SK281972B6 - Process for preparing alkylsubstituted cyclene derivatives - Google Patents
Process for preparing alkylsubstituted cyclene derivatives Download PDFInfo
- Publication number
- SK281972B6 SK281972B6 SK1172-98A SK117298A SK281972B6 SK 281972 B6 SK281972 B6 SK 281972B6 SK 117298 A SK117298 A SK 117298A SK 281972 B6 SK281972 B6 SK 281972B6
- Authority
- SK
- Slovakia
- Prior art keywords
- derivative
- benzylaziridine
- cyclene
- derivatives
- substituted
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Vynález sa týka spôsobu prípravy 1,4,7,10-tetraazacyklododekánu (cyklén) ajeho derivátov.The present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane (cyclene) and derivatives thereof.
Doterajší stav technikyBACKGROUND OF THE INVENTION
1,4,7,10-Tetraazacyklododekán (cyklén) má široké využitie nielen ako makrocyklický ligand, ale tiež ako edukt pri príprave rôznych, kov obsahujúcich, farmaceutický používaných komplexov, ako napríklad gadobutrol (ΓΝΝ), gadobenat (INN) alebo gadoteridol (INN).1,4,7,10-Tetraazacyclododecane (cyclene) is widely used not only as a macrocyclic ligand, but also as a starting material in the preparation of various metal-containing, pharmaceutically used complexes such as gadobutrol (ΓΝΝ), gadobenate (INN) or gadoteridol (INN) ).
1,4,7,10-Tetraazacyklododekán je spravidla pripravovaný niekoľkostupňovou syntézou cyklickou kondenzáciou dvoch lineárnych východiskových produktov (J. Chem. Rev. 1989, 929, The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, U.K. 1989).1,4,7,10-Tetraazacyclododecane is generally prepared by a multi-step synthesis by cyclic condensation of two linear starting products (J. Chem. Rev. 1989, 929, The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, U.K. 1989).
Nevýhodou tejto metódy je vysoký počet stupňov syntézy, nízky celkový výťažok, ako i vysoké množstvo z toho vzniknutých anorganických solí, ktoré vzniknú počas syntézy.The disadvantage of this method is the high number of synthesis steps, the low overall yield, and the high amount of the inorganic salts formed therefrom, which are formed during the synthesis.
Podstatne jednoduchší spôsob prípravy 1,4,7,10-tetraazacyklododekánu predstavuje cyklotetramerizácia N-substituovaných aziridinov. V odbornej literatúre sú opísané rôzne varianty tejto reakcie. Pritom je najprv z benzyletanolamínu pripravený zodpovedajúci N-substituovaný aziridín a potom izolovaný. Aziridín je potom v prítomnosti Bronstedových kyselín, ako napríklad p-TsOH (J. Heterocyclic Chem. 1968, 305), alebo Lewisových kyselín, ako napríklad trialkylhliník (US patent 3,828,023), alebo BF3-eterát (Tetrahedron Letters, 1970, 1367), v malom výťažku cyklotetramerizovaný. Hoci je tento spôsob vykonateľný iba na prípravu malých množstiev (menšie ako 5 g), tvorí, ešte 16 rokov po prvej publikácii, stav techniky (WO 95/31444).A substantially simpler process for the preparation of 1,4,7,10-tetraazacyclododecane is cyclotetramerization of N-substituted aziridines. Various variants of this reaction have been described in the literature. The corresponding N-substituted aziridine is first prepared from benzylethanolamine and then isolated. Aziridine is then in the presence of Bronsted acids, such as p-TsOH (J. Heterocyclic Chem. 1968, 305), or Lewis acids, such as trialkyl aluminum (US patent 3,828,023), or BF 3 -etherate (Tetrahedron Letters, 1970, 1367) , in small yield cyclotetramerized. Although this method is feasible only for the preparation of small quantities (less than 5 g), it still constitutes, prior to 16 years after the first publication, a prior art (WO 95/31444).
Všetky doteraz opísané cyklotetramerizačné reakcie vyžadujú použitie čistých aziridinov, ktoré, ako je známe, majú silné mutagénne a rakovinotvomé účinky (Roth, Giftliste, VCH Weinheim). Z tohto dôvodu je cyklomerizácia aziridinov, ktorá sa zdá ako najľahší spôsob prípravyAll the cyclotetramerization reactions described so far require the use of pure aziridines which, as is known, have potent mutagenic and carcinogenic effects (Roth, Giftliste, VCH Weinheim). For this reason, the cycllomeration of aziridines is the easiest method of preparation
1,4,7,10-tetraazacyklododekánu, bez praktického využitia v technickom meradle. Z toho vyplýva veľký záujem o technicky uskutočniteľný, životné prostredie málo znečisťujúci a podstatne bezpečnejší spôsob prípravy 1,4,7,10-tetraazacyklododekánu.1,4,7,10-tetraazacyclododecane, without practical use on a technical scale. This implies great interest in a technically feasible, environmentally less polluting and substantially safer process for preparing 1,4,7,10-tetraazacyclododecane.
