-yl, or 1-methyl-4,5-diphenyl-2-imidazolyl, especially suitable 2-benzimidazolyl or 2-benzthiazolyl.
Iz gcre iznetog sledi da su naročito pogodna takva jedinje3 v nja formule I, u kcjima R oznacava izopropil, RJ oznaČava 1 izobutiriloksi ili metoksiacetiloksi, R oznacava fluor,It is apparent from the above that such compounds of formula I, in which R is isopropyl, R J is 1 isobutyryloxy or methoxyacetyloxy, R is fluoro, are particularly suitable.
R označava metil, X oznacava propilen, butilen, pentametilen ili heksametilen, A označava 2-benzimidazolil ili 2-benzitiazolil i n označava broj 1.R stands for methyl, X stands for propylene, butylene, pentamethylene or hexamethylene, A stands for 2-benzimidazolyl or 2-benzthiazolyl and n stands for number 1.
Naročito pcgodna jedinjenja formule I su:Particularly preferred compounds of formula I are:
2-|2-||3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1 <Z-izopropil-2 /S-naftilmetoksiacetat, |1S,2S|-2-|-||5-(2-benzitiazolil)-pentil|-metilamino|-eti1|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat i |1S,2S|-2-|2-||3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat.2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-2 / S-naphthylmethoxyacetate, | 1S, 2S | -2- | - || 5- (2-Benzothiazolyl) -pentyl | -methylamino | -ethyl] -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate i | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthylmethoxyacetate.
6.6.
one soli ovih jedinjenja mogu se dobiti takothose salts of these compounds can be obtained thus
Jedinjenja formule I u obliku racemata i optičkih antipoda, kao i N-oksidi i farmaceutski primenljive kiselinske adicišto seThe compounds of formula I in the form of racemates and optical antipodes, as well as N-oxides and pharmaceutically acceptable acid additionally
a) reaguje jedinjenje opšte formulea) the compound of the general formula reacts
OH t \ / \:OH t \ / \:
T ίί ΐ\ /*vT ίί ΐ \ / * v
1/Λ./Χ/- * Ϊ2ΙΧ)η-Α la1 / Λ. / Χ / - * Ϊ2 ΙΧ) η- Α la
2 u kojoj R, R R , A, X i n. imaju gore dato značenjer sa sredstvom za acilovanje koje odaje nizu alkilkarbonil ili nižu alkoksi-nižu alkilkarbonil-grupu, i ako se to želi, što se2 in which R, RR, A, X and n. have the meaning given above r with an acylating agent which attaches to a lower alkylcarbonyl or lower alkoxy-lower alkylcarbonyl group, and if desired,
b) dobiveno jedinjenje oksiduje u odgovarajuči N-oksid, i/ilib) the resulting compound is oxidized to the corresponding N-oxide, and / or
c) dobiven racemat razdvaja u optičke antipode, i/ili »j . ' ίίc) separates the resulting racemate into optical antipodes, and / or »j. 'ίί
d) _dobiveno jedinjenje prevodi u farmaceutski primenlji. J vu kiselinsku adicionu so.d) The resulting compound is translated into pharmaceutical applications. J vu acid addition salt.
Acilovanje jedinjenja formule la vrši se prema po sebi poznatim metodama, pogodna sredstva za acilovanje su naročito aktivirani derivati kiselina, kao što su halogenidi kiselina i anhidridi kiselina ili mešoviti kiselinski anhidridi. ReakThe acylation of compounds of formula Ia is carried out by methods known per se, suitable acylating agents are particularly activated acid derivatives, such as acid halides and acid anhydrides or mixed acid anhydrides. Reak
7.7.
cija se izvodi u organskom rastvaraču koji je inertan pod datim reakcionim uslovima ili u smeši takvih rastvarača pri temperaturi izmedju oko 0°C i temperature refluksovanja. Kao rastvarači dolaze u obzir naročito aromatični ugljovodonici, kao benzol, toluol ili ksilol, hlorovani ugljovodcnici, kao metilenhlorid ili hloroform, etri, kao dietiletar, tetrahidrofuran ili dioksan,i torne slično.which is carried out in an organic solvent which is inert under the given reaction conditions or in a mixture of such solvents at a temperature between about 0 ° C and a reflux temperature. Especially aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, and friction-like ones are considered as solvents.
Dobiveno jedinjenje takodje se može napo sebi poznat način prevesti u odgovarajuci N-oksid, dejstvom oksidacionog sred stva, kao što je vodonik-peroksid ili perkiselina, na primer, persircetna kiselina ili perbenzoeva kiselina, u nekom rastvaraču, kao što je alkancl, napr., metanol ili etanol, i torne slično, pri temperaturi izmedju oko 0° i 50°C, prvenstveno pri sobnej temperaturi.The resulting compound can also be converted in a known manner in a suitable N-oxide by the action of an oxidizing agent, such as hydrogen peroxide or peracid, for example, persicacetic acid or perbenzoic acid, in a solvent such as an alkanol, e.g. , methanol or ethanol, and friction alike, at a temperature between about 0 ° and 50 ° C, preferably at room temperature.
Polazne materije formule la su nove i mcgu se debiti tako što se jedinjenje opšte formule ? OH /*\ /*\:The starting materials of the formula la are new and mcgu is debuted by having a compound of the general formula? OH / * \ / * \:
i II 11 and II 11
RX/ V u kojoj Z označaVa odlazeču grupu a R i R1 imaju gore dato značenje, reaguje sa aminom opšte formuleR X / V in which Z denotes a leaving group and R and R 1 have the meaning given above, reacts with an amine of the general formula
HN-(X) -A nHN- (X) -A n
IIIIII
8.8.
v u kojoj R , A, X i n imaju gore dato značenje.v in which R, A, X and n have the meaning given above.
Jedinjenje formule II reaguje se na po sebi poznatim metodama sa aminom formule III. Reakcija se izvodi u prisustvu ili odsustvu organskog rastvarača koji je ped datim reakcionim uslovima inertan, pri temperaturi izmedju oko 20° i 150°C prvenstveno izmedju oko 80° i 120°C. Pri ovoj reakciji kao rastvarači dolaze u obzir dimetilformamid, dimetilsulfoksid, alkoholi, kao izopropanol ili terc.-butanol, etri, kao tetrahidrofuran ili dioksa, aromatični ugljovodcnici, kao benzol, toluol ili ksilol, hlorovani ugljovodcnici, kao metilenhlorid, ugljentetrahlorid ili hlorbenzol, i torne slično. Reakcija se pogodno izvodi u prisustvu sredstva za vezivanje kiseline, kao što je tercijarni amin, kao trimetilamin, trietilamin, etildiizopropilamin ili 1,5-diazabiciklo|4.3·0|non-5-en, pri čemu kao sredstvo za vezivanje kiseline može služiti i višak amina formule III. Svrsishodno je da se radi pri atmosferskem pritisku, mada se takodje mogu primeniti i viši pritisci.The compound of formula II is reacted by methods known per se with the amine of formula III. The reaction is carried out in the presence or absence of an organic solvent which is inert under the given reaction conditions, at a temperature between about 20 ° and 150 ° C, preferably between about 80 ° and 120 ° C. In this reaction, solvents include dimethylformamide, dimethylsulfoxide, alcohols, such as isopropanol or tert-butanol, ethers, such as tetrahydrofuran or dioxa, aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinated hydrocarbons, such as methylene chloride, hydrochloride, carbon towers similarly. The reaction is conveniently carried out in the presence of an acid-binding agent, such as a tertiary amine, such as trimethylamine, triethylamine, ethyldiisopropylamine or 1,5-diazabicyclo | 4.3 · 0 | non-5-ene, wherein the acid-binding agent may also serve an excess of an amine of formula III. It is expedient to operate at atmospheric pressure, although higher pressures may also apply.
Predproizvodi formula II i III su. poznati ili se mogu dobiti u analogiji sa dobivanjem poznatih jedinjenja. U sledečim shemama I-III prikazan je po jedan postupak za dobivanje jednog jedinjenja formule III, u kejoj A označava hetercciklus koji je vezan preko atoma azota ili ugljenika, odnosno di- ili tri-supstituisani 2-imidazolil koji je vezan preko etilenske grupe, pni čemu Boc označava terc.-butoksikarbonil, Bz označava benzil a Ph označava fenil-gnupu. Reakcioni uslovi za reakcije prikazane na pomenutim shemama opisani su u delu sa primerima izvodjenja.The preforms of formulas II and III are. known or may be obtained in analogy with the preparation of known compounds. The following Schemes I-III show one process for the preparation of one compound of formula III, in which A denotes a heterocycle attached via a nitrogen or carbon atom, or di- or tri-substituted 2-imidazolyl which is linked via an ethylene group, e.g. to which Boc stands for tert-butoxycarbonyl, Bz stands for benzyl and Ph stands for phenyl ring. The reaction conditions for the reactions shown in the above schemes are described in the embodiment examples section.
9.9.
Schema I h2n-(CH2)6-ohScheme I h 2 n- (CH 2 ) 6 -oh
IVIV
Boc-NH-(CHO),0H Z o iBoc-NH- (CH O ), 0H Z oi
Boc-NH-(CH2)g-0SO2CH3 Boc-NH- (CH 2 ) g -OSO 2 CH 3
VI ·' \.VI · '\.
BOC-NH- (CH„) .-Nf \j- ·(BOC-NH- (CH „).-Nf \ j- · (
Z b \ / x \ /With b \ / x \ /
VII /’\ z Boc-N-(CH,)^ CH3VII / '\ z Boc-N- (CH,) ^ CH 3
VIIIVIII
HN-(CH_)c-Nx ;NHHN- (CH_) c -N x ; NH
Au 2 6 \ /Au 2 6 \ /
CH3 z**\ ? \ • · \ / lila B°c-n-(ch2)6-n( X>h ČH3 /'T * · \ /CH 3 z ** \? \ • · \ / lila B ° cn- (ch 2 ) 6 -n ( X > h ČH 3 / 'T * · \ /
IX / \IX / \
Boc-N- (CH0 ) C-N. N-CH-,Boc-N (CH 0) C-N. N-CH-,
ČH 25 X.-.Z 3 Un3 '/ \ / \ČH 25 X .-. Z 3 Un 3 '/ \ / \
HN-(CH„)-N ;N-CHq 6h, 2 6 >-< 3 3 / \ \ / • — ·HN- (CH „) - N; N-CH q 6h, 2 6 > - < 3 3 / \ \ / • - ·
IHbIHb
10.10.
Schema IIScheme II
BzOC-NH-CH2-«\ /*-COOH XIBzOC-NH-CH 2 - «\ / * - COOH XI
BzOC-N-CH„-*f ^‘-COOH XIIBzOC-N-CH „- * f ^ '- COOH XII
OC-tiJ-CH2'H3OC-tiJ-CH 2 ' H 3
HN-CH2-·HN-CH 2 - ·
:h.: h.
XIVXIV
Illd t 7 x i — · · — ♦ \ /Illd t 7 x i - · · - ♦ \ /
..
,/ \ /, / \ /
Schema IIIScheme III
HOOC-CH--/ i 2HOOC-CH - / i 2
Λ /ph Ph / ph
XVXV
PhPh
HNOC-CH--·; |HNOC-CH-- ·; |
Ah 2 \ z*\ CH3 XNZ XPhA h 2 \ z * \ CH 3 X N ZX Ph
XVI * A zh XVI * A with h
HNCHnCHn-»C ί :h.HNCH n CH n - »C ί: h.
S/ XPhS / X Ph
UleUle
Ph ./ \ /Ph ./ \ /
BzO-C-N-CH-CH--.; 1 :«3 2 2 V\h BzO-CN-CH-CH--; 1 : «3 2 2 V \ h
XVIIXVII
CH z\ /Ph rHaCH z \ / Ph r H a
XVIIIXVIII
CHCH
I X /Ph IX / Ph
HN-CH-CH,,-*/ ’HN-CH-CH ,, - * / '
CH-. 2 2 \ /’\ XN PhCH-. 2 2 \ / '\ X N Ph
IllfIllf
12.12.
Jedinjenja opšte formule I sadrže najmanje jedan asimetričan centar (položaj 2) i otuda se mogu nalaziti u obliku optičkih antipoda ili racemata. Jedinjenja formule I, koja sadrže više od jednog asimetričnog centra nalaze se u relativnoj konfiguraciji koja je data formulom I. Racemati formule I mcgu se razdvojiti uz primenu po sebi poznatih metoda, napr., reakcijom sa optički aktivnom kiselinom i frakcionom kristalizacijom dobivene soli, pri čemu dolazi do razdvajanja na optičke antipode.The compounds of general formula I contain at least one asymmetric center (position 2) and can therefore be in the form of optical antipodes or racemates. Compounds of formula I containing more than one asymmetric center are in the relative configuration given by formula I. The racemates of formula I mcgu are separated by applying known methods, for example, by reaction with an optically active acid and by fractional crystallization of the resulting salt, at resulting in separation into optical antipodes.
Jedinjenja formule I imaju izračeno kalcijum-antagonistiČno dejstvo i otuda se mogu primenjivati kao lekovi, naročito za suzbijanje odnosno sprečavanje angine pektoris, ishemije, aritmija, visokog krvnog pritiska i insuficijencija srca.The compounds of formula I have a pronounced calcium-antagonistic effect and can therefore be used as medicaments, especially for the suppression or prevention of angina, ischemia, arrhythmias, high blood pressure and heart failure.
U dole opisanom testu su pokazani kalcijum-antagonističko dejstvo kao osobine snižavanja krvnog pritiska pomoču jedinjenja datih ovim pronalaskom:The test described below has shown calcium-antagonistic activity as blood pressure lowering properties by the compounds of the present invention:
A. H-Desmetoksiverapamil-vezivna odredjivanja:A. H-Desmetoxiverapamil-binding determinations:
Odredjivanje je izvodjeno na delimično očiščenim membranama srca mcrskog praseta. Reakciona mešavina se sastoji (0,3 ml)Determination was performed on partially cleared membranes of the heart of a black pig. The reaction mixture was combined (0.3 ml)
O od 0,2-0,8 mg membranskog proteina, 2,5 nM H-desmetoksiverapamila i različitih koncentacija ispitivanih supstanci. Inkubacija traje 120 minuta pri 37°C i zaustavlja se razblaživanjem sa inkubacionim puferom; zatim sledi filtriranje. Radioaktivnost vezana za filtrat meri se scintilacionim brojačem. Specifično vezivanje (tj. za receptor vezano) definiše se kao razlika izmedju ukupne i nespecifično vezaneAbout 0.2-0.8 mg of membrane protein, 2.5 nM of H-desmethoxyrapamil and various concentrations of test substances. The incubation lasts for 120 minutes at 37 ° C and is stopped by dilution with incubation buffer; followed by filtering. The radioactivity associated with the filtrate is measured by a scintillation counter. Specific binding (ie receptor bound) is defined as the difference between total and non specific binding
13.13.
radioaktivnosti. Nespecifično vezivanje odredjeno je u prisustvu viška verapamila (10/UM) koji nije bio radioaktivan.radioactivity. Non-specific binding was determined in the presence of excess verapamil (10 / UM) that was not radioactive.
Aktivnost (potencija) nekog jedinjenja u ovom testu definisana je preko vrednosti Ιΰ^θ. ΙΟ^θ je ona koncentracija supstance (u Mol/1) koja prouzrokuje polovinu maksimalne inhibicije specifičnog vezivanja H-desmetoksiverapamila. Ova vrednost je ekstrapolisana iz krive koja predstavlja funkciju koncentracije i vezivanja.The activity (potency) of a compound in this test is defined by the value of Ιΰ ^ θ. ΙΟ ^ θ is that concentration of a substance (in Mol / 1) that causes half the maximum inhibition of specific binding of H-desmethoxyrapamil. This value is extrapolated from the curve representing the concentration and binding function.
B. Izolovano, perfundirano srce morskog praseta prema Langendorff-u:B. Isolated, perfused guinea pig according to Langendorff:
Uspava se morsko prase težine od otprilike 400 g sa uretanom (1 g/kg i.p.) i brzo se udalji njegovo srce. Aorta se kanulira i srce retrogradno perfundira sa modificiranim Krebs-Henseleit-ovim rastvorom sledeceg sastava u mM:The sleeping piglet weighs approximately 400 g with urethane (1 g / kg i.p.) and quickly removes its heart. The aorta is cannulated and the heart is retrograde perfused with a modified Krebs-Henseleit solution of the following composition in mM:
NaCl 114,7, KC1 4,7, MgSO^ 1,2, KH2PC4 1,5, NaHCO3 25,NaCl 114.7, KC1 4.7, MgSO ^ 1.2, KH 2 PC 4 1.5, NaHCO 3 25,
CaCl2 2,5 i glukoza 11,1. Ovaj rastvor se gasira sa oksikarbonom (smešom od 95% kiseonika i 5% ugljendioksida) pri pH 7,3 pri temperaturi od 37°C. Pritisak perfuzije je održavan konstantnim pri vrednosti od 90 cm H20 (8,83 kPa).CaCl 2 2.5 and glucose 11.1. This solution was quenched with oxycarbon (a mixture of 95% oxygen and 5% carbon dioxide) at pH 7.3 at 37 ° C. The perfusion pressure was kept constant at 90 cm H 2 0 (8.83 kPa).
U levu srčanu komoru je uvučen Millerov kateter mikrotipa kao tarnsduktor pritiska (PC-350) za merenje levog ventrikularnog pritiska. Celokupni tok srčane arterije sakupljen je u levak i meren pomccu elektromagnetnog merača protoka. Svi mereni parametri su prikazani na aparatu za registrovanje parametara (Gould, model 2800). Posle adaptiranja u toku 45 minuta počinje ogled. Supstance su infundirane brzinom od 1% u odnosu na ukupnu brzinu srčanog toka (koronar-ncg toka). Za svaku ispitivanu supstancu je napravljenaA Miller microtype catheter was inserted into the left heart chamber as a pressure transducer (PC-350) to measure left ventricular pressure. The entire course of the cardiac artery was collected in a funnel and measured using an electromagnetic flowmeter. All measured parameters are displayed on the parameter recording apparatus (Gould, model 2800). After the adaptation, the experiment begins within 45 minutes. The substances were infused at a rate of 1% relative to the total heart rate (coronary-ncg flow). It is made for each test substance
14.14.
-1 Ο kompletna kriva zavisnosti dejstvo-koncentracija (10 do 10 M). Oba najvažnija merna parametra su: (1) CBF:-1 Ο complete effect-concentration curve (10 to 10 M). The two most important measurement parameters are: (1) CBF:
koronarni protok krvi (u ml/min) - brzina protoka krvi kroz koronarne arterije i (2) dp/dt: stupanj rasta levog ventrikularnog pritiska (u mmHg/sek) - što predstavlja brzinu porasta levog ventrikularnog pritiska, kao mere za šilu (mcc) kontraktivnosti srca; ova vrednost je data kao % maksimalne promene u odnosu na polaznu vrednost (A%) po datoj dozi.coronary blood flow (in ml / min) - rate of blood flow through the coronary arteries and (2) dp / dt: rate of growth of left ventricular pressure (in mmHg / sec) - representing the rate of increase of left ventricular pressure, as a measure of spike (mcc ) contractility of the heart; this value is given as% of maximal change from baseline (A%) by given dose.
C. Hemodinamički parametri kod narkotiziranog psa:C. Hemodynamic parameters in a narcotic dog:
Četiri najvažnija merna parametra (sa odgovarajucim mernim jedinicama) hemodinamičkih ogleda su: (1) CBF: Coronary Blood Flow (u ml/min) - brzina protoka krvi kroz koronarne arterije; (2) HR: Heart Rate (u udarima/min) - frekvencija srca; (3) BP: Blood Pressure (u mmHg) - krvni pritisak; i (4) dp/dt: Rate of increase in left ventricular pressure (u mmHg/sek) - brzina porasta levog ventrikularnog pritiska kao mera za kontraktivnost (snagu kontraktincst-i) srca. Vrednosti su date kao % maksimalne promene početne (polazne) vrednosti (Δ%) po datoj dozi.The four most important measurement parameters (with appropriate measurement units) of hemodynamic examinations are: (1) CBF: Coronary Blood Flow (in ml / min) - rate of blood flow through coronary arteries; (2) HR: Heart Rate (in beats / min) - heart rate; (3) BP: Blood Pressure (in mmHg) - blood pressure; and (4) dp / dt: Rate of increase in left ventricular pressure (in mmHg / sec) - rate of increase of left ventricular pressure as a measure of cardiac contractility (strength of contraction). Values are given as% of maximal change in baseline (Δ%) by given dose.
Na ovaj način dobiva se ne samo celokupna slika dejstva supstance, več takodje i procena o potencijalnoj selektivnosti za jedan odredjen deo sistema krvotoka u celokupnom organizmu. Posle davanja anestetičkcg sredstva pas se intubira i pusti da veštački diše. Krvni Ph, pCC^, p02 i hemoglobin su mereni svaki sat pomocu analizatora krvi i gasa u krvi. Krvni pritisak (sistolni i dijastolni) meren je pcmocu sonde abdominalno u abdominalnoj aorti. Frekvencija srcaIn this way, not only the overall picture of the action of the substance is obtained, but also the assessment of the potential selectivity for a particular part of the bloodstream system in the whole organism. After administration of the anesthetic agent, the dog is intubated and allowed to breathe artificially. Blood Ph, pCC ^, p0 2 and hemoglobin were measured every hour using a blood and gas analyzer. Blood pressure (systolic and diastolic) was measured by the probe tube abdominally in the abdominal aorta. Heart frequency
15.15.
je pracena pomoču tahometra, kcji je odvojen od pulsa krvnog pritiska. Za druga merenja srce mora biti prvo oslobodjeno da bi se u levu veritrikulu (levu srčanu komoru) megla ubaciti jedna sonda koja služi za merenja pritiska (dp/dt). Koronarni protok krvi meren je na levoj koronarnoj arteriji (descedens) pomoču jedne sonde za merenje protoka.was monitored by a tachometer separated from the blood pressure pulse. For other measurements, the heart must first be released in order to insert a single probe for pressure measurements (dp / dt) into the left veritrix (left heart chamber). Coronary blood flow was measured on the left coronary artery (descedens) using a single probe to measure flow.
Rezultati koji su dobiveni u ovim testovima sakupljeni su i prikazani na sledečoj tabeli:The results obtained in these tests are summarized and shown in the following table:
TabelaTable
16.16.
A = |1S,2S|-2-|2-||3-(2-benzimidazolil)-propil|-metilamini|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil2-naftilmetoksiacetatA = | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamines | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl2- naphthylmethoxyacetate
B = |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2|metil-|6-(2-okso-1-benzimidazolinil)-heksil|-amino|etil|-2-naftilmetoksiacetatB = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 | methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -amino | ethyl | -2-naphthylmethoxyacetate
C = |1S,2S|-2-|2-||3-(2-benzimidazolil)-propil|-metil-Noksidoamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-naftilmetoksiacetatC = | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methyl-knoxidoamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1isopropyl- 2-naphthylmethoxyacetate
D = |1S,2S|-2-|2-| |7-(1-dodecil-2-benzimidazolil)-heptil|metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-naftilmetoksiacetatD = | 1S, 2S | -2- | 2- | 7- (1-dodecyl-2-benzimidazolyl) -heptyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate
E = |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2||3-(1-metil-4,5-difenilimidazol-2-il)-propil|-metilamino|-etil|-2-naftilmetoksiacetatE = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 || 3- (1-methyl-4,5-diphenylimidazol-2-yl) - propyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate
F = |1S,2S|-2-|2-||5-(2-benztiazolil)-pentil|-metilamino|etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetatF = | 1S, 2S | -2- | 2- || 5- (2-Benzthiazolyl) -pentyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthylmethoxyacetate
G = |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2||4-|(2-benzimidazolil)-metil|-benzil|-metilamino|etil|-2-naftilmetoksiacetatG = | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 || 4- | (2-benzimidazolyl) -methyl | -benzyl | -methylamino | ethyl -2-naphthylmethoxyacetate
Jeidnjenja formule I mogu se prlmenjivati kao lekovi, napr., u obliku farmaceutskih preparata. Ovi farmaceutski preparati mogu se davati oralno, napr., u obliku tableta, lakih tableta, dražea, kapsula sa tvrdim i mekim želatinom, rastvora, emulzija ili suspenzija. Davanje može biti i rektalno, napr.,Formula I supplements may be administered as medicaments, for example, in the form of pharmaceutical preparations. These pharmaceutical preparations may be administered orally, for example, in the form of tablets, light tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration may also be rectal, for example,
17.17.
u obliku supozitorija, ili parenteralno, napr., u obliku injekcionih rastvora.in the form of suppositories, or parenterally, e.g., in the form of injectable solutions.
Za dobivanje tableta, lakih tableta, dražeja i kapsula sa tvrdim želatinom jedinjenja formule I mogu se preraditi sa farmaceutski inertnim, neorganskim ili organskim ekscipijen tima. Kao takvi ekscipijenti mogu se primeniti, napr., za tablete, dražeje i kapsule sa tvrdim želatinom, laktoza, kukuruzni škrob ili njihovi derivati, talk, stearinska kiselina ili njene soli itd.For the preparation of tablets, light tablets, dragees and hard gelatin capsules, compounds of formula I may be processed with a pharmaceutically inert, inorganic or organic excipient. As such excipients can be used, for example, for tablets, dragees and capsules with hard gelatin, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
Za kapsule sa mekim želatinom kao ekscipijenti su pogodni napr. biljna ulja, voskovi, masti, polučvrsti i tečni polioli itd.For soft gelatin capsules as excipients are suitable e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.
Za dobivanje rastvora i sirupa kao ekscipijenti su pogodni napr. voda, polioli, saharoza, invertni šecer, glukoza itd.Suitable excipients are suitable for the preparation of solutions and syrups. water, polyols, sucrose, invert sugar, glucose, etc.
Za injekcione rastvore kao ekscipijenti su pogodni napr., voda, alkoholi, polioli, glicerin, biljna ulja itd.Suitable excipients for excipients include, for example, water, alcohols, polyols, glycerin, vegetable oils, etc.
Za supozitorije su kao ekscipijenti pogodni napr. prirodna i očvrsnuta ulja, voskovi, masti, polutečni ili tečni pclioli itd.For suppositories, excipients are suitable e.g. natural and hardened oils, waxes, fats, semi-liquid or liquid pclioles, etc.
Pored toga farmaceutski preparati mogu sadržati još i sredstva za konzerviranje, prenosnike rastvaranja, sredstva za stabilizovanje, kvašenje, emulgovanje, zasladjivanje, bojenje, aromu, soli za promenu osmotskog pritiska, pufera, sredstva za prevlačenje ili antioksidanse. Oni mogu takodje sadržati još i druge terapeutski dragocene materije.In addition, pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting, emulsifying, sweetening, coloring, flavoring, osmotic pressure salts, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.
Prema ovom pronalasku jedinjenja opšte formule I mogu seAccording to the present invention compounds of the general formula I can be
18.18.
primeniti pri suzbijanju odnosno sprečavanju angine pektoris, ishemije, aritmija, visokog krvnog pritiska i insuficijencije srca. Doziranje se meze varirati unutar širokih granica i naravno u svakom pojedinačnom slučaju mora se prilagoditi individualnim karakteristikama, uopšte pri oralnom davanju dnevna doza bi smela da iznosi od oko 25 do 150 mg jedinjenja opšte formule I, pri čemu može biti prekoračena i data gornja granica ako se pokaže da je to korisnc.to be used to combat or prevent angina, ischemia, arrhythmias, high blood pressure and heart failure. The dosage may vary within wide limits and of course in each individual case it must be adapted to the individual characteristics, in general, when administered orally, the daily dose should be from about 25 to 150 mg of the compounds of general formula I, which may be exceeded if the upper limit is given. it proves to be useful.
Sledci primeri treba da bliže objasne ovaj pronalazak, medjutim, oni ni u kojerc slučaju ne ograničavaju opseg ovog pronalaska. Sve temperature su date u stepenima Celzijusa.The following examples should further explain the present invention, however, they do not in any way limit the scope of the invention. All temperatures are given in degrees Celsius.
Primer 1Example 1
Smeša od 5,4 g (28,7 mmol) 2- | 3-(fnetilamino)-propil | -benzimidazola, 11,4 g (28,7 mmol) 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1oZ. -izopropil-2 73 -naftil)-etil-p-toluolsulfonata i 3,74 (28,7 mmol) Hunigove baze zagreva se 30 minuta pri 120°C. Smeša se zatim sipa na ledenu vodu i ekstrahuje metilenhloridcm. Posle sušenja organske faze iznad magnezijum-sulfata otpari se rastvarači ostatak hromatografiše na silikagelu sa 6:1 smešom metilenhlorida i metanola kao sredstva za eluiranje. Pri torne se dobiva 6,2 g (49%) |1S,2S|-2-|2—||3-(2-benzimidazolil)-propil|-metilamino|etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola, ladfgg = +41,2° (c = 0,8%; metanol).A mixture of 5.4 g (28.7 mmol) 2 - 3- (phenylamino) -propyl | -benzimidazole, 11.4 g (28.7 mmol) of 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-10Z-isopropyl-2 73-naphthyl) -ethyl-p-toluenesulfonate and 3.74 (28.7 mmol) of Hunig's base was heated at 120 ° C for 30 minutes. The mixture was then poured onto ice water and extracted with methylene chloride. After drying the organic phase over magnesium sulfate, the solvents are evaporated off, the residue is chromatographed on silica gel with a 6: 1 mixture of methylene chloride and methanol as the eluting agent. 6.2 g (49%) of 1S, 2S | -2- | 2 - | 3- (2-benzimidazolyl) -propyl | -methylamino | ethyl | -6-fluoro-1,2,3 are obtained , 4-tetrahydro-1-isopropyl-2-naphthalinol, ladfg = + 41.2 ° (c = 0.8%; methanol).
2-|3-(Metilamino)-propil|-benzimidazol, koji je ovde upotreb ljen kao polazna materija, debiven je na sledeči način:2- | 3- (Methylamino) -propyl | -benzimidazole, which is used herein as a starting material, is debuted as follows:
19.19.
22,8 g (91 mmol) 4-|1-(Benziloksi)-N-metilformamido|-buterne kiseline rastvori se u 200 ml tetrahidrofurana. Smeša se ohladi, i pri temperaturi od -15°C ukapava 13 ml (128 mmol) trietilamina i 12 ml (91,5 mmol) izobutil-estra hlormravlje kiseline. Posle 2,5 sata ukapa se pri -10°C u toku 30 minuta 10,3 g (95 mmol) o-fenilendiamina u 85 ml tetrahidrofurana. Posle jedncčasovnog mešanja pri sobnoj temperaturi rastvarač se upari pod sniženim pritiskom. Na to se doda voda i ekstrahuje etilacetatom. Organska faza se ispira zasecenim vodenim rastvorom natrijum-bikarbonata i zasičenim vodenim rastvorom kuhinjske soli. Posle sušenja iznad magnezi jum-sulfata i otpanavanja rastvarača dobiva se 27,05 g sirovog proizvoda koji se hromatografiše na silikagelu uz primenu etilacetata kao sredstva za eluiranje. Pni torne se dobiva 20,1 g (71%) benzil-|3-|(2-aminofenil)-karbamoil|propil|-metilkarbamata.22.8 g (91 mmol) of 4- | 1- (Benzyloxy) -N-methylformamido | -butyric acid were dissolved in 200 ml of tetrahydrofuran. The mixture was cooled, and 13 ml (128 mmol) of triethylamine and 12 ml (91.5 mmol) of hydrochloric acid isobutyl ester were added dropwise at -15 ° C. After 2.5 hours, 10.3 g (95 mmol) of o-phenylenediamine in 85 ml of tetrahydrofuran was added dropwise at -10 ° C for 30 minutes. After stirring at room temperature for one hour, the solvent was evaporated under reduced pressure. Water was added thereto and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After drying over magnesium sulfate and dissolving the solvent, 27.05 g of crude product are obtained which is chromatographed on silica gel using ethyl acetate as the elution agent. Pipers were obtained with 20.1 g (71%) of benzyl- [3- ((2-aminophenyl) -carbamoyl] propyl] -methylcarbamate.
MS: M+ 341.MS: M + 341.
20,1 g (59 mmol) Benzil-|3-|(2-aminofenil)-kanbamoil|-propil | -metilkarbamata rastvori se u 450 ml toluola i pomeša sa 7 g (37 mmol) p-toluolsulfonske kiseline. Reakciona smeša se potom zagreva uz nefluksovanje u toku perioda od 2 sata, pni čemu se obnazovana voda udaljava iz neakcione smeše pomoču izdvajača vode. Posle upanavanja i rastvananja ostatka u etilacetatu ispira se dva puta sa zasičenim vodenim rastvorom natrijum-bikarbonata i dva puta sa zasičenim vodenim rastvorom kuhinjske soli. Organska faza se osuši iznad magnezijum-sulfata i upari. Hnomatografija sirovog proizvoda na silikagelu sa etilacetatom kao sredstvom za eluiranje daje 11 g (58%) benzil-|3-(2-benzimidazolil)-propil|metilkarbamata, t.t. 83-86°C.20.1 g (59 mmol) Benzyl- | 3- | (2-aminophenyl) -carbamoyl | -propyl | -methylcarbamate was dissolved in 450 ml of toluene and mixed with 7 g (37 mmol) of p-toluenesulfonic acid. The reaction mixture is then heated under reflux for a period of 2 hours, whereby the recovered water is removed from the non-reaction mixture by a water extractor. After settling and dissolving the residue in ethyl acetate, it is washed twice with saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated. A silica gel crude product chromatography with ethyl acetate as the elution medium gave 11 g (58%) of benzyl- | 3- (2-benzimidazolyl) -propyl | methylcarbamate, m.p. 83-86 ° C.
20.20.
11,0 g (34 mmol) Benzil-|3-(2-benziroidazolil)-propil|-metil kanbamata redukuje se u 150 ml metanola u prisustvu 2,5 g paladijuma na uglju (5%-nog katalizatora) kao katalizatora sa vodonikom. Pri torne se dobiva 5,45 g (85%) 2-|3-(metilamino)-propil|-benzimidazola, t.t. 134-136°C.11.0 g (34 mmol) of Benzyl- | 3- (2-benziroidazolyl) -propyl | -methyl carbamate is reduced to 150 ml of methanol in the presence of 2.5 g of palladium on charcoal (5% catalyst) as a hydrogen catalyst . 5.45 g (85%) of 2- | 3- (methylamino) -propyl | -benzimidazole, m.p. 134-136 ° C.
Primer 2Example 2
6,2 g (14,6 mmol) |1S,2S|-2-|2-||3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluon-1,2,3,4-tetnahidno-1-izopnopil-2-naftalinola nastvori se u 50 ml hloroforma. U to se doda, pri 0°C, 2,5 ml (15 mmol) N-etildiizopnopilamina i 5 ml (55 mmol) metoksiacetilhlonida. Reakciona smeša se meša preko noči pri sobnoj. temperaturi i zatim pomeša sa 100 ml 1 N rastvora natrijum-hidroksida u vodi, i ekstrahuj hloroformom. Posle sušenja iznad magnezijum-sulfata i otparavanja rastvarača ostatak se hromatografiše na silikagelu uz primenu smeše (6:1) metilenhlonida i metanola kao sredstva za eluiranje. Pri torne se dobiva 6,2 g ulja koje se rastvori υ 30 ml etanola i pomeša sa 15 ml etra zasicenog hlorovodonikom. Nakon toga se reakciona smeša upari i ostatak kristališe iz smeše etanola 1 dietiletra. Pni torne se dobiva 5,4 g (65%) |1S,2S|-2-|2-|]3-(2-berzimidazolil)propil|-metilamino|-etil|-6-flucr-1,2,3,4-tetrahidno-1 izopropil-2-naftilmetoksiacetata-dihidrohlorida, t.t. 128°C6.2 g (14.6 mmol) | 1S, 2S | -2- | 2- || 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluon-1,2,3, 4-Tetnahid-1-isopnopyl-2-naphthalinol was formed in 50 ml of chloroform. To this was added, at 0 ° C, 2.5 ml (15 mmol) of N-ethyldiisopropylamine and 5 ml (55 mmol) of methoxyacetyl chloride. The reaction mixture was stirred overnight at room temperature. and then mixed with 100 ml of 1 N sodium hydroxide solution in water, and extracted with chloroform. After drying over magnesium sulfate and evaporating the solvent, the residue is chromatographed on silica gel using a mixture of (6: 1) methylene chloride and methanol as the eluting agent. For this, 6.2 g of an oil are obtained which is dissolved in 30 ml of ethanol and mixed with 15 ml of hydrochloric acid saturated ether. The reaction mixture was then evaporated and the residue crystallized from a mixture of ethanol 1 diethyl ether. Pipernic was obtained 5.4 g (65%) of 1S, 2S | -2- | 2- | 3- (2-benzimidazolyl) propyl | -methylamino | -ethyl | -6-fluoro-1,2,3 , 4-Tetrahydro-1 isopropyl-2-naphthylmethoxyacetate dihydrochloride, m.p. 128 ° C
Primer 3Example 3
Smeša od 4,2 g (10,35 mmol) 2-(6-fluor-1,2,3,4-tetrahidro2-hidnoksi-1<Z-izopropil-2jj,-naftil )-etil-p-toluolsulfonata .A mixture of 4.2 g (10.35 mmol) of 2- (6-fluoro-1,2,3,4-tetrahydro2-hydroxy-1 H -isopropyl-2 H, -naphthyl) -ethyl-p-toluenesulfonate.
i 4,5 g (20,7 mmol) 2-|5-(metilamino)-pentil|-benzimidazola zagreva se 30 minuta pri 100°C. Potom se doda prvo 100 ml hloroforma, zatim nakon hladjenja 100 ml etra i najzad 100 ml 1 N vodenog rastvora sone kiseline. Posle 30-minutnog mešanja reakcione smeše ova se učini baznom sa koncentrovanim vodenim rastvorom natrijum-hidroksida i organska faza odekantuje, osuši i upari. Posle hromatografisanja na silikagelu uz primenu smeše (6:1) metilenhlorida i metanola kao sredstva za eluiranje dobiva se 2,7 g (58,2%) |1S,2S|-2-|2-||5-(2-benzimidazolil)-pentil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrabidro-1-izopropil-2-naftalinola, |o6| ggg = +36,8° (c = 0,25; metanol).and 4.5 g (20.7 mmol) of 2- | 5- (methylamino) -pentyl] -benzimidazole were heated at 100 ° C for 30 minutes. Then 100 ml of chloroform is added first, then after cooling of 100 ml of ether and finally 100 ml of 1 N aqueous hydrochloric acid. After stirring the reaction mixture for 30 minutes, this was made basic with a concentrated aqueous sodium hydroxide solution and the organic phase was decanted, dried and evaporated. Chromatography on silica gel using a mixture of (6: 1) methylene chloride and methanol as the elution medium afforded 2.7 g (58.2%) of 1S, 2S | -2- | 2- || 5- (2-benzimidazolyl). ) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrabidro-1-isopropyl-2-naphthalinol, | o6 | ggg = + 36.8 ° (c = 0.25; methanol).
Primer 4 g (13,2 mmol) |1S,2S|-2-|2-| |5-(2-benzimidazolil)-pentil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola, 20 ml anhidrida metoksisircetne kiseline i 1,05 g (13,3 mmol) piridina, uz mešanje se zagreva na 70°C. Posle dva sata ohladi se i pomeša sa 500 ml 3 N rastvora natrijum-hidroksida i 500 ml metilenhlorida i snažno meša. Organska faza se osuši iznad magnezijumsulfata i upari. Ostatak se rastvori u etanolu i pomeša sa 16 ml etra zasicenog hlorovodonikom. Posle uparavanja i kristalisanja iz smeše etanol/etar dobiva se 6,2 g (78,5%) dihidrohlorida |1S,2S|-2-12-||5-(2-benzimidazolil)-pentil|metilamino|-etil|-6-flucr-1,2,3,4-tetrahidro-1-izopropil2-naftilmetoksiacetata, t.t. 196-198°C.Example 4 g (13.2 mmol) | 1S, 2S | -2- | 2- | 5- (2-Benzimidazolyl) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, 20 ml methoxyacetic acid anhydride and 1.05 g (13.3 mmol) of pyridine was heated to 70 ° C with stirring. After two hours, it was cooled and mixed with 500 ml of 3 N sodium hydroxide solution and 500 ml of methylene chloride and stirred vigorously. The organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in ethanol and mixed with 16 ml of ether saturated with hydrogen chloride. Evaporation and crystallization from an ethanol / ether mixture afforded 6.2 g (78.5%) of dihydrochloride | 1S, 2S | -2-12- || 5- (2-benzimidazolyl) -pentyl | methylamino | -ethyl | - 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl2-naphthylmethoxyacetate, m.p. 196-198 ° C.
22.22.
Primer 5Example 5
Na način analogan onom kcji je opisan u primerima 1 i 3 do bivena su sledeča jedinjenja:In a manner analogous to that described in Examples 1 and 3, the following compounds were obtained:
Polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi -1 -e6-izopropil-2&-naftil)-etil-p-toluolsulfonata i 2-|4-(metilamino)-butil|-benzimidazola dobiven je 11S,2S|-2-|2 —|| 4-(2-benzimidazolil)-butil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2naftalinola, MS: M+ 437;Starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-e6-isopropyl-2H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 4- (methylamino) -butyl | -benzimidazole obtained 11S, 2S | -2- | 2 - || 4- (2-benzimidazolyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2naphthalinol, MS: M + 437;
polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi - 1o6-izopropil-2Jb-naftil) -etil-p-toluolsulfonata i 2-|7-(metilamino)-heptil|-benzimidazola dobiva se |1S,2S|-2-|2-||7-(2-benzimidazolil)-heptil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinol-dihidrohlorid, |ai||gg = +32,9° (c = 1%; metanol);starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-6-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | - of benzimidazole gives | 1S, 2S | -2- | 2- || 7- (2-benzimidazolyl) -heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2-naphthalenol dihydrochloride, | αi || gg = + 32.9 ° (c = 1%; methanol);
pclazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi K-izopr opil-2iJ-naf til)-etil-p-toluolsulfonata i 2-|11-(metilamino)-undecil|-benzimidazola dobiva se |1S,2S|-2-|2-||11-(2-benzimidazolil)-undecil|metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1izoprcpil-2-naftalinol;derived from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy N-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 11- (methylamino) -undecyl | -benzimidazole gives | 1S, 2S | -2- | 2- || 11- (2-benzimidazolyl) -undecyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2 -naphthalinol;
polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi Ιού-izopropil-2&-naftil)-etil-p-toluolsulfonata istarting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy Ιού-isopropyl-2β-naphthyl) -ethyl-β-toluenesulfonate and
5,6-dimetil-2-|7-(metilamino)-heptil|-benzimidazola dcbiva se 11S,2S|-2-12-1|7-(5,6-dimetil-2benziroidazolil)-heptil|-metilamino|-etil|-6-fluor1,2,3,4-tetrahidro-1-izopropil-2-naftalinol, lodggg = +33,6° (c = 0,5%; metanol);5,6-dimethyl-2- | 7- (methylamino) -heptyl | -benzimidazole is added 11S, 2S | -2-12-1 | 7- (5,6-dimethyl-2-benzyridazolyl) -heptyl | -methylamino | - ethyl 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, lodgg = + 33.6 ° (c = 0.5%; methanol);
23.23.
polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidrcksi- 1«>0-izopropil-2JJ-naf til) -etil-p-toluolsulfonata i 2-|5-(dodecilamino)-pentil|-benzimidazola dobiva se |1S,2S|-2-|2-||5-(2-benzimidazolil)-pentil|dodecilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-naftalinol, MS: M 606;starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 '> 0-isopropyl-2 H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 5- (dodecylamino) -pentyl | -benzimidazole gives | 1S, 2S | -2- | 2- || 5- (2-Benzimidazolyl) -pentyl | dodecylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro- 1isopropyl-2-naphthalinol, MS: M 606;
pclazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi.starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy).
- 1</-izopropil-24i-naftil)-etil-p-toluolsulfonata i 2-|7-(metilamino)-heptil|-1H-imidazo|4,5-c|-piridina dobiva se |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-|2-||7 — (1H-imidazo|4,5-c|piridin-2-il)heptil|metilamino|-etil|-2-naftalinol, MS: M+ 480.- 1H-isopropyl-2H-naphthyl) -ethyl-p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | -1H-imidazo | 4,5-c | -pyridine give | 1S, 2S | - 6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | 7- (1H-imidazo | 4,5-c | pyridin-2-yl) heptyl | methylamino | -ethyl | - 2-Naphthalinol, MS: M + 480.
Derivati benzimidazola koji su upotrebljeni kao polazne materije dobiveni su analogno načinu opisanom u primeru 1.Benzimidazole derivatives used as starting materials were prepared analogously to the method described in Example 1.
Primer 6Example 6
Na anlogan način onom koji je opisan u primerima 2 i 4, uz primenu metoksiacetilovanja, dobiveni su odgovarajuči derivati (hidroksi-derivati) sledečih jedinjenja:In the same manner as described in Examples 2 and 4, with the use of methoxyacetylation, the corresponding hydroxy derivatives of the following compounds were obtained:
|1S,2S|-2-|2-||4-(2-benzimidazolil)-butil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil -2-naf ti Ime toksiace tat a-dihidrohlor id , |cs6j2g9 = +28,6° (c = 1%; metanol);| 1S, 2S | -2- | 2- || 4- (2-Benzimidazolyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2- naf ti Toxiace tat name a-dihydrochlor id, | cs6j 2 g 9 = + 28.6 ° (c = 1%; methanol);
|1S,2S|-2-|2-| |7-(2-benzimidazolil)-heptil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-dihidrohlorid,| 1S, 2S | -2- | 2- | 7- (2-benzimidazolyl) -heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride,
Ic^lfgg = +25,4° (c = 1%; metanol);Ic ^ lfgg = + 25.4 ° (c = 1%; methanol);
24.24.
|1S,2S|-2-|2-||11-(2-benzimidazolil)-undecil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-dihidrohlorid, |oJ||g9 = +23,7° (c = 1%; metanol);| 1S, 2S | -2- | 2- || 11- (2-Benzimidazolyl) -undecyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- naphthylmethoxyacetate dihydrochloride, oJ || g 9 = + 23.7 ° (c = 1%; methanol);
|1S,2S|-2-|2-||7-(5,6-dimetil-2-benzimidazolil)heptil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftiImetoksiacetat-hidrohlorid , (1:1,85), I0/I589 = +26,5° (c = 1%; metanol);| 1S, 2S | -2- | 2- || 7- (5,6-Dimethyl-2-benzimidazolyl) heptyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1 -isopropyl-2-naphthylmethoxyacetate hydrochloride, (1: 1.85), IO / I589 = + 26.5 ° (c = 1%; methanol);
|1S,2S|-2-|2-||5-(2-benzimidazolil)-pentil|-dodecilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-dihidrohlorid, |o0||gg = +22,0° (c = 0,25%; metanol);| 1S, 2S | -2- | 2- || 5- (2-Benzimidazolyl) -pentyl | -dodecylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- naphthylmethoxyacetate dihydrochloride, | o0 || gg = + 22,0 ° (c = 0.25%; methanol);
|1S,2S|-6-fluon-1,2,3,4-tetrahidro-1-izopropil-2-|2-||7-(1H-imidazo|4,5-c|piridin-2-il)-heptil|-metilamine|-etil|-2-naftilmetoksiacetat-dihodrohlorid, t.t. 112-115°C.| 1S, 2S | -6-Fluon-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 7- (1H-imidazo | 4,5-c | pyridin-2-yl) -heptyl | -methylamine | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 112-115 ° C.
Primer 7Example 7
0,79 g (3,8 mmol) 2-|3-(metilamino)-propil|-benztiazola, 1,54 g (3,8 mmol) 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi- 1<Z-izopropil-2.Pr-naf til )-etil | -p-toluolsulfonata i 0,49 g (3,8 mmol) Hunig-ove baze meša se 2,5 časa pri 120°C Posle hladjenja i rastvaranja taloga sa malo metilenhlorida reakcioni rastvor se hromatografiše na silikagelu uz primenu smeše (12:1) metilenhlorida i metanola kao eluensa. pri torne se dobiva 1,12 g (76%) |1S,2S|-2-|2-||3-(2-benztiazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola, MS: M+ 440.0.79 g (3.8 mmol) 2- | 3- (methylamino) -propyl | -benzthiazole, 1.54 g (3.8 mmol) 2- (6-fluoro-1,2,3,4-tetrahydro) -2-hydroxy-1 <Z-isopropyl-2.Pr-naphthyl) -ethyl | -p-toluenesulfonate and 0.49 g (3.8 mmol) of Hunig's base were stirred for 2.5 hours at 120 ° C. After cooling and dissolving the precipitate with little methylene chloride, the reaction solution was chromatographed on silica gel using a mixture (12: 1 ) methylene chloride and methanol as eluent. 1.12 g (76%) of 1S, 2S | -2- | 2- || 3- (2-benzthiazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2 were obtained. 3,4-tetrahydro-1-isopropyl-2-naphthalinol, MS: M + 440.
25.25.
Na način analogan gore opisanom dobivena su sledeča jedinje nja:In the manner analogous to the above, the following compounds were obtained:
Polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi- 1cZ-izopropil-2ΐι-naftil )-etil | -p-toluolsulfonata i 2-|5-(metilamino)-pentil|-benzitiazola dobiva se |1S,2S|-2—|2-||5-(2-benztiazolil)-pentil|-metilamino| etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinol, MS: M+ 468;Starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1CZ-isopropyl-2H-naphthyl) -ethyl | -p-toluenesulfonate and 2- | 5- (methylamino) -pentyl | -benzythiazole give | 1S, 2S | -2- | 2- || 5- (2-benzthiazolyl) -pentyl | -methylamino | ethyl 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, MS: M + 468;
polazeci od 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi- W-izopropil-2i>-naftil) -etil | -p-toluolsulfonata i 2-|7-(metilamino)-heptil|-benzitiazola dobiva se |1S,2S|-2-|2-||7-(2-benzitiazolil)-heptil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2naftalinol, MS: M+ 496.starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-N-isopropyl-2 H -naphthyl) -ethyl | -p-toluenesulfonate and 2- | 7- (methylamino) -heptyl | -benzythiazole give | 1S, 2S | -2- | 2- || 7- (2-benzthiazolyl) -heptyl | -methylamino | -ethyl | - 6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2naphthalinol, MS: M + 496.