Podstata vynálezuSUMMARY OF THE INVENTION
Úlohou predloženého vynálezu je vypracovať praktikovateľný spôsob prípravy 1,4,7,10-tetraazacyklododekánu v technickom meradle, ktorý prekoná uvedené nevýhody a hlavne sa vyhne ľudskému ohrozeniu mutagénnymi a rakovinotvomými aziridínovými medzistupňami.It is an object of the present invention to provide a practicable process for the preparation of 1,4,7,10-tetraazacyclododecane on an industrial scale that overcomes these disadvantages and, in particular, avoids human threats to mutagenic and cancer-forming aziridine intermediate steps.
Táto úloha je vyriešená spôsobom podľa vynálezu. Ide pritom o spôsob prípravy derivátov cyklénu cyklotetramerizáciou derivátov benzylaziridínu, ktorého podstata spočíva v tom, že sa derivát benzylaziridínu pripraví in situ a bez izolácie sa tetramerizuje pridaním silnej kyseliny k derivátu tetrabenzylcyklénu a nakoniec sa benzylové skupiny oddelia hydrogenáciou.This object is achieved by the method according to the invention. It is a process for the preparation of cyclene derivatives by cyclotetramerization of benzylaziridine derivatives, which is characterized in that the benzylaziridine derivative is prepared in situ and, without isolation, tetramerized by addition of a strong acid to the tetrabenzylcyclene derivative and finally the benzyl groups are separated by hydrogenation.
V rámci predloženého vynálezu výraz derivát cyklénu zahrnuje nielen 1,4,7,10-tetraazacyklododekán, ale tiež také deriváty, pri ktorých etylénové mostíky majú alkylové sub stituenty. Takto zahrnuje pojem derivát cyklénu napríklad zlúčeniny [2S-(2a,5a,8a,lla)]-2,5,8,ll-tetrametyl- 1,4,7,10-tetraazacyklododekán a [2S-(2a,5a,8a,lla)]-2,5,8,11 -tetraetyl-1,4,7,1O-tetraazacyklododekán.In the present invention, the term cyclene derivative includes not only 1,4,7,10-tetraazacyclododecane, but also such derivatives in which ethylene bridges have alkyl substituents. Thus, the term cyclene derivative includes, for example, [2S- (2a, 5a, 8a, 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane and [2S- (2a, 5a, 8a) (11a)] - 2,5,8,11-Tetraethyl-1,4,7,1O-tetraazacyclododecane.
Analogickým spôsobom výraz derivát tetrabenzylcyklénu v rámci predloženého vynálezu zahrnuje ako 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyklododekán, tak tiež deriváty, pri ktorých etylénové mostíky majú alkylové substituenty. Výraz derivát benzylaziridínu v rámci predloženého vynálezu zahrnuje benzylaziridín, ako i také deriváty, pri ktorých aziridínový kruh má alkylové substituenty. Takto zahrnuje pojem derivát benzylaziridínu napríklad tiež zlúčeninu (S)-l-benzyl-2-metyl-aziridín a (S)-l-benzyl-2-etyl-aziridín.Analogously, the term tetrabenzylcyclene derivative within the scope of the present invention includes both 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane and derivatives wherein ethylene bridges have alkyl substituents. The term benzylaziridine derivative within the scope of the present invention includes benzylaziridine as well as derivatives wherein the aziridine ring has alkyl substituents. Thus, the term benzylaziridine derivative also includes, for example, the compound (S) -1-benzyl-2-methyl-aziridine and (S) -1-benzyl-2-ethyl-aziridine.
Vynález teda zahrnuje spôsob prípravy prípadne substituovaných derivátov 1,4,7,10-tetraazacyklododekánu tetramerizáciou zodpovedajúcich eduktov. Výhodne zahrnuje vynález prípravu 1,4,7,10-tetraazacyklododekánu.Thus, the invention includes a process for preparing optionally substituted 1,4,7,10-tetraazacyclododecane derivatives by tetramerization of the corresponding starting materials. Preferably, the invention includes the preparation of 1,4,7,10-tetraazacyclododecane.