2-|3-(Metilamino)-propil|-benztiazol, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:2- | 3- (Methylamino) -propyl | -benzthiazole, which was used as starting material, was obtained as follows:
5,0 g (19,9 mmol) 4-|1-(beziloksi)-N-metilformamido|-buterne kiseline rastvori se u 175 ml tetrahidrofurana. Rastvoru, koji je ohladjen na -20°C, doda se 2,95 ml (2,1 g;5.0 g (19.9 mmol) of 4- | 1- (bezyloxy) -N-methylformamido | -butyric acid were dissolved in 175 ml of tetrahydrofuran. To the solution, which was cooled to -20 ° C, was added 2.95 ml (2.1 g;
mmol) trietilamina i 2,95 ml (22 mmol) izobutil-estra hlormravlje kiseline. Reakciona smeša se potom meša 1 sat pri ovoj temperaturi. Zatim se doda 2,45 g (19,6 mmol) 2-aminotiofenola i reakciona smeša meša 20 sati pri sobnoj temperaturi. Potom se doda 250 ml vode i ekstrahuje etilacetatom. Organska faza se osuši iznad magnezijum-sulfata i upari pod sniženim pritiskom. Posle hromatografisanja na silikagelu uz primenu smeše (1:1) etilacetata i heksana kao eluensa dobiva se 1,7 g (25,1%) benzil-|3-(2-bentiazolil)propil|-metilkarbamata u vidu ulja, MS: M+ 340.mmol) of triethylamine and 2.95 ml (22 mmol) of hydrochloric acid isobutyl ester. The reaction mixture was then stirred for 1 hour at this temperature. 2.45 g (19.6 mmol) of 2-aminothiophenol are then added and the reaction mixture is stirred for 20 hours at room temperature. 250 ml of water are then added and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. Chromatography on silica gel using a mixture of (1: 1) ethyl acetate and hexane as eluent afforded 1.7 g (25.1%) of benzyl- | 3- (2-bentiazolyl) propyl | -methylcarbamate as an oil, MS: M + 340.
26.26.
1,7 g (4,99 mmol) Benzil-|3-(2-benztiazolil)-propil|metilkarbamata rastvori se pri 0°C u 40%-nom rastvoru bromvodonika u sircetnoj kiselini i meša 20 sati pri sobnoj temperaturi. Na to se doda 60 ml etra i posle 1,5 sat odfiltrira pri torne obrazovan talog. Posle ispiranja kristalnog taloga etrom i sušenja dobiva se 1,71 g (93,1%)1.7 g (4.99 mmol) of benzyl- 3- (2-benzthiazolyl) -propylmethylcarbamate were dissolved at 0 ° C in 40% hydrobromic acid in acetic acid and stirred at room temperature for 20 hours. To this was added 60 ml of ether and after 1.5 hours the precipitate formed was filtered off. Washing the crystalline residue with ether and drying afforded 1.71 g (93.1%)
2-|3-(metilamino)-propil|-benztiazol-dihidrobromida, t.t. 196-197°C.2- | 3- (methylamino) -propyl | -benzothiazole-dihydrobromide, m.p. Mp 196-197 ° C.
Na način analogan onom koji je gore opisan dobivena su sledeča jedinjenja:In a manner analogous to that described above, the following compounds were obtained:
2-|5-(Metilamino)-pentil|-benztiazol, MS: M+ 234; 2-|7-(Metilamino)-heptil|-benztiazol, MS: M+ 262.2- | 5- (Methylamino) -pentyl] -benzothiazole, MS: M + 234; 2- | 7- (Methylamino) -heptyl | -benzothiazole, MS: M + 262.
Primer 8Example 8
1,12 g (2,54 mmol) 11S,2S|-2-|2-||3-(2-benztiazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola rastvori se u 0,2 g piridina. U to se deda 5 ml anhidrida metoksisirčetne kiseline. Reakciona smeša se zagreva 2 sata na 60°C. Na to se deda 100 ml 1 N rastvora natrijum-hidroksida pri 0°C i ekstrahuje sa 100 ml etilacetata. Organska faza se osuši iznad magnezijum-sulfata, filtrira i upari pod sniženim pritiskom. Ostatak se hromatografiše na silikagelu uz primenu smeše (30:1) metilenhlorida i metanola kao eluensa. Pri torne se dobiva 0,9 g uljastog proizvoda, koji se rastvori u etilacetatu i tretira sa 2 ml etra zasicenog sa hlorovodonikom. Posle uparavanja na zapreminu od 20 ml doda se 40 ml etra i reakciona1.12 g (2.54 mmol) 11S, 2S | -2- | 2- || 3- (2-Benzthiazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4 -tetrahydro-1-isopropyl-2-naphthalinol was dissolved in 0.2 g of pyridine. 5 ml of methoxyacetic acid anhydride is added thereto. The reaction mixture was heated at 60 ° C for 2 hours. This was deduced with 100 ml of 1 N sodium hydroxide solution at 0 ° C and extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of (30: 1) methylene chloride and methanol as eluent. 0.9 g of an oily product are obtained, which is dissolved in ethyl acetate and treated with 2 ml of ether saturated with hydrogen chloride. After evaporation to a volume of 20 ml, 40 ml of ether are added and the reaction is reached
27.27.
smeša meša 1 sat. Istaložen talog se odfiltrira i suši. Pri torne se dobiva 0,9 g (64,5%) |1S,2S|-2-|2-||3-(2-benztiazolil)-propil|-metilamino|-eti1-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-naftilmetoksiacetat-dihidrohlorida, t.t. 13O-134°Cthe mixture stirred for 1 hour. The precipitated precipitate is filtered off and dried. 0.9 g (64.5%) of 1S, 2S | -2- | 2- || 3- (2-benzthiazolyl) -propyl | -methylamino | -ethyl 1-6-fluoro-1,2 are obtained , 3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, m.p. 13O-134 ° C
Na način analogan gore opisanom uz primenu metoksiacetilovanja dobiveni su odgovarajuči hidroksi-derivati sledečih jedinjenja:In the manner analogous to the one described above with the application of methoxyacetylation, the corresponding hydroxy derivatives of the following compounds are obtained:
| 1S, 2S | — 2 - |2 - | |5-(2-ber.ztiazolil) -per.til | -metilamino | etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-hidrohlorid (5:8), |©6| |g^ = +27,4° (c = 0,5%; metanol);| 1S, 2S | - 2 - | 2 - | 5- (2-Ber.zthiazolyl) -per.til | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride (5: 8), | © 6 | | g = 27.4 ° (c = 0.5%; methanol);
|1S,2S|—2—|2—||7-(2-benztiazolil)-heptil|-metilamino|etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-hidrohlorid (4:5), |o6||gg - +25,8° (c = 1%; metanol).| 1S, 2S | -2- | 2- || 7- (2-Benzthiazolyl) -heptyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate -hydrochloride (4: 5), | o6 || gg - + 25.8 ° (c = 1%; methanol).
Primer 9Example 9
Na način analogan onim koji su opisani u primerima 1 i 4, polazeci od (S)-6-|1-(benziloksi)-N-metilformamido|-heptanske kiseline, preko |1S,2S|-2-|-2-||(S)-5-(2-benzimidazolil)-1-metilpentil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro- 1-izopropil-2-naftalinola, dobiva se |1S,2S|-2-|2-||(S)-5-(2-benzimidazolil)-1-metilpentil|-metilamino|—etil|—6— -flucr-1,2,3,4-tetrahidro-1-izopropi1-2-naftilmetoksiacetat-dihidrohlorid, |cZ||gg = +20,0° (c = 0,7%; metanol).In a manner analogous to those described in Examples 1 and 4, starting from (S) -6- | 1- (benzyloxy) -N-methylformamido | -heptanoic acid via | 1S, 2S | -2- | -2- | | (S) -5- (2-Benzimidazolyl) -1-methylpentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol, yielding | 1S , 2S | -2- | 2- || (S) -5- (2-Benzimidazolyl) -1-methylpentyl | -methylamino | -ethyl | -6- -fluoro-1,2,3,4-tetrahydro-1 -isopropyl 1-2-naphthylmethoxyacetate dihydrochloride, | cZ || g g = + 20.0 ° (c = 0.7%; methanol).
Kao polazna materija upctrebljena (S)-6-|1-(benziloksi)-N-metilformamido|-hepatinska kiselina dobivena je naThe starting material used is (S) -6- | 1- (benzyloxy) -N-methylformamido | -hepatic acid was obtained at
28.28.
sledeči način:as follows:
20C g (1,39 mcl) 6-Oksoheptanske kiseline rastvori se u 1,2 litra metilenhlorida. Pri -20°C doda se 14 ml koncentrovane sumporne kiseline. Zatim se pri -4°C kondenzuje 0,6 1 (6,3 mol) izobutilena i to pusti da destiluje u reakcioni balon. Zatim se reakeiona smeša ostavi da reaguje 6 dana pri sobnoj temperaturi uz refluksovanje reagensa. Potom se doda 1 litar zasicenog vodenog rastvora natrijum-bikarbonata što se vrši uz snažno mešanje. Vodena faza se ekstrahuje metilenhloridom. Spojene organske faze se osuše iznad magnezijum-sulfata i upare pod sniženim pritiskom. Pri torne se dobiva 268,0 g (1,338 mol; 96,4%) terc-butil-6-oksoheptanoata, koji se zatim zajedno sa 162,1 g (1,338 mol) (S)-(-)-1-feniletilamina i 5,8 g (30,5 mmol) p-toluolsulfonske kiseline i 1,9 1 toluola zagreva 12 sati uz refluksovanje i istovremeno odvajanje vode. Posle uparavanja rastvarača dobiva se 395,5 g (1,3 mol; 97,4%) terc-butil-(E/Z)-6-||(R)-(/-metilbenzil |-imino |-heptanoata, koji se rastvara u 7 1 metanola. U to se doda 43 g Raney-nikla i hidrogenizuje pri pritisku od 10 bara u toku 24 sata. Potom se filtrira i upari rastvarač. Dobiveno je 378,5 g ulja kcje se rastvori u20C g (1.39 mcl) of 6-Oxoheptanoic acid was dissolved in 1.2 liters of methylene chloride. At -20 ° C, 14 ml of concentrated sulfuric acid is added. Then 0.6 -4 (6.3 mol) of isobutylene is condensed at -4 ° C and this is allowed to distill into the reaction balloon. The reaction mixture was then allowed to react for 6 days at room temperature with the reflux of the reagent. Then 1 liter of saturated aqueous sodium bicarbonate solution is added, which is stirred vigorously. The aqueous phase is extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. In this case, 268.0 g (1.338 mol; 96.4%) of tert-butyl-6-oxoheptanoate are obtained, which is then combined with 162.1 g (1,338 mol) of (S) - (-) - 1-phenylethylamine and 5.8 g (30.5 mmol) of p-toluenesulfonic acid and 1.9 l of toluene were heated for 12 hours with reflux and simultaneous separation of water. Evaporation of the solvent gave 395.5 g (1.3 mol; 97.4%) of tert-butyl- (E / Z) -6- (R) - (R-methylbenzyl | -imino | -heptanoate, which dissolved in 7 l of methanol, 43 g of Raney-nickel was added and hydrogenated at a pressure of 10 bar for 24 hours, then filtered and the solvent was evaporated to give 378.5 g of an oil which was dissolved in
1,1 litra etilacetata i pri 0°C pomeša sa 130 ml 10 N etanolskcg rastvora sone kiseline. Posle jednočasovnog mešanja pri 0°C obrazovani kristali se odfiltriraju i osuše. Tri puta ponavljanim prekristalisavanjem dobivenih 282 g kristala iz etilacetata dobiva se 172,7 g (38,9%) terc-butil-(S)-6-| | (S)-iZ-metilbenzil |-amino |-heksancata-hidrohlorida , t.t. 154-155°C.1.1 liters of ethyl acetate and at 0 ° C mixed with 130 ml of 10 N ethanol solution of hydrochloric acid. After stirring at 0 ° C for one hour, the formed crystals were filtered off and dried. Repeated crystallization of 282 g of ethyl acetate crystals three times yielded 172.7 g (38.9%) of tert-butyl- (S) -6- | | (S) -IZ-methylbenzyl | -amino | -hexanate hydrochloride, m.p. Mp 154-155 ° C.
160 g (0,648 mol) gornjeg hidrohlorida rastvori se u 2,4 1 etanola i hidrogenizuje u prisustvu 20 g paladijuma na uglju (koji je 5%-an) pri pritisku od 10 bara. Posle odfiltriranja160 g (0.648 mol) of the above hydrochloride was dissolved in 2.4 l of ethanol and hydrogenated in the presence of 20 g of palladium on coal (which is 5%) at a pressure of 10 bar. After filtration
29.29.
katalizatora rastvarač se upari, i ostatak kristališe iz 560 ml etilacetata i 240 ml heksana. Pri torne se dobiva 101 g (90,8%) terc-butil(S)-6-aminoheptanoathidrohlorida, t.t. 107-109°C.The catalyst was evaporated, and the residue was crystallized from 560 ml of ethyl acetate and 240 ml of hexane. 101 g (90.8%) of tert-butyl (S) -6-aminoheptanoathydrochloride, m.p. Mp 107-109 ° C.
g (374 mmol) terc-butil(S)-6-aminoheptanoat-hidrohlorida rastvori se u 1,3 1 metilenhlorida. Rastvor se zasiti sa hlorovodonikom i 4 sata zagreva uz refluksovanje. Posle odfiltriranja i sušenja nagradjenog taloga dobiva se 60,8 g (89,5%) (S)-6-aminoheptancve kiseline u obliku hidrohlorida, t.t. 157-16O°C.g (374 mmol) of tert-butyl (S) -6-aminoheptanoate hydrochloride was dissolved in 1.3 L of methylene chloride. The solution was saturated with hydrogen chloride and refluxed for 4 hours. Filtration and drying of the precipitated precipitate afforded 60.8 g (89.5%) of (S) -6-aminoheptanoic acid as hydrochloride, m.p. 157-16 ° C.
U rastvor od 30 g (166 mmol) hidrohlorida (S)-6-aminoheptanove kiseline u 57 ml vode doda se 57 ml 4 N rastvora natrijum-hidroksida u vodi i potom istovremenc ukapava pri 10°C 92 ml vodenog rastvora natrijum-hidroksida i 42 ml (294 mmol) benzil-estra hlormravlje kiseline tako da vrednost pH stalno iznosi negde izmedju 10 i 12. Posle izdvajanja sirovog proizvoda meša se još dva sata pri 0°C. Zatim se doda 300 ml vode, i reakciona smeša ekstrahu.je etrom. Vodena faza se zakiseli sa 20 ml koncentrcvane sone kiseline i ekstrahuje metilenhloridom. Metilenhloridna faza se osuši iznad magnezijum-sulfata i upari. Dobiveni kristali se prekristališu iz hloroforma/heksana, pri čemu se dobiva 33,1 g (72%) (S)-6-|1-(benziloksi)-formamido|-heptanove kiseline, t.t. 82-83°C.To a solution of 30 g (166 mmol) of hydrochloride (S) -6-aminoheptanoic acid in 57 ml of water was added 57 ml of 4 N sodium hydroxide solution in water and then, at 10 ° C, 92 ml of aqueous sodium hydroxide solution was added dropwise. 42 ml (294 mmol) of hydrochloric acid benzyl ester such that the pH is constantly between 10 and 12. After separation of the crude product, it is stirred for another two hours at 0 ° C. Then 300 ml of water was added and the reaction mixture was extracted with ether. The aqueous phase was acidified with 20 ml of concentrated hydrochloric acid and extracted with methylene chloride. The methylene chloride phase was dried over magnesium sulfate and evaporated. The crystals obtained were recrystallized from chloroform / hexane to give 33.1 g (72%) of (S) -6- | 1- (benzyloxy) -formamido | -heptanoic acid, m.p. 82-83 ° C.
U suspenziji od 3,05 g 55%-nog natrijum-hidrida (70 mmol) u 200 ml dimetilformamida doda se 6,5 g (23 mmol) (S)-6-|1-(benziloksi)-formamido|-heptanove kiseline i ostavi da reaguje na 40° u toku 30 minuta. Potom se ukapa 13 g (90 mmol) metil-jodida, i reakciona smeša zagreva 1 satTo a suspension of 3.05 g of 55% sodium hydride (70 mmol) in 200 ml of dimethylformamide was added 6.5 g (23 mmol) of (S) -6- | 1- (benzyloxy) -formamido | -heptanoic acid and allow to react at 40 ° for 30 minutes. 13 g (90 mmol) of methyl iodide are then added dropwise, and the reaction mixture is heated for 1 hour
30.30.
na 70°. Posle upar-avanja rastvarača doda se 120 ml 1 N vodenog rastvora natrijum-hidroksida i 120 ml etanola, i reakciona smeša zagreva 30 minuta uz refluksovanje. Potom se upari na polovinu prvobitne zapremine, doda 100 ml zasicenog rastvora natrijum-bikarbonata i ekstrahuje etilacetatom. Vodena faza se zakiseli i ekstrahuje metilenhloridcm. Organska faza se osuši iznad magnezijum-sulfata i upari. Ostatak se hromatografiše (5 g) na koloni silikagela uz primenu smeše (12:1) metilenhlorida i metanola kao eluensa, pri čemu se iz početnih 5 g ostatka dobiva 3,5 g (52,2%) (S)-6-11 -(ber.ziloksi)-N-metilformamido|-heptanove kiseline, MS: M+ 293·at 70 °. After evaporation of the solvent, 120 ml of 1 N aqueous sodium hydroxide and 120 ml of ethanol were added, and the reaction mixture was refluxed for 30 minutes. It was then evaporated to half its original volume, added to 100 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate. The aqueous phase was acidified and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. The residue was chromatographed (5 g) on a silica gel column using a mixture of (12: 1) methylene chloride and methanol as eluent to give 3.5 g (52.2%) of (S) -6-11 from the initial 5 g of residue. - (Ber.Zyloxy) -N-methylformamido | -heptanoic acid, MS: M + 293 ·
Primer 10Example 10
U 55%-nu suspenziju od 436 mg (10 mmol) 55%-nog natrijumhidrida u 20 ml tetrahidrofurana doda se 2,0 g (4,43 mmol) |1S,2S|-2-|2-||5-(2-benzimidazolil)-pentil|-metilamino|etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola rastvorenog u 30 ml tetrahidrofurana. Posle 45 minutnog mešanja pri sobnoj temperaturi doda se 1,42 g (10 mmol) metil-jodida. Posle još jedan sat mešanja dodaju se voda i metilenhlorid i reakciona smeša snažno promucka. Organska faza se osuši iznad magnezijum-sulfata i upari. Ostatak se hromatografiše na silikagelu uz primenu smeše od metilenhlorida i metanola (6:1) kao eluensa, pri čemu se dobiva 1,2 g (60%) |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil-|5-(1-metil-2-benzimidazolil)-pentil|-amino|-etil|-2-naftalinola, MS: M+ 465.To a 55% suspension of 436 mg (10 mmol) of 55% sodium hydride in 20 ml of tetrahydrofuran was added 2.0 g (4.43 mmol) of 1S, 2S | -2- | 2- || 5- ( 2-Benzimidazolyl) -pentyl | -methylamino | ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol dissolved in 30 ml of tetrahydrofuran. After stirring at room temperature for 45 minutes, 1.42 g (10 mmol) of methyl iodide was added. After another hour of stirring, water and methylene chloride were added and the reaction mixture was shaken vigorously. The organic phase was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of methylene chloride and methanol (6: 1) as eluent to give 1.2 g (60%) of 1S, 2S | -6-fluoro-1,2,3,4- tetrahydro-1-isopropyl-2- | 2- | methyl- | 5- (1-methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthalinol, MS: M + 465.
Na analogan način kao što je gore opisano, reakcijom sa dodecil-jodidom, dobiven je |1S,2S|-2-|2-||7-(1-dodecil-2benzimidazolil)-heptil|-metilamino|-etil|-6-fluor-1,2,3,4tetrahidro-1-izopropil-2-naftalinol.In an analogous manner as described above, reaction with dodecyl iodide gave | 1S, 2S | -2- | 2- || 7- (1-dodecyl-2benzimidazolyl) -heptyl | -methylamino | -ethyl | -6 -fluoro-1,2,3,4tetrahydro-1-isopropyl-2-naphthalinol.
31.31.
Primer 11Example 11
Smeša od 1,2 g (2,58 mmol) |lS,2S|-6-fluon-1,2,3,4-tetnahidro-1-izopropil-2- 12- |metil - | 5-( 1-metil-2-benzimidazolil)-pentil|-amino|-etil|-2-naftalinola, 206 mg (2,6 mmol) pinidina i 4 ml anhidnida metoksisircetne kiseline zagreva se 2 sata pri 70°. Potom se doda 100 ml 3 N vodenog rastvora natrijum-hidnoksida i ekstrahuje sa 100 ml metilenhlorida. Organska faza se osuši iznad magnezijum-sulfata i upari. Sirov proizvod se hromatografiše na koloni silikagela uz primenu (15:1) smeše metilenhlorida i metanola kao eluensa. Dobiva se 550 mg ulja koje se rastvori u 50 ml etilacetata i pomeša sa 1 ml etra zasicenog sa hlonovodonikom. Posle uparavanja rastvarača kristališe se iz smeše etilacetat/etar pri čemu se dobiva 600 mg (41%) 11S,2S|-6-fluor-1,2,3,4tetrahidro-1-izopropil-2-|2-|metil-|5-(1-metil-2-benzimidazolil)-pentil|-amino|-etil|-2-naftilmetoksiacetat-dihidrohlonida, t.t. 203-205°.Mixture of 1.2 g (2.58 mmol) | 1S, 2S | -6-fluon-1,2,3,4-tetnahydro-1-isopropyl-2- 12- | methyl - | 5- (1-Methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthalinol, 206 mg (2.6 mmol) of pinidine and 4 ml of methoxyacetic acid anhydride were heated at 70 ° for 2 hours. Then 100 ml of 3 N aqueous sodium hydroxide solution was added and extracted with 100 ml of methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. The crude product is chromatographed on a silica gel column using (15: 1) mixtures of methylene chloride and methanol as eluent. 550 mg of oil are obtained which is dissolved in 50 ml of ethyl acetate and mixed with 1 ml of ether saturated with hydrogen chloride. After evaporation of the solvent, it was crystallized from ethyl acetate / ether to give 600 mg (41%) of 11S, 2S | -6-fluoro-1,2,3,4tetrahydro-1-isopropyl-2- | 2- | methyl- | 5- (1-Methyl-2-benzimidazolyl) -pentyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 203-205 °.
Na analogan način onom koji je gone opisan dobiven je |1S,2 S|—2-|2-| |7-(1-dodecil-2-benzimidazolil)-heptil|metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-dihidrohlorid, |o6| |gg = +20,4° (c = 0,9%; metanol).In the analogous manner to the one described above, | 1S, 2S | -2- | 2- | was obtained 7- (1-dodecyl-2-benzimidazolyl) -heptyl | methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate dihydrochloride, | o6 | | gg = + 20.4 ° (c = 0.9%; methanol).
Primer 12Example 12
0,425 g (1 mmol) |1S,2S|-2-|2-||3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetata rastvori se u 60 ml metanola i zatim pomeša sa 10 ml 6%-nog vodonikpenoksida i 50 mg0.425 g (1 mmol) | 1S, 2S | -2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro- 1-Isopropyl-2-naphthylmethoxyacetate was dissolved in 60 ml of methanol and then mixed with 10 ml of 6% hydrogenpenoxide and 50 mg
32.32.
(0,15 mmol) natrijum-volframata. posle mešanja u toku perio da od 20 sati pri sobnoj temperaturi doda se 100 mg platine na uglju (5%-na platina) u 2 ml vode i meša još jedan sat. Nakon toga se filtrira, koncentruje filtrat, razblaži sa malo metilenhlorida i hromatografiše ova smeša na silikagelu sa smešom (15:1) metilenhlorida i metanola kao sredstva za eluiranje. Pri torne se dobiva 0,18 g (35,2%) prvog diastereomera 11S,2S|-2-12-||3-(2-benzimidazolil)-propil|metil-N-oksidoamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1izopropil-2-naftilmetoksiacetata sa vrednošcu = 0,33, |οό||°9 = +39,4° (c = 0,5%; metanol) i 0,276 g (54%) drugog diastereomera pomenutog jedinjenja sa vrednošcu = 0,26 (metilenhlorid/metanol 6:1), |cZ| |gg = +34,8° (c = 0,5%; metanol).(0.15 mmol) of sodium tungstate. After stirring for 20 hours at room temperature, 100 mg of platinum on coal (5% platinum) in 2 ml of water is added and stirred for another hour. It is then filtered, concentrated by filtrate, diluted with a little methylene chloride and chromatographed on silica gel with a mixture of (15: 1) methylene chloride and methanol as the eluting agent. 0.18 g (35.2%) of the first diastereomer of 11S, 2S | -2-12- || 3- (2-benzimidazolyl) -propyl | methyl-N-oxidoamino | -ethyl | -6-fluoro are obtained -1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate with a value = 0.33, | οό || ° 9 = + 39.4 ° (c = 0.5%; methanol) and 0.276 g (54 %) of another diastereomer of said compound with value = 0.26 (methylene chloride / methanol 6: 1), | cZ | | gg = + 34.8 ° (c = 0.5%; methanol).
Primer 13Example 13
6,1 g (15 mmol) |lS,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i6.1 g (15 mmol) -1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and
6,8 g (30 mmol) 1 -|2-(metilamino)-etil|-2-benzimidazolinonhidrohlorida meša se 4,5 sata pri 130° u smeši od 30 ml dimetilformamida i 30 ml N-etildiizopropilamina. Reakciona smeša se sipa na 600 ml ledene vode i ekstrahuje sa 700 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalcijum-karbonata i upari. Tako dobiven sirov proizvod se hromatografiše na koloni od 150 g silikagela uz primenu metilenhlorida i 0-10% izopropanola kao sredstva za eluiranje, pri čemu se dobiva 5,2 g (72%) 1-|2-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-etil-2-benzimidazolinona u obliku ulja.6.8 g (30 mmol) of 1- | 2- (methylamino) -ethyl | -2-benzimidazolinone hydrochloride were stirred for 4.5 hours at 130 ° in a mixture of 30 ml of dimethylformamide and 30 ml of N-ethyldiisopropylamine. The reaction mixture was poured onto 600 ml of ice water and extracted with 700 ml of methylene chloride. The extract was washed with water, dried over calcium carbonate and evaporated. The crude product thus obtained is chromatographed on a column of 150 g of silica gel using methylene chloride and 0-10% isopropanol as the elution medium to give 5.2 g (72%) of 1- | 2- || 2- || 1S , 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -ethyl-2-benzimidazolinone in the form of an oil.
-|2-(Metilamino-etil|-2-benziroidazolinon-hidrohlorid koji- | 2- (Methylamino-ethyl | -2-benziroidazolinone hydrochloride which
33.33.
je upotrebljen kao pclazna materija dobiven je na sledeči način:was used as the starting material was obtained as follows:
U rastvor od 24,8 g (150 mmol) 2-(N-benzil-N-metilamino)etanola, rastvorenog u'250 ml apsolutnog tetrahidrofurana, pri 0-5° ukapa se rastvor od 93,8 ml (150 mmol) n-butillitijuma (ca. 1,6 M) u heksanu. Posle mešanja u toku perioda od 15 minuta pri 0° ukapa se 11,7 ml (150 mmol) metansulfohlorida u 50 ml tetrahidrofurana pri temperaturi izmedju 0 i 5°, potom reakciona smeša meša 30 minuta pri 0°.To a solution of 24.8 g (150 mmol) of 2- (N-benzyl-N-methylamino) ethanol dissolved in 250 ml of absolute tetrahydrofuran, a solution of 93.8 ml (150 mmol) was added dropwise at 0-5 ° -butillitium (ca. 1.6 M) in hexane. After stirring for 15 minutes at 0 °, 11.7 ml (150 mmol) of methanesulfochloride in 50 ml of tetrahydrofuran was added dropwise at a temperature between 0 and 5 °, then the reaction mixture was stirred for 30 minutes at 0 °.
5,8 g (133 mmol) 55%-ne disperzije natrijum-hidrida u mineralnom ulju ispere se heksanom da se oslobodi ulja i suspenduje u 40 ml dimetilformamida. Zatim se ukapa 23,1 g (132,5 mmol) 1—(1-metilvinil)-benzimidazolin-2-ona u 90 ml dimetilformamida pri sobnoj temperaturi i dobivena reakciona smeša meša dalje još 15 minuta.5.8 g (133 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release the oil and suspended in 40 ml of dimethylformamide. Then, 23.1 g (132.5 mmol) of 1- (1-methylvinyl) -benzimidazolin-2-one in 90 ml of dimethylformamide are added dropwise at room temperature and the resulting reaction mixture is stirred for an additional 15 minutes.
Ova reakciona smeša se ukapa pri 0° u gore opisani reakcioni rastvor. Potom se zagreje na 70° i meša 3 sata. Zatim se reakciona smeša sipa na 1 litar ledene vode i ekstrahuje sa 600 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijum-karbonata i upari. Tako dobiven sirov proizvod se hromatografiše na koloni od 500 g silikagela uz primenu metilenhlorida i 0-5% izopropancla kao sredstva za eluiranje, pri čemu se dobiva 26,8 g (63%) 1-(1-metilvinil)-3-|2-(N-benzil-N-metilamino)-etil|-2-benzimidazolinona u obliku ulja.This reaction mixture was added dropwise at 0 ° to the reaction solution described above. It is then heated to 70 ° and stirred for 3 hours. The reaction mixture was then poured onto 1 liter of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The crude product thus obtained is chromatographed on a column of 500 g of silica gel using methylene chloride and 0-5% isopropanol as the eluting agent to give 26.8 g (63%) of 1- (1-methylvinyl) -3- | 2 - (N-Benzyl-N-methylamino) -ethyl | -2-benzimidazolinone as an oil.
26,5 g (82,5 mmol) gore pomenutog jedinjenja rastvori se u 265 ml etanola, uz mešanje pomeša sa 26,5 ml koncentrovane vodene sone kiseline i zagreva 1 sat uz refluksovanje. Posle hladjenja reakcione smeše na 5° kristališe26.5 g (82.5 mmol) of the above compound was dissolved in 265 ml of ethanol, stirred with 26.5 ml of concentrated aqueous hydrochloric acid and heated for 1 hour under reflux. After cooling the reaction mixture to 5 ° crystallizes
34.34.
1-|2-(N-benzil-N-metilamino-etil|-2-benzimidazolinon u obliku hidrohlorida, t.t. 107-109°; prinos 24,2 g (92%).1- | 2- (N-Benzyl-N-methylamino-ethyl | -2-benzimidazolinone as hydrochloride, mp 107-109 °; yield 24.2 g (92%).
22,9 g (72 mmol) 1 -|2-|N-benzil-N-metilamino)-etil|-2-benzimidazolinon-hidrohlorida rastvori se u 250 ml metanola, pomeša sa 2,5 g (10%-nog) paladijuma na uglju i hidrogenizuje 90 minuta pri sobnoj temperaturi. Ostatak koji je dobiven nakon filtriranja i koncentrovanja prekristališe se iz smeše metanol/etar, pri čemu se dobiva 15,5 g (94%) 1-|2-(metilamino)-etil|-2-benzimidazolinon-hidrohlorida, t.t. 177-180°.22.9 g (72 mmol) of 1- | 2- | N-benzyl-N-methylamino) -ethyl | -2-benzimidazolinone hydrochloride was dissolved in 250 ml of methanol, mixed with 2.5 g (10%). palladium on charcoal and hydrogenates for 90 minutes at room temperature. The residue obtained after filtration and concentration was recrystallized from methanol / ether to give 15.5 g (94%) of 1- | 2- (methylamino) -ethyl | -2-benzimidazolinone hydrochloride, m.p. 177-180 °.
Primer 14 /Example 14 /
4,57 g (10,7 mrrol) 1 - 12-| | 2-| 11S, 2S |-6-f luor-1 ,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-etil|-2-benzimidazolinona ratsvori se u 15 ml metilenhlorida, pomeša sa 2,2 ml piridina i 7,0 g (43 mmol) anhidrida metoksisircetne kiseline i meša 20 sati pri sobnoj temperaturi. Zatim se uz hladjenje ledom pomeša sa 30 ml 3 N vodenog rastvora natrijum-hidroksida i meša 15 minuta pri sobnoj temperaturi. Zatim se reakciona smeša sipa na 400 ml ledene vode i ekstrahuje sa 600 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijumkarbonata i koncentruje. Pri torne se dobiva 6,9 g ulja (N,O-diacilovan proizvod), koje se rastvori u 30 ml metanola i pri sobnoj temperaturi pomeša sa 11,5 ml 1 N vodenog rastvora natrijum-hidroksida.4.57 g (10.7 mrrol) 1- 12- | 2- | 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -ethyl | -2-benzimidazolinone was dissolved in 15 ml. of methylene chloride, mixed with 2.2 ml of pyridine and 7.0 g (43 mmol) of methoxyacetic acid anhydride and stirred for 20 hours at room temperature. It was then stirred under ice-cooling with 30 ml of 3 N aqueous sodium hydroxide solution and stirred for 15 minutes at room temperature. The reaction mixture was then poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and concentrated. The resultant is 6.9 g of an oil (N, O-diacylated product), which is dissolved in 30 ml of methanol and mixed at room temperature with 11.5 ml of 1 N aqueous sodium hydroxide.
Posle mešanja u toku 30 minuta smeša se sipa na 400 ml ledene vode i ekstrahuje sa 600 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijum-karbonata, upari, tretira sa ekvivalentom hlorovodonika u metanolu, ponovo upari iAfter stirring for 30 minutes, the mixture was poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate, evaporated, treated with hydrogen chloride equivalent in methanol, evaporated again and
35.35.
najzad prekristališe iz metanola/etra. Pri torne se dobivafinally crystallized from methanol / ether. At the towers it is obtained
3,9 g (72%) |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil|-2- (2-okso-1-benzimidazolinil)-etil|-amino|-etil|-2-naftilmetoksiacetata-hidrohlorida, t.t. 130-133° (raspadanje); |οό| = +26,0° (c = 1%; metanol).3.9 g (72%) | 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl | -2- (2-oxo-1- benzimidazolinyl) -ethyl | -amino | -ethyl | -2-naphthylmethoxyacetate-hydrochloride, m.p. 130-133 ° (decay); | οό | = + 26.0 ° (c = 1%; methanol).
Primer 15Example 15
Analogno primeru 13, reakcijom |lS,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata sa 1-|6-(metilamino)-heksil|-2-benzimidazolinonom, dobiva se 1 -|6-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-heksil|-2-benzimidazolinon u obliku ulja.Analogous to Example 13, by reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate with 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone, yields 1- | 6- || 2- || 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 -isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -2-benzimidazolinone as an oil.
-|6-(Metilamino)-heksil|-2-benzimidazolinon, kcji je upotrebljen kao polazna materija, dcbiven je na sledeči način:- | 6- (Methylamino) -hexyl | -2-benzimidazolinone, used as a starting material, is obtained as follows:
U rastvoru od 32,7 g (150 mmol) di-terc-butildikarbonata u 100 ml metanola ukapa se 17,6 g (150 mmol) 6-amino-1-heksanola rastvorenog u 50 ml metanola što se vrši pri sobnoj temperaturi. Posle mešanja u toku 4 sata pri sobnoj temperaturi reakciona smeša se upari, pri čemu se dobiva 36,6 g terc-butil-(6-hidroksiheksil)-karbamata u obliku ulja, koje se direktno primenjuje u sledečem stupnju.In a solution of 32.7 g (150 mmol) of di-tert-butyldicarbonate in 100 ml of methanol was added 17.6 g (150 mmol) of 6-amino-1-hexanol dissolved in 50 ml of methanol, which was carried out at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was evaporated, yielding 36.6 g of tert-butyl- (6-hydroxyhexyl) -carbamate in the form of an oil, which was directly applied in the next step.
34,8 g terc-Butil-(6-hidroksiheksil)-karbamata rastvori se u 250 ml metilenhlorida i pri 0° pomeša sa 24,0 ml (174 mmol) trietilamina. Zatim se pri -60° u toku 15 minuta ukapa 12,9 ml (166 mmol) metansulfohlorida u 50 ml metilenhlorida i reakciona smeša potom meša 90 minuta pri -60°C. Zatim se reakcioni34.8 g of tert-Butyl- (6-hydroxyhexyl) -carbamate were dissolved in 250 ml of methylene chloride and mixed at 0 ° with 24.0 ml (174 mmol) of triethylamine. Then 12.9 ml (166 mmol) of methanesulfochloride in 50 ml of methylene chloride were added dropwise at -60 ° C for 15 minutes and the reaction mixture was then stirred at -60 ° C for 90 minutes. It is then reacted
36.36.
rastvor sipa na 600 ml ledene vode i ekstrahuje sa 800 ml metilenhlorida. Organski ekstrakt se ispira vodom, osuši iznad magnezijum-sulfata i upari. Pri torne se dobiva 58,6 g terc-butil-|6-|(metilsulfonil)-oksi|-heksil|-karbamata u obliku ulja, koje se bez prečišcavanja može dalje preraditi.the solution is poured into 600 ml of ice water and extracted with 800 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulfate and evaporated. The resultant is 58.6 g of tert-butyl- [6- (methylsulfonyl) -oxy] -hexyl | -carbamate in the form of an oil, which can be further processed without purification.
5,9 g (135 mmol) 55%-ne disperzije natrijum-hidrida u mineralnom ulju ispere se heksanom da se oslobodi od ulja i zatim prelije sa 100 ml dimetilformamida. U ovu suspenziju se pri sobnoj temperaturi ukapa 22,3 g (128 mmol) 1-(1-metilvinil)-benzimidazolin-2-ona u 100 ml dimetilformamida. Posle mešanja pri sobnoj temperaturi u toku 2 sata ukapa se 55,0 g terc-butil-|6-|(metilsulfonil)-oksi|-heksil|-karbamata u 10C ml dimetilformamida i reakciona smeša meša 18 sati pri sobnoj temperaturi. Potom se ova reakciona smeša sipa na 1 litar vode i ekstrahuje sa 750 ml metilenhlorida. Organski ekstrakt se ispora vodcm, osuši iznad kalijum-karbonata i upari. Tako dcbiven ostatak se hromatografiše na koloni od 950 g silikagela uz primenu smeše metilenhlorid/heksan, čistog metilenhlorida i smeše (95:5) metilenhlorida/izopropanola kao sredstava za eluiranje, pri čemu se dobiva 45,3 g terc-butil-|6-|3-(1-metilvinil)-2-okso-1-benzimidazolinil|-heksil|-karbamata u obliku ulja.5.9 g (135 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release from the oil and then topped with 100 ml of dimethylformamide. 22.3 g (128 mmol) of 1- (1-methylvinyl) -benzimidazolin-2-one in 100 ml of dimethylformamide were added dropwise to this suspension at room temperature. After stirring at room temperature for 55 hours, 55.0 g of tert-butyl- [6- (methylsulfonyl) -oxy] -hexylcarbamate are added dropwise into 10C ml of dimethylformamide and the reaction mixture is stirred for 18 hours at room temperature. This reaction mixture was then poured onto 1 liter of water and extracted with 750 ml of methylene chloride. The organic extract was evaporated with hydrogen, dried over potassium carbonate and evaporated. The crude residue was chromatographed on a column of 950 g of silica gel using methylene chloride / hexane, pure methylene chloride and (95: 5) methylene chloride / isopropanol mixture as eluting agent to give 45.3 g of tert-butyl- | 6- 3- (1-Methylvinyl) -2-oxo-1-benzimidazolinyl | -hexyl | -carbamate in the form of an oil.
5,3 g (121 mmol) 55%-ne disperzije natrijum-hidrida u mineralnom ulju ispere se heksanom da se oslobodi od ulja i zatim prelije sa 100 ml dimetilformamida. U ovu suspenziju ukapa se 45,0 g (121 mmol) terc-butil-|6-|3-(1-metilvinil)-2-okso-1-benzimidazolinil|-heksil|-karbamata u 100 ml dimetilformamida pri sobnoj temperaturi i reakciona smeša meša 90 minuta pri toj temperaturi. Zatim se ukapa 9,0 ml5.3 g (121 mmol) of a 55% sodium hydride dispersion in mineral oil was washed with hexane to release from the oil and then topped with 100 ml of dimethylformamide. 45.0 g (121 mmol) of tert-butyl- | 6- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl] -hexyl | -carbamate were added dropwise to this suspension in 100 ml of dimethylformamide at room temperature and the reaction mixture was stirred at this temperature for 90 minutes. 9.0 ml was then added dropwise
37.37.
(155 mmol) metil-jodida u 50 ml dimetilformamida pri 10° i reakciona smeša 1 sat meša pri 10° i 16 sati pri sobnoj temperaturi. Potom se reakcioni rastvor sipa na 800 ml ledene vode i ekstrahuje sa 600 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijum-karbonata i upari. Tako dobiven ostatak se hromatografiše na 500 g silikagela uz primenu heksana/etilacetata (4:1 i 1:1) kao sredstva za eluiranje, pri čemu se dobiva 39,1 g terc-butilmetil-|6-|3-(1-metiIvini1)-2-okso-1-benzimidazolinil|-heksil|-karbamata u obliku ulja.(155 mmol) of methyl iodide in 50 ml of dimethylformamide at 10 ° and the reaction mixture was stirred at 10 ° for 1 hour and at room temperature for 16 hours. The reaction solution was then poured onto 800 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The residue thus obtained is chromatographed on 500 g of silica gel using hexane / ethyl acetate (4: 1 and 1: 1) as the eluting agent to give 39.1 g of tert-butylmethyl- | 6- | 3- (1-methylvinyl) ) -2-Oxo-1-benzimidazolinyl | -hexyl | -carbamate as an oil.
38,8 g (100 mmol) poslednjeg pomenutog jedinjenja rastvori se u 300 ml apsolutnog etanola, uz mešanje tretira sa 40 ml koncentrovane vodene sone kiseline i 75 minuta zagreva uz refluksovanje. Posle hladjenja na 40° reakciona smeša se koncentruje pod sniženim pritiskom i sipa na 500 ml ledene vode. Vodena faza se dodatkom koncentrovanog vodenog rastvora aminijaka podesi na vrednost pH 8-9 i ekstrahuje metilenhloridom. Ekstrakt se ispira vodom i zatim odbaci. Spojene vodene faze se sa 3 N vodenim rastvorom natrijum-hidroksida podese na vrednost pH 10-11 i šest puta ekstrahuju sa po 150 ml smeše metilenhlorid/izopropanol (4:1). Spojeni ekstrakti se osuše iznad kalijum-karbonata i upare, pri čemu se dobiva 21,6 g 1-|6-(metilamino)-heksil|-2-benzimidazolinona u obliku ulja.38.8 g (100 mmol) of the last mentioned compound was dissolved in 300 ml of absolute ethanol, treated with stirring with 40 ml of concentrated aqueous hydrochloric acid and heated under reflux for 75 minutes. After cooling to 40 °, the reaction mixture was concentrated under reduced pressure and poured onto 500 ml of ice water. The aqueous phase was adjusted to pH 8-9 by addition of concentrated aqueous ammonia and extracted with methylene chloride. The extract was washed with water and then discarded. The combined aqueous phases were adjusted to pH 10-11 with 3 N aqueous sodium hydroxide solution and extracted six times with 150 ml of methylene chloride / isopropanol (4: 1) each. The combined extracts were dried over potassium carbonate and evaporated to give 21.6 g of 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone as an oil.
Primer 16Example 16
Analogno primeru 15, reakcijom 11S,2S|-2-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropi1-2-nafti1)-etil-p-toluolsulfonata i 1-metil-3-|6-(metilamino)-heksil|-2-benzimidazolinona dobiven je 1-|6-||2-| |1S,2S|-6-fluos-1,2,3,4-tetra38.Analogous to Example 15, by reaction of 11S, 2S | -2-6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and 1-methyl-3 - | 6- (methylamino) -hexyl | -2-benzimidazolinone is obtained 1- | 6- || 2- | | 1S, 2S | -6-Fluos-1,2,3,4-tetra38.
hidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-heksil|-3-metil-2-benziroidazolinon u obliku ulja.Hydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -3-methyl-2-benziroidazolinone as an oil.
1-Metil-3-|6-(metilamino)-heksil|-2-benzimidazolinon, koji je upotrebijen kao polazna materija, dobiven je na sledeči način:1-Methyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:
U rastvor od 10,0 g (40,4 mmol) 1-|6-(metilamino)-heksil|-2-benzimidazolinona u 150 ml metanola pri sobnoj temperaturi se ukapava rastvor od 9,7 g (44,5 mmol) di-terc-butildikarbonata u 50 ml metanola i reakeiona smeša meša 16 sati pri sobnoj temperaturi. Potom se doda 6,9 ml (49,5 mmol) trietilamina i daljih 9,7 g di-terc-butildikarbonata u 50 ml metanola i meša daljih 16 sati pri sobnoj temperaturi. Zatim se reakeiona smeša sipa na 200 ml vode i ekstrahuje sa 400 ml metilenhlorida. Ekstrakti se ispiraju vodom, osuše iznad kalijum-karbonata i upare, pri čemu se dobiva 14,1 g terc-butil-metil-|6-(2-okso-1-benzimidazolinil)-heksil|-karbamata u obliku ulja.A solution of 9.7 g (44.5 mmol) is added dropwise to a solution of 10.0 g (40.4 mmol) of 1- | 6- (methylamino) -hexyl | -2-benzimidazolinone in 150 ml of methanol at room temperature. of tert-butyldicarbonate in 50 ml of methanol and the reaction mixture was stirred for 16 hours at room temperature. Then 6.9 ml (49.5 mmol) of triethylamine and a further 9.7 g of di-tert-butyldicarbonate in 50 ml of methanol were added and stirred for 16 hours at room temperature. The reaction mixture was then poured onto 200 ml of water and extracted with 400 ml of methylene chloride. The extracts were washed with water, dried over potassium carbonate and evaporated to give 14.1 g of tert-butyl methyl- [6- (2-oxo-1-benzimidazolinyl) -hexyl] -carbamate as an oil.
2,6 g (59,6 mmol) 55%-ne disperzije natrijum-hidrida u mineralnom ulju ispira se heksanom da se oslobodi od ulja i zatim prelije sa 30 ml dimetilformamida. U ovu suspenziju ukapava se 13,8 g (39,7 mmol) terc-butil-metil-|6-(2-okso-1-benzimidazolinil)-heksil|-karbamata u 90 ml dimetilformamida u toku perioda od 20 minuta pri sobnoj temperaturi. Posle mešanja u toku 90 minuta pri sobnoj temperaturi ukapava se 6,2 ml (99,3 mmol) metil-jodida u 30 ml dimetilformamida pri sobnoj temperaturi i reakeiona smeša meša daljih 16 sati pri ovoj temperaturi. U cilju obrade reakciona smeša se sipa na 20C ml vode i ekstrahuje metilen-hloridom. Metilenhloridni ekstrakt ispira se vodom, osuši iznad kalijum-karbonata i upari. Ostatak se hromatografiše2.6 g (59.6 mmol) of a 55% sodium hydride dispersion in mineral oil were washed with hexane to release from the oil and then topped with 30 ml of dimethylformamide. 13.8 g (39.7 mmol) of tert-butyl-methyl- [6- (2-oxo-1-benzimidazolinyl) -hexyl] -carbamate were added dropwise to this suspension in 90 ml of dimethylformamide over 20 minutes at room temperature. temperature. After stirring for 90 minutes at room temperature, 6.2 ml (99.3 mmol) of methyl iodide in 30 ml of dimethylformamide were added dropwise at room temperature and the reaction mixture was stirred for a further 16 hours at this temperature. For the treatment, the reaction mixture was poured onto 20C ml of water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over potassium carbonate and evaporated. The residue is chromatographed
39.39.
na koloni silikagela (110 g) uz primenu metilenhlorida i smeše metilenhlorid/izopropanol (99:1 i 98:2) kao sredstva za eluiranje, pri čemu se dobiva 9,0 g terc-butil-metil-|6-(3-metil-2-okso-1-benzimidazolinil)-heksil|-karbamata u obliku ulja.on a silica gel column (110 g) using methylene chloride and methylene chloride / isopropanol (99: 1 and 98: 2) as eluant to give 9.0 g of tert-butyl methyl- | 6- (3-methyl -2-Oxo-1-benzimidazolinyl) -hexyl | -carbamate in the form of an oil.
Analogno primeru 15, poslednji stav, iz gore dcbivenog jedinjenja dobiven je 1-metil-3-|6-(metilamino)-heksil|-2-benzimidazolinon u obliku ulja.Analogous to Example 15, last paragraph, from the above compound, 1-methyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone was obtained in the form of an oil.
Primer 17Example 17
Na analogan način onom koji je opisan u primeru 15, reakcijom |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1 -|p-|4-(metilami no)-butil|-fenil|-imidazola, dobiven je 11S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||4-|p-(imidazol-1-il)-fenil|-butil|-metilarcino|-etil|-2-naftalinol u obliku ulja.In an analogous manner to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- p-toluenesulfonate and 1- {p- | 4- (methylamino) -butyl | -phenyl | -imidazole, 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl- 2- | 2- || 4- | p- (Imidazol-1-yl) -phenyl | -butyl | -methylarcino | -ethyl | -2-naphthalinol as an oil.