Výhodná forma vyhotovenia vychádza z ľahko dostupného benzyletanolamínu, ktorý sa zahrievaním (80 - 150 °C, výhodne 90 - 110 °C) s 1 až 1,4 ekvivalentmi koncentrovanej kyseliny sírovej v organickom rozpúšťadle (napríklad toluén, cyklohexán, heptán atď., koncentrácie: 10 - 20 %) a azeotropnou destiláciou pritom vzniknutej vody premení na zodpovedajúci ester kyseliny sírovej. Reakcia pritom trvá 2 až 10 hodín. Ester sa potom zahrieva s 2 až 5 ekvivalentmi vodných lúhov (napríklad NaOH, KOH) a pritom vzniknutý benzylaziridín sa v druhej reakčnej nádobe, ktorý s prvou tvorí uzatvorený systém, neustále azeotropne oddestilováva s vodou. Tým vzniknutá vodná benzylaziridínová emulzia sa môže, po zriedení organickým rozpúšťadlom (napríklad etanolom, metanolom, THF), neustálym pridávaním aspoň 0,25 až 0,4 mól (výhodne 0,25 až 0,35 mól) silnej kyseliny na mól benzylaziridínu (to znamená ekvivalentné množstvo kyseliny vzhľadom na produkt) prekvapujúco úplne premeniť na tetrabenzylcyklén.A preferred embodiment starts from readily available benzylethanolamine, which is heated (80-150 ° C, preferably 90-110 ° C) with 1 to 1.4 equivalents of concentrated sulfuric acid in an organic solvent (e.g., toluene, cyclohexane, heptane, etc., concentration). 10 - 20%) and the azeotropic distillation of the resulting water into the corresponding sulfuric acid ester. The reaction takes 2 to 10 hours. The ester is then heated with 2 to 5 equivalents of aqueous lyes (e.g. NaOH, KOH) and the benzylaziridine formed therefrom is continuously azeotroped with water in a second reaction vessel, which first forms a closed system. The resulting aqueous benzylaziridine emulsion can, after dilution with an organic solvent (e.g., ethanol, methanol, THF), by continuously adding at least 0.25 to 0.4 mol (preferably 0.25 to 0.35 mol) of strong acid per mole of benzylaziridine (i.e. surprisingly, the equivalent amount of acid relative to the product) is completely converted to tetrabenzylcyclene.
Ako organické rozpúšťadlo možno použiť napríklad etanol, metanol alebo tetrahydrofúrán (THF). Ako silná kyselina môže byť použitá para-toluénsulfónová kyselina (p-TsOH), metánsulfónová kyselina (MsOH), kyselina sírová alebo BF3-etcrát.As the organic solvent, for example, ethanol, methanol or tetrahydrofuran (THF) can be used. As a strong acid, para-toluenesulfonic acid (p-TsOH), methanesulfonic acid (MsOH), sulfuric acid or BF 3 -acetate can be used.
Produkt sa získa po alkalizácii (0,2 až 0,5 ekvivalentov bázy, napríklad NaOH, KOH) reakčnej zmesi kryštalizáciou v polárnych rozpúšťadlách (napríklad THF, etanol, acetón, izopropanol, dietyléter, etylacetát, fúrán, dioxán, voda alebo ich zmesi) a hneď potom sa hydrogenuje pomocou katalyzátora (Pd/C, množstvo 5 až 20 %, vzťahujúc na derivát tetrabenzylcyklénu, tlak 0,1 až 2,0 MPa). Po filtrácii katalyzátora a oddestilovaní rozpúšťadla sa získa 1,4,7,10tetraazacyklododekán s výťažkom 45 až 60 % celkového teoretického výťažku.The product is obtained after alkalization (0.2 to 0.5 equivalents of base, e.g. NaOH, KOH) of the reaction mixture by crystallization in polar solvents (e.g. THF, ethanol, acetone, isopropanol, diethyl ether, ethyl acetate, furan, dioxane, water or mixtures thereof) and immediately thereafter hydrogenated by means of a catalyst (Pd / C, 5 to 20%, based on the tetrabenzylcyclene derivative, at a pressure of 0.1 to 2.0 MPa). After filtering the catalyst and distilling off the solvent, 1,4,7,10-tetraazacyclododecane is obtained in a yield of 45 to 60% of the total theoretical yield.