1-|p-|4-(Metilamino)-butil|-fenil|-imidazol, kcji je upotrebljen kao polazna materija, dobiven je na sledeči način:1- | p- | 4- (Methylamino) -butyl | -phenyl | -imidazole, used as starting material, is obtained as follows:
A) 53,1 g (116 mmol) |2-(m-Dioksan-2-il).etil|-trifenilfosfonijum-bromida suspenduje se u 160 ml tetrahidrofurana i pri -25° u toku 15 minuta pomeša sa 77,3 ml (116 mmol) rastvora n-butil-litijum (ca. 1,5 M u heksanu). Potom se meša 15 minuta pri -25°. Zatim se doda 10 ml smeše tetrahidrofurana i 1,3-dimetil-3,4,5,6-tetrahidro-2-(lH)-pirimidinona (1:1), meša dal jih 5 minuta pri -25° i potom u tokuA) 53.1 g (116 mmol) of 2- (m-Dioxan-2-yl) ethyl | -triphenylphosphonium bromide are suspended in 160 ml of tetrahydrofuran and mixed at -25 ° for 77 minutes with 77.3 ml. (116 mmol) solution of n-butyl lithium (ca. 1.5 M in hexane). It was then stirred for 15 minutes at -25 °. Then 10 ml of a mixture of tetrahydrofuran and 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (1: 1) are added, stirred for 5 minutes at -25 ° C and then in a stream
40.40.
minuta pri -25° pomeša sa 20 g (116 mmol) p-imidazol-1-il-benzaldehida u 18O ml tetrahidrofuran/1,3-dimetil-3,4,5,6-tetrahidro-2-(1H)-pirimidinona (1:1). Posle završenog dodavanja reakciona smeša se zagreje na sobnu temperaturu i meša 15 minuta pri toj temperaturi. Potom se reakciona smeša sipa na 1 litar ledene vode i ekstrahuje sa 600 ml metilenhlorida. Metilenhloridni ekstrakt se ispira vodom, osuši iznad magnezijum-sulfata i upari. Pri torne se dobije 42,4 g polukristalnog proizvoda, koji se rastvori u 600 ml metanola i zatim iscrpno hidrogenizuje u prisustvu 18 g (5%-nog) paladijuma na uglju. Posle odfiltriranja katalizatora i uparavanja filtrata dobiva se 36,6 g polukristalnog ostatka, koji se sa svoje strane rastvori u 700 ml metanola, pomeša sa 22,4 g monohidrata p-toluolsulfonske kiseline i 2,5 sata zagreva uz refluksovanje. posle hladjenja na sobnu temperaturu pH vrednost se podesi na 7 pomocu 36 g natrijum-karbonata, reakciona smeša upari, ostatak sipa na 500 ml vode i ekstrahuje sa 600 ml metilenhlorida. Metilenhloridni ekstrakt se ispira vodom i zasičenim vodenim rastvorom natrijum-hlorida, osuši iznad magnezijum-sulfata i upari, pri čemu se dobiva 36,1 g polukristalnog ostatka. Ovaj se rastvori u 400 ml tetrahidrofurana, pomeša sa 110 ml 3 N vodenog rastvora sone kiseline, meša 3 sata pri sobnoj temperaturi i zatim koncentruje pod sniženim pritiskom. Potom se reakciona smeša sipa na 500 ml ledene vode i tri puta ekstrahuje sa po 200 ml etra. Vodena faza se zatim pomocu kalijum-karbonata podesi na vrednost pH 9 i ekstrahuje sa 600 ml metilenhlorida. Metilenhloridni ekstrakt se ispira vodom, osuši iznad kalijum-karbonata i upari. Ostatak se hromatografiše na 240 g silikagela uz primenu metilenhlorida i 0-5% izopropanola kao sredstva za eluiranje. Pri torne se dobiva 13,2 g (53%) 4-|p-(imidazol-1-il)-fenil|butanala kao ulje.minutes at -25 ° is mixed with 20 g (116 mmol) of p-imidazol-1-yl-benzaldehyde in 18O ml of tetrahydrofuran / 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (1: 1). After complete addition, the reaction mixture was warmed to room temperature and stirred for 15 minutes at that temperature. The reaction mixture was then poured onto 1 liter of ice water and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water, dried over magnesium sulfate and evaporated. The resultant is 42.4 g of semi-crystalline product, which is dissolved in 600 ml of methanol and then exhaustively hydrogenated in the presence of 18 g (5%) of palladium on coal. Filtration of the catalyst and evaporation of the filtrate afforded 36.6 g of semi-crystalline residue, which in turn was dissolved in 700 ml of methanol, mixed with 22.4 g of p-toluenesulfonic acid monohydrate and refluxed for 2.5 hours. After cooling to room temperature, the pH was adjusted to 7 with 36 g of sodium carbonate, the reaction mixture was evaporated, the residue poured into 500 ml of water and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 36.1 g of semi-crystalline residue. This was dissolved in 400 ml of tetrahydrofuran, mixed with 110 ml of 3 N aqueous hydrochloric acid, stirred for 3 hours at room temperature and then concentrated under reduced pressure. The reaction mixture was then poured onto 500 ml of ice water and extracted three times with 200 ml of ether each. The aqueous phase was then adjusted to pH 9 with potassium carbonate and extracted with 600 ml of methylene chloride. The methylene chloride extract was washed with water, dried over potassium carbonate and evaporated. The residue was chromatographed on 240 g of silica gel using methylene chloride and 0-5% isopropanol as the eluting agent. In this case, 13.2 g (53%) of 4- | p- (imidazol-1-yl) -phenyl] butanal are obtained as an oil.
41.41.
B) 37,8 g (558 mmol) Metilamin-hidrohlorida rastvori se u 200 ml metanola i nakon toga tretira sa 45,8 g (558 mmol) natrijum-acetata i 3,9 g (62,1 mmol) natrijum-cijan-borhidrida. Reakciona smeša se meša u toku 15 minuta pri sobnoj temperaturi, i potom ukapava 12,05 g (56,24 mmol) 4-|p-(imidazol-1-il)-fenil|-butanala u 40 ml metanola u toku perioda od 15 minuta pri sobnoj temperaturi i reakciona smeša potom meša 3 sata pri sobnoj temperaturi. Zatim se reakciona smeša koncentruje pod sniženim pritiskom, ostatak sipa na 1 litar ledene vode i ekstrahuje sa 800 ml metilenhlorida. Organski ekstrakt se ispira vodom, osuši iznad mag nezijum-sulfata i upari. Tako dobiven ostatak se hromatogra fiše na 100 g silikagela uz primenu smeša metilenhlorid/izo propanol/vodeni, 25%-ni rastvor amonijaka (160:40:1 odnosno 7:3:0,3), pri čemu se dobiva 3,8 g (29%) 1-|p-^-(metilamino ) -butil | -fenil | -imidazola u obliku ulja.B) 37.8 g (558 mmol) of methylamine hydrochloride is dissolved in 200 ml of methanol and then treated with 45.8 g (558 mmol) of sodium acetate and 3.9 g (62.1 mmol) of sodium cyanide. of borohydride. The reaction mixture was stirred for 15 minutes at room temperature, and then 12.05 g (56.24 mmol) of 4- | p- (imidazol-1-yl) -phenyl | -butanal in 40 ml of methanol was added dropwise over a period of 15 minutes at room temperature and the reaction mixture was then stirred for 3 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, the residue poured into 1 liter of ice water and extracted with 800 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulphate and evaporated. The residue thus obtained is chromatographed on 100 g of silica gel using methylene chloride / iso propanol / aqueous, 25% ammonia solution (160: 40: 1 and 7: 3: 0,3) to give 3.8 g (29%) 1- | p - ^ - (methylamino) -butyl | -phenyl | -imidazole in the form of oil.
Primer 18Example 18
Na način analogan onom koji je opisan u primeru 13, reakcijom 11S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-|4-(metilamino)-butil|-2-benzimidazolinona, dobiven je 1-|4-||2— | 11S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|butil|-2-benzimidazolinon u obliku ulja.In a manner analogous to that described in Example 13, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p -toluenesulfonate and 1- | 4- (methylamino) -butyl | -2-benzimidazolinone to give 1- | 4- || 2— | 11S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | butyl | -2-benzimidazolinone in the form of an oil.
-|4-(Metilamino)-butil|-2-benzimidazolinon, koji je upotrebljen kao polazna materija, dobiven je na sledeči način :- | 4- (Methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:
42.42.
Analogan načinu opisanom u primeru 15 iz 4-(metilamino)-1-butanola dobiven je terc-butil-metil-|4-|(metilsulfonil)-oksi|-butil|-karbamat u obliku ulja, koji je zatim preveden u terc-butil-metil-|4-|3-(1-metilvinil)-2-okso-1-benzimidazolinil | -butil | -karbamat . Ovo jedinjenje, dcbiveno takodje u obliku ulja, prevedeno je sa svoje Strane (ponovo analogno primeru 15) u 1-|4-(metilamino)-butil|-2-benzimidazolinon koji se izdvaja u obliku ulja.Analogous to the process described in Example 15 from 4- (methylamino) -1-butanol, tert-butyl-methyl- | 4- | (methylsulfonyl) -oxy | -butyl | -carbamate was obtained in the form of an oil, which was then converted into tert-butyl butyl-methyl- | 4- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl | -butyl | -carbamate. This compound, also obtained in the form of an oil, was converted from its Side (again analogous to Example 15) to 1- | 4- (methylamino) -butyl | -2-benzimidazolinone which was separated in the form of an oil.
Primer 19Example 19
Na analogan način onom koji je opisan u primeru 15, reakcijom |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-izopropil-3-|4-(metilamino)-butil|-2-benzimidazolinona, dobiven je 1 -|4-||2 —||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil j-etil|-metiamino|-butil|-3-izopropil-2-benzimidazolinon u obliku ulja.In an analogous manner to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- p-toluenesulfonate and 1-isopropyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, 1 - | 4- || 2 - || 1S, 2S | -6-fluoro-1,2 was obtained. 3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl-1-ethyl | -methylamino | -butyl | -3-isopropyl-2-benzimidazolinone in the form of an oil.
1-Izopropil-3-j 4-(metilamino)-butil|-2-benzimidazolinon, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:1-Isopropyl-3-yl 4- (methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:
8,14 g (22,6 mmol) terc-butil-metil-|4-|3-(1-metilvinil)-2-okso-1-benzimidazolinil|-butil|-karbamata rastvori se u 80 ml metanola i nakon dodavanja 1,6 g (5%-nog) paladijuma na uglju hidrogenizuje u toku 4 sata. Posle toga se reakciona smeša filtrira 1 upari, pri čemu se dobiva 8,5 g terc-butil-metil-|4-(3-izopropil-2-okso-1-benzimidazolinil|-butil|-karbamata u obliku ulja. Ovo jedinjenje se analogno načinu opisanom u poslednjem stavu primera 15 prevodi u 1-izopropil-3-|4-(metilamino)-butil|-2-benzimidazolinon koji se takodje izdvaja u obliku ulja.8.14 g (22.6 mmol) of tert-butyl-methyl- | 4- | 3- (1-methylvinyl) -2-oxo-1-benzimidazolinyl | -butyl | -carbamate was dissolved in 80 ml of methanol and after addition 1.6 g (5%) of palladium on charcoal is hydrogenated for 4 hours. The reaction mixture was then filtered 1 evaporated to give 8.5 g of tert-butyl-methyl- | 4- (3-isopropyl-2-oxo-1-benzimidazolinyl | -butyl | -carbamate as an oil. This compound is converted to 1-isopropyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, which is also isolated in the form of an oil, analogously to the method described in the last paragraph of Example 15.
43.43.
**
Primer 20Example 20
Na način analogan onom koji je opisan u primeru 15, reakcijom |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-butil-3-|6-(metilamino)-heksil|-2-benzimidazolinona, dobiven je 1 - J 6—||2—|11S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etilj-metilamino|-heksil|-3-butil-2-benzimidazolinon u obliku ulja.In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1-butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, gave 1- J 6 - | 2 - | 11S, 2S | -6-fluoro-1,2,3 , 4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl-methylamino | -hexyl | -3-butyl-2-benzimidazolinone as an oil.
1-Butil-3-|6-(metilamino)-heksil|-2-benzimidazolinon, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:1-Butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which was used as starting material, was obtained as follows:
Analogno primeru 16, iz terc-butil-metil-|6-(2-okso-1-benzimidazolinil)-heksil|-karbamata i butiljodida, dobiven je terc-butil-metil-|6-(3-butil-2-okso-1-benzimidazolinil)-heksil|-karbamat u obliku ulja. Ovo jedinjenje se analogno primeru 15 prevodi u 1-butil-3-|6-(metilamino)-heksil|-2-benzimidazolinon koji je takodje dobiven u obliku ulja.In analogy to Example 16, tert-butyl-methyl- | 6- (3-butyl-2-oxo is obtained from tert-butyl-methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -carbamate and butyl iodide -1-Benzimidazolinyl) -hexyl | -carbamate in the form of an oil. This compound is converted to 1-butyl-3- | 6- (methylamino) -hexyl | -2-benzimidazolinone, which is also obtained in the form of an oil, analogously to Example 15.
Primer 21Example 21
Na način analogan onom koji je opisan u primeru 15, reakcijom |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-(2-morfolinoetil)-3-|6-(metilamino)-heksil|-2-benzimidazolinona, dobiven je 1-|6-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidro ksi-1-izopropil-2-naftil|-etil|-metilamino|-heksil|-3-(2-morfolinoetil)-2-benzimidazolinon u obliku ulja.In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1- (2-morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimidazolinone to give 1- | 6- || 2- || 1S, 2S | -6-fluoro- 1,2,3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -3- (2-morpholinoethyl) -2-benzimidazolinone in the form of an oil.
1-(2-Mrfolinoetil)-3-|6-(metilamino)-heksil|-2-benzimida44.1- (2-Morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimide44.
zolinon, koji je upotrebljen kao pclazna materija, dobiven je na sledeči način:zolinone, which was used as the starting material, was obtained as follows:
9,0 g (25,9 mmol) terc-butil-metil-|6-(2-okso-1-benzimidazolinil ) -heksil | -karbamata rastvori se u 250 ml metanola, pomeša sa 35 g (259 mmol) kalijum-karbonata, 0,5 g kalijum-jodida i u porcijama sa 16,9 g (90,6 mmol) hloretilmorfolin-hidrohlorida. Potom se reakciona smeša zagreva 16 sati uz refluksovanje. Posle hladjenja reakciona smeša se sipa na 1 litar ledene vode i ekstrahuje sa 800 ml metilenhlorida. Ekstrakt se ispira vodom, osuši i koncentruje. Ostatak se rastvori u 50 ml etra i po jedanput ekstrahuje sa po 15 ml i potom 5 ml 3 N metansulfonske kiseline u vodi i po jedanput sa 5 ml vode. Spojene vodene faze se podese sa amonijakom na vrednost pH 8-9 i tri puta ekstrahuju sa po 100 ml metilenhlorida. Spojeni ekstrakti se ispiraju vodom, osuše iznad kalijum-karbonata i upare, pri čemu se dobiva 7,8 g (65,4%) terc-butil-metil-|6-|3-(2-morfolinoetil)-2-okso-1-benzimidazolinil|-heksil|-karbamata u obliku ulja.9.0 g (25.9 mmol) of tert-butyl-methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -carbamate is dissolved in 250 ml of methanol, mixed with 35 g (259 mmol) of potassium carbonate, 0.5 g of potassium iodide and in portions with 16.9 g (90.6 mmol) of chloroethylmorpholine hydrochloride. The reaction mixture was then heated at reflux for 16 hours. After cooling, the reaction mixture was poured onto 1 liter of ice water and extracted with 800 ml of methylene chloride. The extract was washed with water, dried and concentrated. The residue was dissolved in 50 ml of ether and extracted once with 15 ml each and then 5 ml of 3 N methanesulfonic acid in water and once with 5 ml of water. The combined aqueous phases were adjusted with ammonia to pH 8-9 and extracted three times with 100 ml of methylene chloride each. The combined extracts were washed with water, dried over potassium carbonate and evaporated to give 7.8 g (65.4%) of tert-butyl-methyl- | 6- | 3- (2-morpholinoethyl) -2-oxo- 1-Benzimidazolinyl | -hexyl | -carbamate in the form of an oil.
Ovaj se analogno primeru 15 potom prevodi u 1-(2-morfolinoetil )-3-|6-(metilamino)-heksil|-2-benzimidazolinon-dihidrohlorid, t.t. 229-232°.This analogous to Example 15 is then converted to 1- (2-morpholinoethyl) -3- | 6- (methylamino) -hexyl | -2-benzimidazolinone dihydrochloride, m.p. 229-232 °.
Primer 22Example 22
Analogno načinu iz primera 15, reakcijom 11S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-benzil-3-|4-(metilamino)-butil|-2-benzimidazolinona, dobiven je 1-benzil-3-|4-||2-| |1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-butil|-2-benzimidazolinon u obliku ulja.Analogous to the method of Example 15, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p-toluenesulfonate and 1- benzyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, 1-benzyl-3- | 4- || 2- | 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -2-benzimidazolinone as an oil.
45.45.
1-benzil-3-|4-(metilamino)-butil|-2-benzimidazolinon, koji je upotrebljen kao polazna materija, dobiven je analogno primeru 16 iz 1-|4-(metilamino)-butil|-2-benzimidazolinona preko terc-butil-metil-|4-(2-okso-1-benzimidazolinil)-butil|-karbamata.1-Benzyl-3- | 4- (methylamino) -butyl | -2-benzimidazolinone, which was used as starting material, was obtained analogously to Example 16 from 1- | 4- (methylamino) -butyl | -2-benzimidazolinone via tert. -Butyl-methyl- | 4- (2-oxo-1-benzimidazolinyl) -butyl | -carbamate.
Primer 23Example 23
Na način analogan onom koji je opisan u primeru 15, reakcijom |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonata i 1-|4-(metilamino)-butil|-3-(2-piridilmetil)-2-benzimidazolinona, dobiven je 1-|4-||2-||lS,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropi1-2-naftil|-etil|-metilamino|-butil|-3-(2-piridilmetil)-2-benzimidazolinon u obliku ulja.In a manner analogous to that described in Example 15, the reaction of | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl- of p-toluenesulfonate and 1- | 4- (methylamino) -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone, to give 1- | 4- || 2- || 1S, 2S | -6-fluoro- 1,2,3,4-Tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone in the form of an oil.
-|4-(Metilamino)-butil|-3-(2-piridilmetil)-2-benzimidazolinon, koji je upotrebljen kao polazna materija, dobiven je analogno primeru 16 polazeci od terc-butil-metil-|4-(2-okso-1-benzimidazolinil)-butil|-karbamata.- | 4- (Methylamino) -butyl | -3- (2-pyridylmethyl) -2-benzimidazolinone, which was used as starting material, was obtained analogously to Example 16 starting from tert-butyl-methyl- | 4- (2-oxo -1-Benzimidazolinyl) -butyl | -carbamate.
Primer 24Example 24
Na način analogan onom koji je opisan u primeru 13, reakcijom 11S,2 S|—2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil|-p-toluolsulfonata i 1,3-dihidro-3-|6-(metilamino)-heksil|-2H-imidazo|4,5-c|piridin-2-ona, dobiven je 3-|6-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-heksil| -1,3-dihidro-2H-imidazo|4,5-c|piridin-2-on u obliku ulja.In a manner analogous to that described in Example 13, by reaction of 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl | -p-toluenesulfonate and 1,3-dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | pyridin-2-one to give 3- | 6- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -hexyl | -1,3-Dihydro-2H-imidazo | 4,5-c | pyridin-2-one as an oil.
1,3-Dihidro-3-|6-(metilamino)-heksil|-2H-imidazo|4,5-c|pi46.1,3-Dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | pi46.
ridin-2-on, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:ridin-2-one, which was used as starting material, was obtained as follows:
Na način analogan onom koji je opisan u primeru 15, izIn a manner analogous to that described in Example 15, from
6-(metilamino)-1-heksanola dobiven je terc-butil-metil-(6-hidroksiheksil)-karbamat u obliku ulja, koji je zatim preko terc-butil-metil-|6-|(metilsulfonil)-oksi|heksil|-karbamata, koji se takodje izdvaja u obliku ulja, preveden u terc-butil-metil-|6-|-(1-metilvinil)-1,2-dihidro-2-okso-3H-imidazo|4,5-c|piridin-3-il|-heksil|-karbamat; ovaj proizvod je takodje dobiven u obliku ulja.6- (methylamino) -1-hexanol the tert-butyl-methyl- (6-hydroxyhexyl) -carbamate was obtained in the form of an oil, which was then tert-butyl-methyl- | 6- (methylsulfonyl) -oxy | hexyl | -carbamate, which is also isolated in the form of an oil, converted to tert-butyl-methyl- | 6- | - (1-methylvinyl) -1,2-dihydro-2-oxo-3H-imidazo | 4,5-c | pyridin-3-yl | -hexyl | -carbamate; this product is also obtained in the form of oil.
12,2 g (31,4 mmol) na posletku pomenutog jedinjenja rastvori se u 100 ml etanola, tretira sa 13 ml koncentrovane vodene sone kiseline i zagreva 40 sati uz refluksovanje. Potom se uz hladjenje ledom vrednost pH podesi na 9-10 pomoču razblaženog vodenog rastvora natrijum-hidroksida, reakcioni rastvor zasiti natrijum-hloridom i ekstrahuje kontinualno 16 sati sa hloroformom. Ekstrakt se osuši iznad kalijum-karbonata i upari, pri čemu se dobiva 7,2 g (92%) 1,3-dihidro-3-|6-(metilamino)-heksil|-2H-imidazo|4,5-c|-piridin-2-ona u obliku ulja, koje se dalje preradjuje bez daljeg prečiščavanja.12.2 g (31.4 mmol) of the title compound was dissolved in 100 ml of ethanol, treated with 13 ml of concentrated aqueous hydrochloric acid, and refluxed for 40 hours. Then, under ice-cooling, the pH was adjusted to 9-10 with dilute aqueous sodium hydroxide solution, the reaction solution was saturated with sodium chloride and extracted continuously for 16 hours with chloroform. The extract was dried over potassium carbonate and evaporated to give 7.2 g (92%) of 1,3-dihydro-3- | 6- (methylamino) -hexyl | -2H-imidazo | 4,5-c | -pyridin-2-one in the form of oil, which is further processed without further purification.
Primer 25Example 25
Na anlogan način onom koji je opisan u primeru 14 dobivena su sledeča jedinjenja:The following compounds were obtained in an inorganic manner to that described in Example 14:
|1S,2S|-6-fluos-1,2,3,4-tetrahidro-1-izopropil-2—|2—[metil—|6-(2-okso-1-benzimidazolinil)-heksil|-amino|-etil|-2-naftilmetoksiacetat-hidrohlorid,| 1S, 2S | -6-Fluos-1,2,3,4-tetrahydro-1-isopropyl-2- {2- [methyl- | 6- (2-oxo-1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride,
47.47.
|o6|g° = +27,8° (c = 1%; metanol);| o6 | g ° = + 27.8 ° (c = 1%; methanol);
|1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropi1-2-|2-|metil-|4-(2-okso-1-benzimidazolinil)-butil|-amino|-etil|-2-naftilmetoksiacetat-hidrohlorid, |o^° = +28,7° (c = 1%; metanol);| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- (2-oxo-1-benzimidazolinyl) -butyl | -amino | -Ethyl | -2-naphthylmethoxyacetate hydrochloride, 0 ° C = + 28.7 ° (c = 1%; methanol);
|1S,2S|-2-|2-||6—(1,2-dihidro-2-okso-3H-imidazo|4,5-c|-piridin-3-il)-heksil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-dihidrohlorid, |ού| = +26,0° (c = 1%; metanol).| 1S, 2S | -2- | 2- || 6 - (1,2-dihydro-2-oxo-3H-imidazo | 4,5-c | -pyridin-3-yl) -hexyl | -methylamino | - ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, | ού | = + 26.0 ° (c = 1%; methanol).
Primer 26Example 26
4,6 g (9,3 mmol) 1-|6-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino|-heksil|-3-metil-2-benzimidazolinona rastvori se u 15 ml metilenhlorida, pomeša sa 1,9 ml piridina i 6,2 g (38 mmol) anhidrida metoksisircetne kiseline i meša 20 sati pri sobnoj temperaturi. Potom se uz hladjenje ledom tretira sa 45 ml 1 N vodenog rastvora natrijum-hidroksida i potom meša 1 sat pri 10-15°. Zatim se reakciona smeša sipa na 400 ml ledene vode i ekstrahuje sa 600 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijum-karbonata, upari, tretira jednim ekvivalentom hlorovodonika u etanolu i upari. Pri torne se dobiva 5,3 g 11S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|meti1-|6-(3-metil-2-okso-1-benzimidazolinil )-heksil|-amino|-etil|-2-naftiImetoksiacetata-hidrohlorida, |</1 = +27,1° (c = 1%; metanol).4.6 g (9.3 mmol) 1- | 6- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2- Naphthyl | -ethyl | -methylamino | -hexyl | -3-methyl-2-benzimidazolinone was dissolved in 15 ml of methylene chloride, mixed with 1.9 ml of pyridine and 6.2 g (38 mmol) of methoxyacetic acid anhydride and stirred for 20 hours at room temperature. It was then treated with ice-cooling with 45 ml of 1 N aqueous sodium hydroxide solution and then stirred at 10-15 ° for 1 hour. The reaction mixture was then poured onto 400 ml of ice water and extracted with 600 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate, evaporated, treated with one equivalent of hydrogen chloride in ethanol and evaporated. 5.3 g of 11S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 6- (3-methyl-2-oxo) are obtained -1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate-hydrochloride, | </i> = + 27.1 ° (c = 1%; methanol).
48.48.
Analogno primeru 26 dobivena su sledeča jedinjenja:Analogous to Example 26, the following compounds were obtained:
|1S,2 S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2“II4-|p-(imidazol-1-il)-fenil|-butil|-metilamino|-etil|-2-naftilmetoksiacetat-oksalat (1:1), μ|2θ = +27,6° (c = 1%; metanol);| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2 "II4- | p- (imidazol-1-yl) -phenyl | -butyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate oxalate (1: 1), μ | 2 θ = + 27.6 ° (c = 1%; methanol);
|1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil-|4-(3-izopropil-2-okso-1-benzimidazolinil)-butil|-amino|-etil|-2-naftilmetoksiacetat-hidrohlorid, |oZ| 2θ = +27,6° (c = 1%; metanol);| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- (3-isopropyl-2-oxo-1-benzimidazolinyl) -butyl | -Amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, | oZ | 2 θ = + 27.6 ° (c = 1%; methanol);
|1S,2SI-6-fluor-1,2,3,4-tetrabidro-1-izopropil-2-|2-|metil-|6-(3-butil-2-okso-1-benzimidazolinil)-heksil| -amino|-etil|-2-naftilmetoksiacetat-hidrohlorid, |cZl§° = +26,4° (c = 1%; metanol);| 1S, 2SI-6-Fluoro-1,2,3,4-tetrabidro-1-isopropyl-2- | 2- | methyl- | 6- (3-butyl-2-oxo-1-benzimidazolinyl) -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, | zZl§ ° = + 26.4 ° (c = 1%; methanol);
|IS,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil-|6-|3-(2-morfolinoetil)-2-okso-1-benzimidazolinil |-heksil|-amino|-etil|-2-naftilmetoksiacetat-dihidrohlorid, |ο/,|2θ = +22,4° (c = 1%; metanol);| IS, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 6- | 3- (2-morpholinoethyl) -2-oxo-1- benzimidazolinyl | -hexyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, | ο /, | 2 θ = + 22.4 ° (c = 1%; methanol);
|1S,2S|-2-|2-| |4-(3-benzil-2-okso-1-benzimidazolinil)-butil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-hidrohlorid, |οέ|2θ = +25,6° (c = 1%; metanol);| 1S, 2S | -2- | 2- | 4- (3-benzyl-2-oxo-1-benzimidazolinyl) -butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride, | οέ | 2 θ = + 25.6 ° (c = 1%; methanol);
|1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil-|4-|2-okso-3-(2-piridilmetil)-1-benzimidazolinil |-butil|-amino|-etil|-2-naftilmetoksiacetat-dihidrohlorid, I&Z | = +23,3° (c = 1%; metanol).| 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl- | 4- | 2-oxo-3- (2-pyridylmethyl) -1- benzimidazolinyl | -butyl | -amino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, I&Z | = + 23.3 ° (c = 1%; methanol).
49.49.
Primer 28Example 28
1,3 g (3,1 mmol) | 1S, 2S |-2-| 2-| | 3-(2-benzimidaz.olil)-propil | -metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftalinola u 10 ml dimetilformamida pomeša se na sobnoj temperaturi sa 0,19 g (1,53 mmol) 4-dimetilaminopiridina,1.3 g (3.1 mmol) 1S, 2S | -2- | 2- | | 3- (2-benzimidazolol) propyl -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalinol in 10 ml of dimethylformamide was stirred at room temperature with 0.19 g (1.53 mmol) of 4- dimethylaminopyridine,
1,7 ml (12,3 mmol) trietilamina i rastvorom od 0,96 ml (9,24 mmol) hlorida izobuterne kiseline u 5 ml dimetilformamida i meša 2 sata pri sobnoj temperaturi. Potom se reakciona smeša sipa na 20 ml ledene vode, pomeša sa 10 ml 1 N vodenog rastvora natrijum-hidroksida, meša 10 minuta pri 0° i ekstrahuje sa 100 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad kalijum-karbonata i upari. Tako dobiven sirov proizvod se rastvori u 20 ml metanola, tretira sa 1,5 ml 1 N vodenog rastvora natrijum-hidroksida, meša 1 sat pri sobnoj temperaturi, sipa na 50 ml vode i ekstrahuje sa 100 ml metilenhlorida. Ekstrakt se ispira vodom, osuši iznad magnezi jum-sulfata i upari. Ostatak se hromatografiše na koloni od 30 mg silikagela sa metilenhloridom i 1-20% izopropanola kao sredstvom za eluiranje i na koloni od 20 g silikagela uz primenu smeše metilenhlorid/izopropanol/25%-ni vodeni rastvor amonijaka (9:1:0,1) kao sredstva za eluiranje.1.7 ml (12.3 mmol) of triethylamine and a solution of 0.96 ml (9.24 mmol) of isobutyric acid chloride in 5 ml of dimethylformamide and stirred for 2 hours at room temperature. The reaction mixture was then poured into 20 ml of ice water, mixed with 10 ml of 1 N aqueous sodium hydroxide solution, stirred for 10 minutes at 0 ° and extracted with 100 ml of methylene chloride. The extract was washed with water, dried over potassium carbonate and evaporated. The crude product thus obtained was dissolved in 20 ml of methanol, treated with 1.5 ml of 1 N aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, poured into 50 ml of water and extracted with 100 ml of methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a column of 30 mg silica gel with methylene chloride and 1-20% isopropanol as elution medium and on a column of 20 g silica gel using methylene chloride / isopropanol / 25% aqueous ammonia (9: 1: 0.1). ) as eluting agents.
Pri torne se dobiva 360 mg (21%) 11S,2S|-2-|2-| |3-(2-benzimidazolil )-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro- 1 -izopropil-2-naftilizobutirata-dihidrohlorida .Thorne gives 360 mg (21%) of 11S, 2S | -2- | 2- | 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylisobutyrate dihydrochloride.
Primer 29Example 29
Smeša od 4,67 g (11,5 mmol) |1S,2S|-2-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil|-p-toluolsulfonata, 3,5 g (11,5 mmol) 1-metil-2-|3-(metilamino)50.Mixture of 4.67 g (11.5 mmol) 1S, 2S | -2-6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl | - p-toluenesulfonate, 3.5 g (11.5 mmol) of 1-methyl-2- | 3- (methylamino) 50.
-propil|-4,5-difenilimidazola, i 1,5 g (11,5 mmol) N-etil-diizopropilamina meša se 1 sat pri 100°. Ohladjena masa se podeli izmedju vode i metilen hlorida, i organska faza ispira zasičenim vodenim rastvorom natrijum-hlorida, osuši iznad natrijum-sulfata i koncentruje do suva. Preostalo ulj se hromatografiše na koloni od 400 g silikagela uz primenu smeše metilenhlorid/metanol (4:1) kao sredstva za eluiranje Prečiščen kondenzacioni proizvod (5,3 g ulja) rastvori se u 15 ml anhidrida metoksisircetne kiseline, pomeša sa 0,85 ml piridina i rastvor meša 2 sata na 70°. Ohladjena reakeiona smeša se podeli izmedju 400 ml metilen-hlorida i 400 ml 3 N vodenog rastvora natrijum-hidroksida i ova smeša 15 minuta snažno meša pri sobnoj temperaturi. Odvojena vodena faza se ponovo ekstrahuje sa 400 ml metilenhlorida, spojeni ekstrakti ispiraju zasičenim vodenim rastvorom natrijum-hlorida, osuše iznad natrijum-sulfata i koncentruje do suva. Uljast ostatak se hromatografiše na 350 g silikagela uz primenu metilenhlorida/metanola (9:1) kao sredstva za eluiranje. Ulje dobiveno iz homogenih frakcija rastvori se u etilacetatu i tretira sa viškom hlorovodonika u etru. Kristalizat se odfiltrira, ispira etrom i osuši. Dobiva se 4,0 g (51%) |lS,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||3-(1-metil-4,5-difenilimidazol-2-il)-propil|-metilamino|-etil|-2-naftilmetoksiacetata-dihidrohlorida, t.t. 185-189°, u obliku skoro bezbojnog kristalnog praha.-propyl | -4,5-diphenylimidazole, and 1.5 g (11.5 mmol) of N-ethyl-diisopropylamine are stirred at 100 ° for 1 hour. The cooled mass was partitioned between water and methylene chloride, and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The residual oil was chromatographed on a column of 400 g silica gel using methylene chloride / methanol (4: 1) as the elution agent. The purified condensation product (5.3 g of oil) was dissolved in 15 ml of methoxyacetic acid anhydride, mixed with 0.85 ml. of pyridine and the solution stirred for 2 hours at 70 °. The cooled reaction mixture was partitioned between 400 ml of methylene chloride and 400 ml of 3 N aqueous sodium hydroxide and the mixture was stirred vigorously at room temperature for 15 minutes. The separated aqueous phase was re-extracted with 400 ml of methylene chloride, the combined extracts washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The oily residue was chromatographed on 350 g of silica gel using methylene chloride / methanol (9: 1) as the eluting agent. The oil obtained from homogeneous fractions was dissolved in ethyl acetate and treated with excess hydrogen chloride in ether. The crystallizate was filtered off, washed with ether and dried. 4.0 g (51%) of 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 3- (1-methyl-4) are obtained. 5-diphenylimidazol-2-yl) -propyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate-dihydrochloride, m.p. 185-189 °, in the form of an almost colorless crystalline powder.
Kao polazna materija primenjen 1-metil-2-|3-(metilamino)-propil|-4,5-difenilimidazol je dobiven na sledeči način:1-Methyl-2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole was obtained as starting material as follows:
U rastvor od 7,0 g (0,024 mol) 4,5-difenilimidazol-2-propionske kiseline i 3,36 ml (0,024 mol) trietilamina u 80 ml .To a solution of 7.0 g (0.024 mol) of 4,5-diphenylimidazole-2-propionic acid and 3.36 ml (0.024 mol) of triethylamine in 80 ml.
dimetilformamida ukapava se pri -5° 3,2 ml izobutilestra hlormravlje kiseline (0,024 mol). Posle mešanja u toku 30 minuta pni 0-5° doda se 1,64 g (0,024 mol) metilamin-hidnohlonida i 3,36 ml (0,024 mol) trietilamina u 32 ml dimetilformamida i 1,65 ml vode. Pusti se da temperatura reakcione smeše poraste na sobnu tempenaturu i meša još 20 sati. Posle koncentnovanja pod sniženim pritiskom ostatak se pnokuva u 250 ml metanola i pomeša 3,6 ml (0,024 mol) 1,8-diazobiciklo|5.4.0|undec-7-ona (DBU), pni čemu se stvori bistar rastvor. Hladjenjem u ledenom kupatilu kristališe 4,8 g N-metil-4,5-difenilimidazol-2-propionamida, t.t. 195-200° (raspadanje). Iz matičnog luga dobiva se nakcn koncentrovanja i tretiranja vodom daljih 2 g tog istog produkta, t.t. 195-200°. Ukupni prinos: 6,8 g (93%).of dimethylformamide was added dropwise at -5 ° 3.2 ml of hydrochloric acid isobutyl ester (0.024 mol). After stirring for 30 minutes at 0-5 °, 1.64 g (0.024 mol) of methylamine hydrochloride and 3.36 ml (0.024 mol) of triethylamine in 32 ml of dimethylformamide and 1.65 ml of water were added. Allow the reaction mixture to rise to room temperature and stir for another 20 hours. After concentration under reduced pressure, the residue was dipped in 250 ml of methanol and mixed with 3.6 ml (0.024 mol) of 1,8-diazobicyclo | 5.4.0 | undec-7-one (DBU) to give a clear solution. Cooling in an ice bath crystallized 4.8 g of N-methyl-4,5-diphenylimidazol-2-propionamide, m.p. 195-200 ° (decomposition). From the mother liquor, a further concentration of 2 g of the same product, m.p. 195-200 °. Total yield: 6.8 g (93%).
U mešanu suspenziju od 2,3 g (0,06 mol) litijumaluminijum-hidnida u 160 ml tetrahidrofurana u porcijama se dodajeTo a stirred suspension of 2.3 g (0.06 mol) of lithium aluminum hydride in 160 ml of tetrahydrofuran is added portionwise
9,15 g (0,03 mol) N-metil-4,5-difenilimidazol-2-pnopionamida i zatim zagreva 4 sata uz refluksovanje. Pri 5-10° ukapavanjem se doda 6 ml vode, zatim 9 ml 10%-nog vodenog rastvora kalijum-hidnoksida i ponovo 6 ml vode. Talog se odfiltrina i tri puta pnokuva sa po 50 ml tetrahidrofurana. Spojeni filtrati se ispiraju zasičenim vodenim rastvorom na trijum-hlorida, osuše iznad natrijum-sulfata i koncentruju pod sniženim pritiskom do suva. Uljast ostatak se hromatografiše na 200 g silikagela prvo uz primenu smeše hlonofonm/etanol (9:1), zatim sa metanolom kao sredstvom za eluiranje. Prve eluirane homogene frakcije daju nakon upanavanja i tnljanja sa etrom 1,2 g polaznog matenijala. Sledeče eluirane homogene frakcije dale su nakon istog tnetmana9.15 g (0.03 mol) of N-methyl-4,5-diphenylimidazol-2-pionamide and then refluxed for 4 hours. At 5-10 ° C, 6 ml of water is added dropwise, then 9 ml of 10% aqueous potassium hydroxide solution and again 6 ml of water. The precipitate was filtered off and three times foamed with 50 ml of tetrahydrofuran each. The combined filtrates were washed with saturated aqueous solution of tri-chloride, dried over sodium sulfate and concentrated under reduced pressure to dryness. The oily residue was chromatographed on 200 g of silica gel, first using a chlonophon / ethanol mixture (9: 1), then with methanol as the elution agent. The first eluted homogeneous fractions gave after digestion and tanning with ether 1.2 g of starting material. The following eluted homogeneous fractions were obtained after the same tnetman
5,5 g (73%) 2-|3-(metilamino)-propil|-4,5-difenilimidazola u obliku bezbojnih kristala, t.t. 110-113°.5.5 g (73%) of 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole as colorless crystals, m.p. 110-113 °.
52.52.
Rastvor od 5,25 g (0,018 mol) 2-|3-(metilamino)-propil|-4,5-difenilimidazola i 3,8 ml (0,028 mol) benzilestra hlormravlje kiseline u 38 ml dimetilformamida pomeša se sa 5 g fino sprašenog suvog kalijum-karbonata i nakon toga snažno meša 1 sat pri sobnoj temperaturi. Neorganske soli se zatim odfiltriraju, ispiraju metilenhloridom i filtrat koncentruje do suva pod sniženim pritiskom. Uljast ostatak se hromatografiše na 500 g silikagela uz primenu etilacetata kao sredstva za eluiranje. Homogene frakcije su, nakon uparavanja i trijanja ostatka sa heksanom, daleA solution of 5.25 g (0.018 mol) of 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole and 3.8 ml (0.028 mol) of hydrochloric acid benzyl ester in 38 ml of dimethylformamide was mixed with 5 g of finely powdered of dry potassium carbonate and then stirred vigorously for 1 hour at room temperature. The inorganic salts are then filtered off, washed with methylene chloride and the filtrate concentrated to dryness under reduced pressure. The oily residue was chromatographed on 500 g of silica gel using ethyl acetate as the eluting agent. Homogeneous fractions gave, after evaporation and rubbing of the residue with hexane
6,5 g (85%) 2-|3-(N-benziloksikarbonilmetilamino)-propil|-4,5-difenilimidazola u obliku bezbojnog kristala, t.t. 105-108°.6.5 g (85%) of 2- | 3- (N-benzyloxycarbonylmethylamino) -propyl | -4,5-diphenylimidazole as a colorless crystal, m.p. 105-108 °.
Rastvor od 6,4 g (0,015 mol) 2-|3-(N-benziloksikarbonilmetilamino)-propil|-4,5-difenilimidazola u 120 ml dimetilformamida pomeša se pod argonom pri 15-20° sa 0,018 mol natrijum-hidrida (0,8 g 55%-ne disperzije u mineralnom ulju) i nakon toga meša dalje 30 minuta pri sobnoj temperaturi. U toku 15 minuta pri 15-20° doda se rastvor od 1,85 ml (0,03 mol) metiljodida u 10 ml dimetilformamida i meša dalje još 3 sata pri sobnoj temperaturi. Posle koncentrovanja pod sniženim pritiskom ostatak se raspodeli izmedju ledene vode i etilacetata. Organska faza, koja je osušena iznad natrijum-sulfata, upari se i preostalo ulje hromatografiše na 100 g silikagela uz primenu etilacetata kao sredstva za eluiranje. Dobiveni 2-|3-(N-benziloksikarbonilmetilamino).propil|-1-metil-4,5-difenilimidazol (6,4 g ulja) rastvori se u 300 ml metanola i potom hidrogenizuje pri sobnoj temperaturi i normalnom pritisku u prisustvu 1 g 5%-nog paladijuma na aktivnom uglju. Sirov proizvod, koji je izolovan na uobičajen način, hromatografiše se na 70 g silikagela uz primenu smeše metanil/koncentrovan amonijum-hidroksidA solution of 6.4 g (0.015 mol) of 2- | 3- (N-benzyloxycarbonylmethylamino) -propyl | -4,5-diphenylimidazole in 120 ml of dimethylformamide was mixed under argon at 15-20 ° with 0.018 mol of sodium hydride (0 , 8 g of 55% dispersion in mineral oil) and then stirred for a further 30 minutes at room temperature. A solution of 1.85 ml (0.03 mol) of methyl iodide in 10 ml of dimethylformamide was added at 15-20 ° C for 15 minutes and stirred for a further 3 hours at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase, which was dried over sodium sulfate, was evaporated and the residual oil was chromatographed on 100 g of silica gel using ethyl acetate as the elution agent. The resulting 2- | 3- (N-benzyloxycarbonylmethylamino) propyl | -1-methyl-4,5-diphenylimidazole (6.4 g of oil) was dissolved in 300 ml of methanol and then hydrogenated at room temperature and normal pressure in the presence of 1 g 5% palladium on charcoal. The crude product, which is isolated in the usual way, is chromatographed on 70 g of silica gel using a methanyl / concentrated ammonium hydroxide mixture
53.53.
(100:1) kao sredstva za eluiranje. Dobiva se 2,95 g (64%) 1-metil-2-|3-(metilamino)-propil|-4,5-difenilimidazola kao gustog ulja.(100: 1) as eluting agents. 2.95 g (64%) of 1-methyl-2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole are obtained as a thick oil.
Primer 30Example 30
Na način analogan onom koji je opisan u primeru 29 reaguje se |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonat prvo sa 2-|3-(metilamino)-propil|-4,5-difenilimidazolom i zatim sa anhidridom metoksisircetne kiseline. Dobiva se |1S,2S|-6-fluor-1,2,3,4 -tetrahidro-1-izopropil-2-|2-||3-(4,5-difenilimidazol-2-il)-porpil|-metilamino|-etil|-2-naftiImetoksiacetat-dihidrohlorid, t.t. 160-164°, u obliku bezbojnog kristalnog praha.In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 3- (methylamino) -propyl | -4,5-diphenylimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | 3- (4,5-diphenylimidazol-2-yl) -propyl | methylamino | -ethyl | -2-naphthylImethoxyacetate dihydrochloride, m.p. 160-164 °, in the form of a colorless crystalline powder.
Primer 31Example 31
Na način analogan onom koji je opisan u primeru 29 reaguje se |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonat prvo sa 2-|4-|(metilamino)-metil|-benzil|-1-metil-benzimidazolom i potom sa anhidridom metoksisircetne kiseline. Dobiva se |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||4-|(1-metil-2-benzimidazolil)-metil|-benzil|-metilamino|-etil|-2-naftilmetoksiaeetata-dihidrohlorid, t.t. 130-134°, u obliku bezbojnog kristalnog praha.In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 4- | (methylamino) -methyl | -benzyl | -1-methyl-benzimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- ((1-methyl-2-benzimidazolyl) -methyl] -benzyl is obtained | -methylamino | -ethyl | -2-naphthylmethoxyethanol-dihydrochloride, m.p. 130-134 °, in the form of a colorless crystalline powder.
2-|4-|(Metilamino)-metil|-benzil|-1-metilbenzimidazol, koji2- | 4- | (Methylamino) -methyl | -benzyl | -1-methylbenzimidazole, which
54.54.
je primenjen kao polazna materija, dobiven je na sledeči način:was applied as a starting material, obtained as follows:
Smeša od 30 g (0,277 mol) o-fenilendiamina i 150 g estra polifosforne kiseline (PPE) zagreva se na 120°. Kada se diamin rastvori odjednom se doda 33 g (0,205 mol) p-cijanfenilsirčetne kiseline i zagreva još 20 minuta na 120°. Posle hladjenja na sobnu temperaturu viskozna masa se pomeša sa oko 1 litar vode i učini slabo baznom dodavanjem čvrstog natrijum-bikarbonata. Smeša se ekstrahuje metilenhloridom i ekstrakt ispira vodom, osuši iznad natrijum-sulfata i upari do suva. Prekristalizacija ostatka iz smeše metilenhlorid/etilacetat daje 29 g (60%) 2-(p-cijanbenzil)-benzimidazola, t.t. 201-203°, u obliku bezbojnog kristalnog praha.A mixture of 30 g (0.277 mol) of o-phenylenediamine and 150 g of polyphosphoric acid ester (PPE) was heated to 120 °. When the diamine is dissolved, 33 g (0.205 mol) of p-cyanphenylacetic acid are added at once and heated to 120 ° for a further 20 minutes. After cooling to room temperature, the viscous mass is mixed with about 1 liter of water and made weakly basic by the addition of solid sodium bicarbonate. The mixture was extracted with methylene chloride and the extract was washed with water, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from methylene chloride / ethyl acetate gave 29 g (60%) of 2- (p-cyanbenzyl) -benzimidazole, m.p. 201-203 °, in the form of a colorless crystalline powder.
Ratsvor od 21,9 g 2-(p-cijanbenzil)-benzimidazola u smeši od 140 ml metanola i 140 ml tečnog amonijaka hidrogenizuje se na sobnoj temperaturi pod pritiskom od 30 bara u prisustvu 5 g Raney-nikla kao katalizatora. Sirov proizvod, koji je izolovan na uobičajen način, hromatografiše se na 400 g silikagela sa metanolom kao sredstvom za eluiranje. Homogene frakcije daju nakon uparavanja i trljanja ostatka sa etrom 14,7 g (66%) 2-|p-(aminometil)-benzil|-imidazola, t.t. 133-136°, u obliku svetlo smedjeg kristalnog praha.A solution of 21.9 g of 2- (p-cyanbenzyl) -benzimidazole in a mixture of 140 ml of methanol and 140 ml of liquid ammonia was hydrogenated at room temperature under a pressure of 30 bar in the presence of 5 g of Raney-nickel as a catalyst. The crude product, which was isolated in the usual way, was chromatographed on 400 g of silica gel with methanol as the elution agent. Homogeneous fractions gave after evaporation and rubbing of the residue with ether 14.7 g (66%) of 2- | p- (aminomethyl) -benzyl | -imidazole, m.p. 133-136 °, in the form of a light brown crystalline powder.
Rastvor od 9,2 g (0,04 mol) 2-|p-(aminometil)-benzil|-benzimidazola i 8,4 ml (0,06 mol) benzil-estra hlormravlje kiseline u 80 ml dimetilformamida pomeša se sa 10 g fino spra šenog suvog kalijum-karbonata i nakon toga 30 minuta snažno meša pri sobnoj temperaturi, potom se u to doda 12 ml (0,08 1,8-diazabieiklo|5.4.0|undec-7-ena (DBU) i meša dalje pri mol)A solution of 9.2 g (0.04 mol) of 2- | p- (aminomethyl) -benzyl | -benzimidazole and 8.4 ml (0.06 mol) of hydrochloric acid benzyl ester in 80 ml of dimethylformamide is mixed with 10 g of finely powdered dry potassium carbonate and then stirred vigorously at room temperature for 30 minutes, then 12 ml (0.08 1,8-diazabieiclo | 5.4.0 | undec-7-ene (DBU) was added thereto and stirred further at mol)
55.55.
sobnoj temperaturi još 30 minuta. Neorganske soli se odfiltriraju, zatim ispiraju metilenhloridom i filtrat koncentruje do suva pod sniženim pritiskom. Uljast ostatak se hromatografiše na 600 g silikagela prvo sa smešom metilenhlorid/ /etilacetat (4:1) a zatim sa smešom hloroform/etanol (9:1) kao sredstvom za eluiranje. Frakcije eluirane smešom hloroform/etanol nakon uparavanja daju (posle trljanja sa etilacetatom) 10,8 g (73%) benzil-estra |4-|2-(benzimidazolil)-metil|-benzil|-karbaminske kiseline, t.t. 190-194°, u obliku bezbojnog kristalnog praha.room temperature for another 30 minutes. The inorganic salts were filtered off, then washed with methylene chloride and the filtrate concentrated to dryness under reduced pressure. The oily residue was chromatographed on 600 g of silica gel, first with methylene chloride / ethyl acetate (4: 1) and then with chloroform / ethanol (9: 1) as an elution agent. The chloroform / ethanol-eluted fractions after evaporation afforded (after rubbing with ethyl acetate) 10.8 g (73%) of benzyl ester | 4- | 2- (benzimidazolyl) -methyl | -benzyl | -carbamic acid, m.p. 190-194 °, in the form of a colorless crystalline powder.
Rastvor od 8,9 g (0,024 mol) benzil-estra |4-|2-(benzimidazolil)-metil|-benzil|-karbamidne kiseline u 210 ml dimetilformamida, pod argonom se pri 15-20°, pomeša sa 0,056 mol natrijum-hidrida (2,5 g 55%-ne disperzije u mineralnom ulju) i nakon toga meša dalje 30 minuta pri sobnoj temperaturi.A solution of 8.9 g (0.024 mol) of benzyl ester | 4- | 2- (benzimidazolyl) -methyl | -benzyl | -carbamic acid in 210 ml of dimethylformamide, under argon at 15-20 °, was mixed with 0.056 mol of sodium -hydride (2.5 g 55% dispersion in mineral oil) and then stirred for 30 minutes at room temperature.
Pri 15.20° u toku 20 minuta u to se doda rastvor od 7,4 ml (0,12 mol) metiljodida u 22 ml dimetilformamida i meša dalje 10 minuta pri sobnoj temperaturi. Posle koncentrovanja pod sniženim pritiskom ostatak se raspodeli izmedju ledene vode i etilacetata. Organska faza, koja je osušena iznad natri jum-sulfata , upari se i preostalo ulje hromatografiše na koloni od 300 g silikagela uz primenu metilenhlorida/ /etilacetata (1:1) kao sredstva za eluiranje. Prve eluirane homogene frakcije, nakon uparavanja i trljanja sa etrom, daju 4,5 g (45%) benzil-estra |4-|1 -(1-metil-2-benzimidazolil)-etil|-benzilj-metil|-metilkarbamidne kiseline, t.t. 131-133°, u obliku kristalnog praha. Sledeče eluirane frakcije daju (posle koncentrovanja) 3,5 g (37%) benzil-estra |4-|(1-metil-2-benzimidazolil)-metil|-benzil|-metilkarbamidne kiseline, u obliku gustog ulja.At 15.20 ° for 20 minutes a solution of 7.4 ml (0.12 mol) of methyl iodide in 22 ml of dimethylformamide was added and stirred for 10 minutes at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase, which was dried over sodium sulfate, was evaporated and the residual oil was chromatographed on a column of 300 g of silica gel using methylene chloride / ethyl acetate (1: 1) as the elution agent. The first eluted homogeneous fractions, after evaporation and rubbing with ether, afforded 4.5 g (45%) of benzyl ester | 4- | 1- (1-methyl-2-benzimidazolyl) -ethyl | -benzyl-methyl | -methylcarbamic acid , tt 131-133 °, in the form of crystalline powder. The following eluted fractions gave (after concentration) 3.5 g (37%) of benzyl ester | 4- | (1-methyl-2-benzimidazolyl) -methyl | -benzyl | -methylcarbamidic acid, as a thick oil.
56.56.
3,5 g benzil-estra ]4-](1-metil-2-benzimidazolil)-metil|-benzil|-metilkarbamidne kiseline rastvori se u 600 ml meta nola i hidrogenizuje na sobnoj temperaturi i pod normalnim pritiskom uz prisustvo 1 g 5%-nog paladijuma na aktivnom uglju kao katalizatora. Sirov proizvod, koji je izolovan na uobičajen način, hromatografiše se na 150 g silikagela uz, primenu smeše metanol/koncentrovan amonijumhidroksid (100:1) kao sredstva za eluiranje. Dobiva se 2,1 g (90%)3.5 g of benzyl ester] 4 - [(1-methyl-2-benzimidazolyl) -methyl] -benzyl | -methylcarbamic acid are dissolved in 600 ml of methanol and hydrogenated at room temperature and under normal pressure in the presence of 1 g 5 % palladium on activated carbon as catalyst. The crude product, which was isolated in the usual way, was chromatographed on 150 g of silica gel, using a methanol / concentrated ammonium hydroxide (100: 1) mixture as the eluting agent. 2.1 g (90%) are obtained
2-|4-|(metilamino)metil|-benzil|-1-metilbenzimidazola u obliku gustog ulja.2- | 4- | (methylamino) methyl | -benzyl | -1-methylbenzimidazole as a thick oil.
Primer 32Example 32
Na način analogan onom koji je opisan u primeru 29 reaguje se |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonat prvo sa 2-|1-|4-|(me tilamino)-metil|-fenil|-etil|-1-metilbenzimidazolom a potom sa anhidridom metoksisricetne kiseline. Dobiva se J1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||4-|1-(1-metil -2-benzimidazolil )-etil|-benzil|-metilamino,—etil|—2— -naftilmetoksiacetat-dihidrohlorid (smeša dva epimera), t.t. 95-105°, u obliku skoro bezbojnog kristalnog praha.In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate first with 2- | 1- | 4- | (methylamino) -methyl | -phenyl | -ethyl | -1-methylbenzimidazole and then with methoxyacetic acid anhydride. J1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- | 1- (1-methyl -2-benzimidazolyl) -ethyl | benzyl | -methylamino, -ethyl | -2-naphthylmethoxyacetate-dihydrochloride (mixture of two epimers), m.p. 95-105 °, in the form of an almost colorless crystalline powder.
2-|1-|4-|(metilamino)-metil|-fenil|-etil|-1-metilbenzimidazol, koji je upotrebljen kao polazna materija, dobiven je na analogan način kao što je opisano u primeru 31 hidrogenizacijom benzil-estra |4-|1-(1-metil-2-benzimidazolil)-etil|-benzil|-metilkarbamidne kiseline.2- | 1- | 4- | (methylamino) -methyl | -phenyl | -ethyl | -1-methylbenzimidazole, which was used as starting material, was obtained in an analogous manner as described in Example 31 by hydrogenation of benzyl ester | 4- | 1- (1-methyl-2-benzimidazolyl) -ethyl | -benzyl | -methylcarbamic acid.
57.57.
Primer 33Example 33
Na način analogan onom koji je opisan u primeru 29 reaguje se |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonat prvo se 2-|4-/(metilamino ) -metil | -benzil | -benzimidazolom a potom sa anhidridom metoksisircetne kiseline. Dobiva se 11 S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||4-|(2-benzimidazolil)-metil|-benzil|-metilamino|-etil|-2-naftilmetoksiaeetat-dihidrohlorid, t.t. 146-150°, u obliku skoro bezbojnog kristalnog praha .In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl reacts | p-toluenesulfonate is first 2- | 4 - [(methylamino) -methyl] -benzyl | -benzimidazole followed by methoxyacetic acid anhydride. 11 S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- | (2-benzimidazolyl) -methyl | -benzyl | -methylamino | -ethyl | -2-naphthylmethoxyethyl acetate dihydrochloride, mp 146-150 °, in the form of an almost colorless crystalline powder.
2-|4-|(Metilamino)metil|-benzil|-benzimidazol, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:2- | 4- | (Methylamino) methyl | -benzyl | -benzimidazole, which was used as starting material, was obtained as follows:
6,6 g (0,028 mol) 2-(p-cijanbenzil)-benzimidazola zagreva se 2 sata uz refluksovanje u 110 ml 1 N vodenog rastvora natrijum-hidroksida. Dobiveni rastvor se ohledi i ekstrahuje dva puta sa po 100 ml etilacetata i dva puta sa po 100 ml metilenhlorida. Vodena faza se podesi na Ph 6,0 pomoču 2 N sone kiseline i ostavi da stoji 30 minuta u ledenom kupatilu. Talog se procedi na nuču i ispira etrom. Dobiva se6.6 g (0.028 mol) of 2- (p-cyanbenzyl) -benzimidazole are heated for 2 hours with reflux in 110 ml of 1 N aqueous sodium hydroxide solution. The resulting solution was cooled and extracted twice with 100 ml of ethyl acetate and twice with 100 ml of methylene chloride each. The aqueous phase was adjusted to Ph 6.0 with 2 N hydrochloric acid and allowed to stand for 30 minutes in an ice bath. The precipitate was filtered off with suction and washed with ether. It does
5,8 g (83%) p|(2-benzimidazolil)-metil|-benzoeve kiseline, t.t. 265-267°, u obliku bezbojnog praha.5.8 g (83%) of p (2-benzimidazolyl) -methyl-benzoic acid, m.p. 265-267 °, in the form of a colorless powder.
U rastvor od 5,0 g (0,020'mol) p-|(2-benzimidazolil)-metil|-benzoeve kiseline i 2,8 ml (0,020 mol) trietilamina u 68 ml dimetilformamida pri -5° ukapa se 2,8 ml izobutiletra hlormravlje kiseline. Posle mešanja u toku 30 minuta pri 0-5° doda se 1,32 g (0,020 mol) metilamina-hidrohlorida i 2,8 ml (0,020 mol) trietilamina u 28 ml dimetilformamida i 1,4 ml vode. Pusti se da temperatura reakcione smeše poraste na sobnu temperaturu i meša još 18 sati. Posle koncentrovanja pod sniženim pritiskom ostatak se hromatografiše na 400 gTo a solution of 5.0 g (0.020'mol) of p- (2-benzimidazolyl) -methyl-benzoic acid and 2.8 ml (0.020 mol) of triethylamine in 68 ml of dimethylformamide at -5 ° was added dropwise 2.8 ml. isobutylether of hydrochloric acid. After stirring for 30 minutes at 0-5 °, 1.32 g (0.020 mol) of methylamine hydrochloride and 2.8 ml (0.020 mol) of triethylamine in 28 ml of dimethylformamide and 1.4 ml of water were added. Allow the reaction mixture to rise to room temperature and stir for an additional 18 hours. After concentration under reduced pressure, the residue is chromatographed at 400 g
58.58.
silikagela uz primenu smeše hloroform/etanol (4:1) kao sredstva za eluiranje. Uniformne frakcije daju 2,0 g (38%) N-metil-p|(2-benzimidazolil)-metil|-benzamida, t.t.of silica gel using chloroform / ethanol (4: 1) as the elution agent. Uniform fractions afforded 2.0 g (38%) of N-methyl-p | (2-benzimidazolyl) -methyl-benzamide, m.p.
250-255° (raspadanje), u obliku bezbojnog praha.250-255 ° (decomposition), in the form of a colorless powder.
U mešanu suspenziju od 0,58 g (0,0075 mol) litijumaluminijum-hidrida u 40 ml tetrahidrofurana u porcijama se ukapava 1,98 g (0,0075 mol) N-metil-p-|(2-benzimidazolil)-metil|-benzimida i zatira zagreva 4 sata uz refluksovanje. Pri 5-10° ukapavanjem se doda 1,5 ml vode zatim 2,3 ml 10%-nog vodenog rastvora kalijum-hidroksida i zatim ponovo 1,5 ml vode. Talog se odfiltrira i tri puta prokuva sa po 20 ml tetrahidrofurana. Spojeni filtrati se ispiraju zasičenim vodenim rastvorom natrijum-hlorida, osuše iznad natrijum-sulfata i koncentruju do suva pod sniženim pritiskom. Ostatak se hromatografiše na 150 g silikagela uz primenu smeše metanol/konc. amonijum-hidroksid (100:1) kao sredstva za eluiranje. Dobiva se 1,58 g (84%) 2-|4-|(metilamino)-metil(-benzil|-benzimidazola, t.t. 157-160°, u obliku bezbojnog kristalnog praha1.98 g (0.0075 mol) of N-methyl-p- | (2-benzimidazolyl) -methyl are added dropwise to a stirred suspension of 0.58 g (0.0075 mol) of lithium aluminum hydride in 40 ml of tetrahydrofuran. -benzimide and repression is heated for 4 hours with reflux. At 5-10 ° C, 1.5 ml of water is added dropwise followed by 2.3 ml of a 10% aqueous potassium hydroxide solution and then again 1.5 ml of water. The precipitate was filtered off and boiled three times with 20 ml of tetrahydrofuran each. The combined filtrates were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed on 150 g of silica gel using a methanol / conc mixture. ammonium hydroxide (100: 1) as eluting agents. 1.58 g (84%) of 2- | 4- | (methylamino) -methyl (-benzyl | -benzimidazole, mp 157-160 °) are obtained as a colorless crystalline powder
Primer 34Example 34
Na način analogan onom koji je opisan u primeru 29 reaguje se 11S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil)-etil-p-toluolsulfonat prvo sa 2-|trans-4-|(metilamino)-metil|-cikloheksil|-benzimidazolom a potom sa anhidridom metoksisircetne kiseline. Dobiva se |1S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-|metil|-trans-4-(2-benzimidazolil)-cikloheksil|-metilamino|-etil-2-naftilmetoksiacetat-dihidrohlorid, t.t. 150-153°, u obliku bezbojnog kristalnog praha.In the manner analogous to that described in Example 29, 11S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl-p is reacted -toluenesulfonate first with 2- | trans-4- (methylamino) -methyl | -cyclohexyl | -benzimidazole and then with methoxyacetic acid anhydride. 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- | methyl | -trans-4- (2-benzimidazolyl) -cyclohexyl | -methylamino | -ethyl-2-naphthylmethoxyacetate dihydrochloride, mp 150-153 °, in the form of a colorless crystalline powder.
59.59.
2-|trans-4-|(Metilamino)-metil|-cikloheksil|-benzimidazol, koji je upotrebljen kao polazna materija dobiven je na sledeči način:2- | trans-4- | (Methylamino) -methyl | -cyclohexyl | -benzimidazole, which was used as starting material was obtained as follows:
Rastvor od 20,3 g (0,07 mol) trans-4-(N-benziloksikarbonil-aminometil)-cikloheksankarbonske kiseline u 380 ml dimetilformamida, pod argonom se pri 15-20°, pomeša sa 0,21 mol natrijum-hidrida (9,35 g suspenzije koja sadrži 55% natrijum-hidrida u mineralnom ulju) i nakon toga 30 minuta meša dalje još 30 minuta pri sobnoj temperaturi. U to se doda pri 25-30° u toku perioda od 20 minuta rastvor odA solution of 20.3 g (0.07 mol) of trans-4- (N-benzyloxycarbonyl-aminomethyl) -cyclohexanecarboxylic acid in 380 ml of dimethylformamide, under argon at 15-20 °, was mixed with 0.21 mol of sodium hydride ( 9.35 g of a suspension containing 55% sodium hydride in mineral oil) and then stirred for a further 30 minutes at room temperature for 30 minutes. To this was added at 25-30 ° for a period of 20 minutes a solution of
17.5 ml (0,28 mol) metiljodida u 20 ml dimetilformamida i meša dalje još 1 sat pri 70°. posle koncentrovanja pod sniženim pritiskom ostatak se raspodeli izmedju vode i metilenhlorida. Organska faza se koncentruje i preostalo ulje rastvori u smeši od 350 ml etanola i 350 ml 1 N vodenog ras tvora natrijum-hidroksida. Zagreva se 1 sat uz refluksovanje, ohladi i sipa u 700 ml ledene vode. Rastvor se ekstrahuje etilacetatom i zatim zakiseli sa 6 N sonom kiselinom. Oslobodjena kiselina se ekstrahuje metilenhloridom, i ovaj ekstrakt osuši iznad natrijum-sulfata i upari. Preostalo ulje se hromatografiše na 270 g silikagela uz primenu smeše metilenhlorid/etilacetat (4:1) kao sredstva za eluiranje. Dobiva se 13,6 g (64%) trans-4-(N-benziloksikarbonil-N-metil-aminometil)-cikloheksankarbonske kiseline u obliku gustog ulja.17.5 ml (0.28 mol) of methyl iodide in 20 ml of dimethylformamide and stirred for an additional 1 hour at 70 °. after concentration under reduced pressure, the residue is partitioned between water and methylene chloride. The organic phase was concentrated and the remaining oil was dissolved in a mixture of 350 ml of ethanol and 350 ml of 1 N aqueous sodium hydroxide solution. It is refluxed for 1 hour, cooled and poured into 700 ml of ice water. The solution was extracted with ethyl acetate and then acidified with 6 N hydrochloric acid. The liberated acid is extracted with methylene chloride, and this extract is dried over sodium sulfate and evaporated. The remaining oil was chromatographed on 270 g of silica gel using methylene chloride / ethyl acetate (4: 1) as eluant. 13.6 g (64%) of trans-4- (N-benzyloxycarbonyl-N-methyl-aminomethyl) -cyclohexanecarboxylic acid are obtained as a thick oil.
Rastvor od 13,6 g (0,044 mol) trans-4-(N-benziloksikarbonil-N-metil-aminometil)-cikloheksankarbonske kiseline iA solution of 13.6 g (0.044 mol) of trans-4- (N-benzyloxycarbonyl-N-methyl-aminomethyl) -cyclohexanecarboxylic acid and
9.5 ml (0,068 mol) trietilamina u 110 ml tetrahidrofurana pomeša se pri -15° u toku 30 minuta sa 6,5 ml (0,049 mol) izobutil-estra hlormravlje kiseline. Potom se pri -15° u9.5 ml (0.068 mol) of triethylamine in 110 ml of tetrahydrofuran is mixed at -15 ° for 30 minutes with 6.5 ml (0.049 mol) of hydrochloric acid isobutyl ester. Then at -15 ° u
60.60.
toku 45 minuta ukapava rastvor od 5,8 g (0,053 mol) o-fenilendiamida. Meša se 1 sat pri sobnoj temperaturi i ostavi da stoji 20 sati. Posle koncentrovanja pod sniženim pritiskom ostatak se raspodeli izmedju vode i etilacetatat i organ ska faza ispira 5%-nim vodenim rastvorom natrijum-bikarbonata, zatim zasičenim vodenim rastvorom natrijum-hlorida i najzad vodom. Rastvor koji je osušen iznad magnezijum-sulfata upari se i trlja sa etrom. Dobiven čvrst proizvod (9,3 g) se rastvori u 200 ml toluola, u to doda 3 g p-toluolsulfonske kiseline i zagreva 4 sata uz refluksovanje uz primenu odvajača vode. Ratsvor se ohladi, ispira sa 2 N vodenim rastvorom natrijum-karbonata i zasičenim vodenim rastvorom natrijum-hlorida, osuši iznad magnezijum-sulfata i upari do suva pod sniženim pritiskom. Čvrst ostatak se prekristališe iz etilacetata. Dobiva se 5,6 g benzil-estra ||trans-4-(2-benzimidazolil)-cikloheksil|-metil|-metilkarbamidne kiseline, t.t. 146-148°, u obliku bezbojnog kristalnog praha. Nakon hromatografije na koloni silikagela (250 g) uz primenu smeše etilacetat/metilenhlorid (9:1) kao sredstva za eluiranje matični lug daje još 1,1 g ovog istog proizvoda, t.t. 146-148°. Ukupni prinos: 6,7 g (40%).A solution of 5.8 g (0.053 mol) of o-phenylenediamide was added dropwise over 45 minutes. Stirred for 1 hour at room temperature and allowed to stand for 20 hours. After concentration under reduced pressure, the residue is partitioned between water and ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution and finally with water. The solution which was dried over magnesium sulfate was evaporated and rubbed with ether. The resulting solid product (9.3 g) was dissolved in 200 ml of toluene, 3 g of p-toluenesulfonic acid were added thereto and refluxed for 4 hours using a water separator. The solution was cooled, washed with 2 N aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The solid residue was recrystallized from ethyl acetate. 5.6 g of benzyl ester of trans-4- (2-benzimidazolyl) -cyclohexyl-methyl-methyl-carbamic acid are obtained, m.p. 146-148 °, in the form of a colorless crystalline powder. After chromatography on a silica gel column (250 g), using ethyl acetate / methylene chloride (9: 1) as eluent, the mother liquor gave another 1.1 g of this same product, m.p. 146-148 °. Total Yield: 6.7 g (40%).
6,0 g Benzil-estra ||trans-4-(2-benzimidazolil)-cikloheksil|-metil|-metilkarbamidne kiseline rastvori se u 600 ml etanola i hidrogenizuje pri sobnoj temperaturi i pod normalnim pritiskom uz dodatak 1 g 5%-nog paladijuma na aktivnom uglju kao katalizatora. Sirov proizvod koji je izolovan na uobičajen način prekristališe se iz smeše metilenhlorid/etar. Dobiva se 3,0 g (78%) 2-|trans-4-)(metilamino)-metil|-cikloheksil|-benimidazola, t.t. 232-235°, u obliku bezbojnog kristalnog praha.6.0 g of benzyl ester Trans-4- (2-benzimidazolyl) -cyclohexyl | -methyl | -methylcarbamic acid are dissolved in 600 ml of ethanol and hydrogenated at room temperature and under normal pressure with the addition of 1 g of 5% palladium on activated carbon as catalyst. The crude product which was isolated in the usual way was recrystallized from methylene chloride / ether. 3.0 g (78%) of 2- (trans-4 -) (methylamino) -methyl-cyclohexyl-benzimidazole are obtained, m.p. 232-235 °, in the form of a colorless crystalline powder.
..
Primer 35Example 35
Na način analogan onom koji je opisan u primeru 29 negauje se |1S,2S|-2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1 -izopnopil-2-naftil)-etil-p-toluolsulfonat prvo sa 2-|trans-4-|(metilamino)-metil|-cikloheksil|-1-metilbenzimidazola a zatim sa anhidridom metoksisircetne kiseline. Dobiva se 11S,2S|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-(metil-|trans-4-(1-metil-2-benzimidazolil)-cikloheksil|-metilamino |-etil|-2-naftilmetoksiacetat-dihidrohlonid, t.t. 148-152° u obliku bezbojnog kristalnog praha.In a manner analogous to that described in Example 29, | 1S, 2S | -2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl) -ethyl, p-toluenesulfonate first with 2- | trans-4- (methylamino) -methyl | -cyclohexyl | -1-methylbenzimidazole and then with methoxyacetic acid anhydride. 11S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- (methyl- | trans-4- (1-methyl-2-benzimidazolyl) -cyclohexyl is obtained | -methylamino | -ethyl | -2-naphthylmethoxyacetate dihydrochloride, mp 148-152 ° as a colorless crystalline powder.
2-|trans-4-|(Metilamino)-metil|-cikloheksil|-1-metilbenzimidazol, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:2- | trans-4- | (Methylamino) -methyl | -cyclohexyl | -1-methylbenzimidazole, which was used as starting material, was obtained as follows:
Rastvor od 7,2 g (0,019 mol) benzil-estna ||trans-4-(2-benzimidazolil)-cikloheksil|-metil|-metilkarbamidne kiseline u 160 ml dimetilformamida pod argonom i pni temperaturi od 15-20° pomeša se sa 0,023 mol natnijum-hidrida (1,0 g 55%-ne disperzije u mineralnom ulju) i nakon toga dalje meša 30 minuta pni sobnoj temperaturi. U toku 15 minuta pri 15-20° u to se doda rastvor od 2,3 ml (0,038 mol) metiljodida u 10 ml dimetilformamida i meša 3 sata pri sobnoj temperaturi. Posle koncentrovanja pod sniženim pritiskom ostatak se naspodeli izmedju ledene vode i etilacetata. Organska faza osušena iznad natrijum-sulfata upari se i čvrsti ostatak prekristališe iz smeše etilacetat/etar.A solution of 7.2 g (0.019 mol) of benzyl ester trans-4- (2-benzimidazolyl) -cyclohexyl-methyl-carbamidic acid in 160 ml of dimethylformamide under argon and at a temperature of 15-20 ° C was mixed with 0.023 mol of sodium hydride (1.0 g of a 55% dispersion in mineral oil) is then stirred for 30 minutes at room temperature. A solution of 2.3 ml (0.038 mol) of methyl iodide in 10 ml of dimethylformamide was added over 15 minutes at 15-20 ° C and stirred for 3 hours at room temperature. After concentration under reduced pressure, the residue was partitioned between ice water and ethyl acetate. The organic phase dried over sodium sulfate was evaporated and the solid was recrystallized from ethyl acetate / ether.
Dobiva se 5,9 g (79%) benzil-estra ||tnans-4-(1-metil-2-benzimidazolil)-cikloheksil|-metil|-metilkarbamidne kiseline, t.t. 141 —142°, u obliku bezbojnog kristalnog praha.5.9 g (79%) of benzyl ester of tans-4- (1-methyl-2-benzimidazolyl) -cyclohexyl-methyl-methylcarbamic acid are obtained, m.p. 141-142 °, in the form of a colorless crystalline powder.
5,9 g benzil-estna ||trans-4-(1-raetil-2-benzimidazolil)62.5.9 g of benzyl ester trans-4- (1-raethyl-2-benzimidazolyl) 62.
-cikloheksil|-metil|-metilkarbamidne kiseline rastvori se u 600 ml etanola i hidrogenizuje pri sobnoj temperaturi i pod normalnim pritiskom uz dodatak 1 g 55%-nog paladijuma na aktivnom uglju kao katalizatora. Sirov proizvod, koji je izolovan na uobičajen način, hromatografiše se na 250 g silikagela uz primenu prvo smeše metilenhlorid/metanol (1:1) a potom smeše metanol/konc. amonijum-hidroksid (100:1) kao sredstva za eluiranje. Dobiva se 3,3 g (85%) 2-|trans-4-|(metilamino)-metil|-cikloheksil|-1-metilbenzimidazola, u obliku gustog ulja.-cyclohexyl | -methyl | -methylcarbamidic acid is dissolved in 600 ml of ethanol and hydrogenated at room temperature and under normal pressure with the addition of 1 g of 55% palladium on activated carbon as catalyst. The crude product, which was isolated in the usual way, was chromatographed on 250 g of silica gel using first a mixture of methylene chloride / methanol (1: 1) and then a mixture of methanol / conc. ammonium hydroxide (100: 1) as eluting agents. 3.3 g (85%) of 2- | trans-4- (methylamino) -methyl-cyclohexyl-1-methylbenzimidazole are obtained as a thick oil.
Primer 36Example 36
Na način analogan onom koji je opisan u primeru 7, reakcijom 2-(6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1</-izopropil-2-6-naftil)-etil |-p-toluolsulfonata i 3,4-dihidro-4-metil-1-|4-(metilamino)-butil|-2H-1,4-benzodiazepin-2,5-(1H)-diona, dobiven je 1-|4-||2-||lS,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil|-etil|-metilamino |-butil|-3,4-dihidro-4-metil-2H-1,4-benzodiazepin-2,5-(1H)-dion, MS: M+ 509.In a manner analogous to that described in Example 7, by reaction of 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1 H -isopropyl-2-6-naphthyl) -ethyl | -p of toluenesulfonate and 3,4-dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzodiazepine-2,5- (1H) -dione to give 1- | 4- || 2- || 1S, 2S | -6-Fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -3,4 -Dihydro-4-methyl-2H-1,4-benzodiazepine-2,5- (1H) -dione, MS: M + 509.
Na analogan način ovom što je gore opisano, polazeci od 2-( 6-fluor-1,2,3,4-tetrahidro-2-hidroksi- 1o6-izopropil-2$-naftil)-etil|-p-toluolsulfonata 1 (S)-6-hlor-1,2,3,11a-tetrahidro-5H-pirolo|2,1 —c|11,4|benzodiazepin-5,11-(10H)-diona dobiven je (S)-6-hlor-10-|4-||2-||1S,2S|-6-fluor-1,2,3,4-tetrahidro-2-hidroksi-1-izopropil-2-naftil| -etil|-metilamino|-butil|-1,2,3,11a-tetrahidro-5H-pirolo|2,1-c| |1,4|-benzodiazepin-5,11-(10H)-dion, MS: M+ 570.In an analogous manner to that described above, starting from 2- (6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-6-isopropyl-2-naphthyl) -ethyl | -p-toluenesulfonate 1 ( S) -6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo | 2,1 -c | 11,4 | benzodiazepine-5,11- (10H) -dione gave (S) -6- chlor-10- | 4- || 2- || 1S, 2S | -6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl | -ethyl | -methylamino | -butyl | -1,2,3,11a-tetrahydro-5H-pyrrolo | 2,1-c | 1,4-benzodiazepine-5,11- (10H) -dione, MS: M + 570.
3,4-Dihidro-4-metil-1-|4-(metilamino)-butil|-2H-1,4-benzo63.3,4-Dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzo63.
diazepin-2,5-(lH)-dion, koji je upotrebljen kao polazna materija, dobiven je na sledeči način:diazepine-2,5- (1H) -dione, which was used as starting material, was obtained as follows:
g (40 mmol) 4-|1-(benziloksi-N-metilformamido|-buterne kiseline rastvori se u 200 ml etanola i tretira sa 1 ml konc. sumporne kiseline. Potom se reakciona smeša zagreva 4 sata uz refluksovanje i zatim upari rastvarač. Zatim se reakcioni proizvod ekstrahuje metilenhloridom/zasicenim rastvorom natrijum-bikarbonata. Posle sušenja i uparavanja ekstrakta dobiva se 9,24 g smedjeg ulja, koje se rastvori u 200 ml tetrahidrofurana, pomeša sa 7,1 ml 10 M bormetilsulfidnog kompleksa i zagreva 2 sata uz refluksovanje. Potom se ostavi reakciona smeša da stoji preko noči pri sobnoj temperaturi i zatim polako u nju doda toliko metanola da se više ne odigrava razvijanje gasa. Na ovaj način se dobiva bistar rastvor koji se upari. Dobiven ostatak (8,09 g) hromatografiše se sa smešom (1:1) etilacetata i heksana na silikagelu, pri čemu se dobiva 6,82 g (72%) benzil-(4-hidroksibutil)-metilkarbamata, koji se direktno upotrebljava za sledeči stupanj.g (40 mmol) of 4- | 1- (benzyloxy-N-methylformamido | -butaric acid was dissolved in 200 ml of ethanol and treated with 1 ml of sulfuric acid. The reaction mixture was then refluxed for 4 hours and then the solvent was evaporated. The reaction product was then extracted with methylene chloride / saturated sodium bicarbonate solution, after drying and evaporating the extract to give 9.24 g of a brown oil, which was dissolved in 200 ml of tetrahydrofuran, mixed with 7.1 ml of a 10 M bormethylsulfide complex and heated for 2 hours. The reaction mixture was then allowed to stand at room temperature overnight and then slowly added enough methanol to it to prevent gas evolution, thus obtaining a clear evaporating solution. The residue obtained (8.09 g) was chromatographed. with a mixture of (1: 1) ethyl acetate and hexane on silica gel, yielding 6.82 g (72%) of benzyl- (4-hydroxybutyl) -methylcarbamate, which is used directly for the next step.
6,75 g (28,4 mmol) gore dobivenog karbamata i 10,0 g (52,5 mmol) hlorida p-toluolsulfonske kiseline rastvori se pri 0° u 25 ml piridina. Posle stajanja u toku 6 sati doda se led i ekstrahuje etrom. Etarski ekstrakt se ispira sa 4 N sonom kiselinom, zasičenim vodenim rastvorom natrijum-bikarbonata i zasičenim vodenim rastvorom kuhinjske soli, osuši i upari. Na taj način se dobiva 9,38 g (84%) žuckastog ulja benzil-metil-|4-|(p-toluolsulfonil)-oksi|-butil |-karbamata, koji se dalje direktno preradjuje.6.75 g (28.4 mmol) of the carbamate obtained above and 10.0 g (52.5 mmol) of p-toluenesulfonic acid chloride were dissolved at 0 ° in 25 ml of pyridine. After standing for 6 hours, ice was added and extracted with ether. The ether extract was washed with 4 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous brine, dried and evaporated. In this way 9.38 g (84%) of a yellowish oil of benzyl-methyl- | 4- ((p-toluenesulfonyl) -oxy] -butyl | -carbamate are obtained, which is further directly processed.
1,9 g (10 mmol) 4-Metil-3H-1,4-benzodiazepin-2,5-(1H,4H)64.1.9 g (10 mmol) of 4-Methyl-3H-1,4-benzodiazepine-2,5- (1H, 4H) 64.
-diona rastvori se u 20 ml dimetilformamida i doda u suspenziju od 430 mg (10 mmol) 55%-nog natrijum-hidrida u 50 ml dimetilformamida. Posle pola sata nakon dodavanja doda se rastvor od 3,91 g (10 mmol) benzilmetil-|4-|(p-toluolsulfonil)-oksi|-butil|-karbamata u 20 ml dimetilformamida i celokupna reakeiona smeša meša 20 sati pri sobnoj temperaturi. Zatim se rastvarač upari pod sniženim pritiskom pri 50° i zatim doda voda. Posle dvostrukog ekstrahovanja metilenhloridom rastvarač se ponovo upari i ostatak hromatografiše na silikagelu uz primenu smeše (20:1) metilenhlorida i metanola kao sredstva za eluiranje, pri čemu se dobiva 3,92 g (95,8%) benzil metil-|4-(2,3,4,5-tetrahidro-4-metil-2,5-diokso-1H-1,4-benzodiazepin-1-il)-butil|-karbamata,-dione was dissolved in 20 ml of dimethylformamide and added to a suspension of 430 mg (10 mmol) of 55% sodium hydride in 50 ml of dimethylformamide. After half an hour after the addition, a solution of 3.91 g (10 mmol) of benzylmethyl- [4- ((p-toluenesulfonyl) -oxy] -butyl] -carbamate in 20 ml of dimethylformamide was added and the whole reaction mixture was stirred for 20 hours at room temperature. . The solvent was then evaporated under reduced pressure at 50 ° and then water was added. After double extraction with methylene chloride, the solvent was re-evaporated and the residue was chromatographed on silica gel using a mixture of (20: 1) methylene chloride and methanol as the eluting agent to give 3.92 g (95.8%) of benzyl methyl- | 4- ( 2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-yl) -butyl | -carbamate,
MS: M+ 409.MS: M + 409.
Gore dobiveni karbamat, analogno načinu koji je opisan u primeru 7 (u poslednjem stavu), prevodi se u željeniThe carbamate obtained above, analogous to the method described in Example 7 (in the last paragraph), is translated into the desired
3,4-dihidro-4-metil-1-|4-(metilamino)-butil|— 2H—1,4-benzodiazepin-2,5-(1H)-dion, koji se direktno upotnebljava u sledečem stupnju.3,4-Dihydro-4-methyl-1- | 4- (methylamino) -butyl | -2H-1,4-benzodiazepine-2,5- (1H) -dione, which is directly used in the next step.
Na način analogan ovom koji je gore opisan, polazeci od benzil metil-|4-|(p-toluolsulfonil)-oksi|-butil|-karbamata, reakcijom sa odgovarajucim benzodiazepinom, dobiva se (S)-6-hlor-1,2,3-11a-tetrahidro-10-|4-(metilamino)-butil|-5H-pirolo|2,1 —c[|1,4|-benzodiazepin-5,11-(1 OH)-dion.In a manner analogous to the one described above, starting with benzyl methyl- | 4- | (p-toluenesulfonyl) -oxy | -butyl | -carbamate, reaction with the corresponding benzodiazepine yields (S) -6-chloro-1,2 , 3-11a-tetrahydro-10- | 4- (methylamino) -butyl | -5H-pyrrolo | 2,1-c [| 1,4 | -benzodiazepine-5,11- (1 OH) -dione.
Primer 37Example 37
Na način analogan onom koji je opisan u primeru 8, metoksiacetilovanjem odgovarajučih hidroksi-derivata, dobivena su sledeča jedinjenja:In a manner analogous to that described in Example 8, by methoxyacetylation of the corresponding hydroxy derivatives, the following compounds were obtained:
65.65.
|1S,2S j-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-|2-||4-(2,3,4,5-tetrahidro-4-metil-2,5-diokso-1H-1,4-benzodiazepin-1-il)-butil|-metilamino|-etil|-2-naftilmetoksiacetat-hidrohlorid, W|gg = +28,2° (c = 0,5%; metanol);| 1S, 2S 1-6-Fluoro-1,2,3,4-tetrahydro-1-isopropyl-2- | 2- || 4- (2,3,4,5-tetrahydro-4-methyl-2, 5-dioxo-1H-1,4-benzodiazepin-1-yl) -butyl | -methylamino | -ethyl | -2-naphthylmethoxyacetate hydrochloride, W | gg = + 28.2 ° (c = 0.5%; methanol );
|1S,2S|-2-|2-l|4-|(S)-6-hlor-2,3,11,11a-tetrahidro-5,11-diokso-1H-pirolo|2,1-c||1,4|benzodiazepin-10(5H) -il|butil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2-naftilmetoksiacetat-hidrohlorid, l^lfgg = +215,2° (c = 0,5%; metanol).| 1S, 2S | -2- | 2-l | 4- | (S) -6-chloro-2,3,11,11a-tetrahydro-5,11-dioxo-1H-pyrrolo | 2,1-c | 1,4 | benzodiazepine-10 (5H) -yl | butyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthylmethoxyacetate hydrochloride, 1 H -gg = + 215.2 ° (c = 0.5%; methanol).
Primer AExample A
TabletePills
SastavComposition
1) 2-|2-||3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro-1<Z-izopro-1) 2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-
težina tabletatablet weight
300 mg300 mg
66.66.
Postupak dobivanjaObtaining process
Snažno se pomešaju 1-3- Smeša se zatim ovlaži vodenim rast vorom 4 i potom mesi (gnječi), i dobivena masa granulira, suši i proseje. Granulat se pomeša sa 5-7 i presuje u tablete pogodne veličine.Stir vigorously 1-3- The mixture is then moistened with aqueous growth with aroma 4 and then flesh-kneaded, and the resulting mass is granulated, dried and aerated. The granulate is mixed with 5-7 and pressed into suitable sized tablets.
Primer BExample B
TabletePills
SastavComposition
1) 2-|2-Jl3-(2-benzimidazolil)-propil)-metilamino | -etil | -6-fluor-1,2,3,4-tetrahidro- 1o6-izopropil -2«0-naf ti Ime toksiace ta t-hidrohlo-1) 2- | 2-R 3- (2-benzimidazolyl) -propyl) -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-6-isopropyl-2-naphthyl Name Toxicity to t-Hydrochlo-
Postupak dobivanjaObtaining process
Snažno se pomešaju 1-3. Smeša se zatim ovlaži vodenim rast vorom 4 i mesi, i dobivena masa granulira, osuši i proseje Granulat se pomeša sa 5-8 i presuje u tablete pogodne veli čine.Strongly mix 1-3. The mixture was then moistened with aqueous growth with aroma 4 and meat, and the resulting mass was granulated, dried and average The granulate was mixed with 5-8 and pressed into tablets of suitable size.
67.67.
Primer CExample C
TabletePills
SastavComposition
1) 2—|2—||3-(2-benzimidazolil)-propil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro1 <*i-izopr opil-2o6-naf ti Imet oksiacetat-1) 2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl It has oxyacetate-
Postupak dobivanja:Obtaining procedure:
Snažno se pomešaju 1-3. Smeša se zatim ovlaži vodenim rastvorom 4 i mesi, i dobivena masa potom granulira, suši i proseje. Granulat se pomeša sa 5-7 i presuje u tablete pogodne veličine.Strongly mix 1-3. The mixture was then moistened with an aqueous solution of 4 and meat, and the resulting mass was granulated, dried and aerated. The granulate is mixed with 5-7 and pressed into suitable sized tablets.
68.68.
Primer DExample D
KapsuleCapsules
SastavComposition
1) 2—|2—|l3-(2-benzimidazolil)-propil|-metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro- 1oZ-izopr opil-2«C-naftilmet oksiace tat -hidrohlorid 75 mg1) 2- | 2- {3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-10Z-isopropyl-2-C-naphthylmethyl oxy tat hydrochloride 75 mg
2) kristalni mlečni šecer 100 mg2) crystalline milk sugar 100 mg
3) beli kukuruzni škrob 20 mg3) white corn starch 20 mg
4) talk 9 mg4) talc 9 mg
5) magnezijum-stearat 1 mg težina kapsule 205 mg5) magnesium stearate 1 mg capsule weight 205 mg
Postupak dobivanjaObtaining process
Aktivna materija se snažno pomeša sa mlečnim šečerom. U ovu smešu se zatim umešaju kukuruzni škrob, talk i magnezijumstearat i dobivena smeša puni u kapsule pogodne veličine.The active substance is strongly mixed with milk sugar. Cornstarch, talc and magnesium stearate are then mixed into this mixture and the resulting mixture is filled into suitable size capsules.
Primer EExample E
KapsuleCapsules
SastavComposition
2-|2-||3-(2-benzimidazolil)-propil | -metilamino|-etil|-6-fluor-1,2,3,4-tetrahidro- 1<Z-izopropil— 2<Z-naftil69.2- | 2- || 3- (2-Benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1H-isopropyl-2H-naphthyl69.
Postupak dobivanjaObtaining process
Aktivna materija se snažno pomeša sa celulozom. U ovu smešu se zatim umešaju natrijumkarboksimetilceluloza, talk i magnezijum-stearat, i dobivena smeša potom puni u kapsule pogodne veličine.The active substance is strongly mixed with cellulose. Sodium carboxymethylcellulose, talc and magnesium stearate are then mixed into this mixture and the resulting mixture is then filled into suitable size capsules.
Primer FExample F
Rastvor za injekcije mlInjection solution ml
- | 2- | |3-(2-benzimidazolil)-propil|-metilamino|-etil | -6-fluor -1 ,2,3,4-te t rahi dro-1<Z-i zopropil-2<Z-naftilmetoksiacetat-hidrohlorid 8 mg kristalni natrijum-hlorid (Čist) 8,5 mg voda za injekcione rastvore do 1 ml- | 2- | 3- (2-benzimidazolyl) -propyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-th light dro-1 <Z-i zopropyl-2 <Z-naphthylmethoxyacetate hydrochloride 8 mg crystalline sodium chloride (Pure) 8.5 mg water for solution for injection up to 1 ml
70.70.
Primer GExample G
Ako se radi prema postupcima koji su opisani u primerima A-F, polazeci od sledečih, takodje pogodnih jedinjenja i njihovih farmaceutskih primenljivih soli, mogu se dobiti tablete, kapsule i injekcionl preparati:If used according to the methods described in Examples A-F, starting from the following, also suitable compounds and their pharmaceutically acceptable salts, tablets, capsules and injectable preparations can be obtained:
|1S,2S|-2-|2-||3-(2-benzilimidazolil)-propil)-metil amino|-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil -2-naftiImetoksiacetat-hidrohlorid;| 1S, 2S | -2- | 2- || 3- (2-Benzylimidazolyl) -propyl) -methyl amino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2 -Naphthymethoxyacetate hydrochloride;
/1S,2S|-2-|2-||5-(2-benztiazolil)-pentil|-metilamino |-etil|-6-fluor-1,2,3,4-tetrahidro-1-izopropil -2-naf ti Ime toksiace tat -hi dr ohlori d .[1S, 2S | -2- | 2- || 5- (2-Benzthiazolyl) -pentyl | -methylamino | -ethyl | -6-fluoro-1,2,3,4-tetrahydro-1-isopropyl -2- naf ti Name toxiace tat -hi dr ohlori d.
Patentna prijava P.229/88Patent application P.229 / 88
-2-ARAN 4029/6 3987-2-ARAN 4029/6 3987
PODNOSIOCA PRIJAVE O NAJBOLJEM NAČINU ZA PRIVREDNUAPPLICANTS ON THE BEST WAY FOR A BUSINESS
UPOTREBU PRIJAVLJENOG PRONALASKAUSING THE RECORDED FINDING
Najbolji način za privrednu upotrebu pronalaska, prema znanju podnosioca prijave, sastoji se u sledečem postupku:The best way for the commercial use of the invention, to the applicant's knowledge, is as follows:
6,2 g (14,6 mmol) /IS,2S/-2-/2-/2-/ /3-(2-benzimidazolil)propil/-metilamino/-etil/-6-fluor-1,2,3,4-tetrahidro-1-izopropil-2naftalinola rastvori se u 50 ml hloroforma. U to se doda, pri 0°C,6.2 g (14.6 mmol) [IS, 2S] -2- (2- [2- [3- (2-benzimidazolyl) propyl] -methylamino] -ethyl] -6-fluoro-1,2, 3,4-Tetrahydro-1-isopropyl-2naphthalenol was dissolved in 50 ml of chloroform. To this is added, at 0 ° C,
2,5 ml (15 mmol) N-etildiizopropilamina i 5 ml (55 mmol) metoksiacetilhlorida. Reakciona smeša se meša preko noči pri sobnoj temperaturi i zatim pomeša sa 100 ml 1 N rastvora natrijumhidroksida u vodi, i ekstrahuje hloroformom. Posle sušenja iznad magnezijumsulfata i otparavanja rastvarača ostatak se hromatografiše na silikagelu uz primenu smeše (6:1) metilenhlorida i metanola kao sredstva za eluiranje. Pri torne se dobiva 6,2 g ulja koje se rastvori u 30 ml' etanola i pomeša sa 15 ml etra zasičenog hlorovodonikom. Nakon toga se reakciona smeša upari i ostatak kristališe iz smeše etanola i dietiletra. Pri torne se dobiva 5,4 g (65%) /IS,2S/-2-/2-/ /3-(2-benzimidazolil)-propil/-metilamino/-etil/-6fluor-1,2,3,4-tetrahidro-l-izopropil-2-naftilmetoksiacetata— dihidrohlorida, t.t. 128°C.2.5 ml (15 mmol) of N-ethyldiisopropylamine and 5 ml (55 mmol) of methoxyacetyl chloride. The reaction mixture was stirred overnight at room temperature and then mixed with 100 ml of 1 N sodium hydroxide solution in water, and extracted with chloroform. After drying over magnesium sulfate and evaporating the solvent, the residue is chromatographed on silica gel using a mixture of (6: 1) methylene chloride and methanol as the elution agent. The crude was obtained 6.2 g of an oil which was dissolved in 30 ml of ethanol and mixed with 15 ml of hydrochloric acid saturated ether. The reaction mixture was then evaporated and the residue was crystallized from a mixture of ethanol and diethyl ether. 5.4 g (65%) of IS, 2S (-2- [2- [3- (2-benzimidazolyl) -propyl] -methylamino] -ethyl] -6-fluoro-1,2,3 are obtained. 4-Tetrahydro-1-isopropyl-2-naphthylmethoxyacetate-dihydrochloride, m.p. 128 ° C.
F.HOFFMANN-LA ROCHE & CO Aktiengesellschaft,F.HOFFMANN-LA ROCHE & CO. Aktiengesellschaft,
Zastupnici:2/20/2005
Λ 'Λ '
Dr Czk>6<>Dr Czk> 6 <>
Epa κί· m ;Epa κί · m;
('enep;('enep;
seorp>seorp>
Claims (10)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
YU22988A YU46780B (en) | 1988-02-05 | 1988-02-05 | PROCESS FOR PREPARATION OF TETRAHYDRONAFTHALINE DERIVATIVES |
Publications (1)
Publication Number | Publication Date |
---|---|
SI8810229A8 true SI8810229A8 (en) | 1996-12-31 |
Family
ID=25548959
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI8810229A SI8810229A8 (en) | 1988-02-05 | 1988-02-05 | Process for preparation of tetrahydronaphtalene derivatives |
Country Status (2)
Country | Link |
---|---|
SI (1) | SI8810229A8 (en) |
YU (1) | YU46780B (en) |
-
1988
- 1988-02-05 YU YU22988A patent/YU46780B/en unknown
- 1988-02-05 SI SI8810229A patent/SI8810229A8/en unknown
Also Published As
Publication number | Publication date |
---|---|
YU22988A (en) | 1990-04-30 |
YU46780B (en) | 1994-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0268148B1 (en) | Tetrahydronaphthalene derivatives and medicaments containing them | |
JP3301024B2 (en) | Glycine receptor antagonist and use thereof | |
JPS61236778A (en) | 5-substituted pyrazolo(4,3-d)pyrimidin-7-one | |
JP4323803B2 (en) | Substituted 2-anilinobenzimidazoles and their use as NHE inhibitors | |
JPS63502031A (en) | Hydroxy and aminothiozolyl-benzodiazinone compounds, cardiotonic compositions containing the same, and uses thereof | |
TW202023560A (en) | Thyroid hormone receptor beta agonist compounds | |
JP2001502326A (en) | .BETA.-Sulfonamidohydroxamic acids as inhibitors of matrix metalloproteinases and TACE | |
SU1486060A3 (en) | Method of producing derivatives of 2-indolinone | |
CN102652135A (en) | Azocyclic inhibitors of fatty acid amide hydrolase | |
DE60316821T2 (en) | AMINOBENZOTHIAZONE COMPOUNDS WITH NOS-HEMMENDER EFFECT | |
JPS61126025A (en) | Medicinal composition containing azabicyclooctane-carboxylicacid | |
US5547970A (en) | Use of leflunomide for inhibiting tumor necrosis factor alpha | |
CN106518766A (en) | Novel diaryl urea compounds, and preparation method and medical applications thereof | |
BR112016005606B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, AND USES OF A COMPOUND | |
CA2564980A1 (en) | Novel beta agonists, method for producing the same and their use as drugs | |
JP3084302B2 (en) | Novel benzimidazole derivatives, their preparation, their use as medicaments and pharmaceutical compositions containing them | |
JPH11513376A (en) | Selective β ▲ 3 ▼ -Adrenergic agonist | |
JPS6322082A (en) | 1-(hydroxystiryl)-5h-2, 3-benzodiazepine derivative and its production, drug containing said derivative and its production | |
US4600710A (en) | β-Adrenergic receptor agonist alkylaminoalkyl pyridinemethanol derivatives | |
HUT70174A (en) | New 3-phenyl-sulphonyl-3,7-diazabicyclo [3.3.1] nonane compounds and pharmaceutical compounds containing the same | |
SI8810229A8 (en) | Process for preparation of tetrahydronaphtalene derivatives | |
TW411333B (en) | 2-substituted benzimidazole derivatives | |
CN104788423B (en) | A kind of new cystic fibrosis transmembrane conductance regulator inhibitor | |
CA2627090A1 (en) | Benzimidazole derivatives for use as beta-3 receptor agonists | |
EP3833354B1 (en) | Tissue transglutaminase modulators for medicinal use |