Analogicky k tejto syntéze sa môže tiež použiť alkylom substituovaný benzyletanolamín, napríklad L-2-benzylaminopropanol alebo L-2-benzylamino-butanol, na získanie derivátov cyklénu, majúcich rozvetvenie na etylénových mostíkoch. Vo výhodnom spôsobe vykonania tejto syntézy sa analogicky k opísanému procesu získa (S)-l-benzyl-2-metyl-aziridin z L-2-benzylaminopropanolu a bez izolácie sa tetramerizáciou premení na [2S-(2α,5α,8α,1 la)]-2,5,8,ll-tetrametyl-l,4,7,10-tetraaza(benzyl)-1,4,7,10-tetraazacyklododekán, z ktorého sa hydrogenáciou získa [2S-(2a,5a,8a,l la)]-2,5,8,l 1-tetrametyl-1,4,7,10-tetraazacyklododekán.By analogy to this synthesis, an alkyl-substituted benzylethanolamine, for example L-2-benzylaminopropanol or L-2-benzylamino-butanol, can also be used to obtain cyclene derivatives having branching on ethylene bridges. In a preferred method of carrying out this synthesis, (S) -1-benzyl-2-methyl-aziridine is obtained from L-2-benzylaminopropanol analogously to the described process and, without isolation, is converted to [2S- (2α, 5α, 8α, 1α) without tetramerization. -] - 2,5,8,11-tetramethyl-1,4,7,10-tetraaza (benzyl) -1,4,7,10-tetraazacyclododecane, from which hydrogenation gives [2S- (2a, 5a, 8a) 11a)] - 2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane.
Spôsob cyklotetramerizácie derivátov benzylaziridínu podľa vynálezu sa od spôsobov podľa známeho stavu techniky odlišuje tým, že nie je nutná žiadna izolácia aziridínuThe cyclotetramerization of the benzylaziridine derivatives of the invention differs from the prior art methods in that no isolation of aziridine is necessary
SK 281972 Β6 v čistej forme. Opísaný spôsob umožňuje takto vykonanie postupu v uzatvorenom systéme, a tým i vylúčenie ohrozenia človeka a životného prostredia rakovinotvomými aziridínmi.SK 281972 Β6 in pure form. The method thus described allows the process to be carried out in a closed system, thereby avoiding the risk to humans and the environment from cancer-forming aziridines.
Na rozdiel od známeho spôsobu cyklotetramerizácie benzylaziridínov podľa známeho stavu techniky, sa namiesto katalytického množstva kyseliny (p-TsOH, MsOH, kyselina sírová, BF3-eterát alebo trialkylhliník) používa stechiometrické množstvo (0,25 až 0,35 mól, vzťahujúc na jeden mól benzylaziridínu).In contrast to the known prior art cyclotetramerization of benzylaziridines, a stoichiometric amount (0.25 to 0.35 mol, relative to one acid) is used instead of a catalytic amount of acid (p-TsOH, MsOH, sulfuric acid, BF 3 -etherate or trialkyl aluminum). mole of benzylaziridine).
Pri pokusoch vykonať známy spôsob vo zväčšenom meradle a získať tak touto cestou väčšie množstvo 1,4,7,10-tetraazacyklododekánu bolo použitím katalytických množstiev p-TsOH pri premene in situ vzniknutej benzylaziridínovej emulzie dosiahnutých iba 12 až 25 % teoretického výťažku. V súčasnosti sa prekvapujúco zistilo, že stálym pridávaním od 0,25 do 0,35 ekvivalentov p-TsOH (vzťahujúc na benzylaziridín) pri teplote 60 až 78 °C počas 6 až 9 hodín k azeotropne oddestilovanej benzylaziridínovej emulzii, bol výťažok 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyklododekánu zlepšený na 60 až 65 % teoretického výťažku.In attempts to carry out the known process on a larger scale and thus to obtain a larger amount of 1,4,7,10-tetraazacyclododecane, catalytic amounts of p-TsOH in the conversion of the in situ benzylaziridine emulsion produced achieved only 12 to 25% of the theoretical yield. It has now surprisingly been found that by continuously adding from 0.25 to 0.35 equivalents of p-TsOH (relative to benzylaziridine) at 60-78 ° C for 6-9 hours to the azeotropically distilled benzylaziridine emulsion, the yield was 1.4, 7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane improved to 60-65% of the theoretical yield.
Ďalšie výhody tohto spôsobu sú vo vysokom celkovom výťažku a v malých množstvách odpadu (síran sodný pri príprave aziridinu a toluén pri hydrogenácii) v porovnaní so známymi spôsobmi.Further advantages of this process are in high overall yield and in small amounts of waste (sodium sulfate in the preparation of aziridine and toluene in hydrogenation) over the known methods.
zmes zmieša s roztokom 9,5 g NaOH v 20 ml vody. Takto vzniknutý produkt sa filtruje a rekryštalizuje zo 600 ml 2 : 1 zmesi etanol - THF. Takto získaný tetrabenzylcyklén (55,7 g) sa rozpustí v 500 ml izopropanolu a hydrogenuje s 10 g Pd/C (10 %) pri 80 °C a tlaku H2 2,0 MPa. Po odfiltrovaní katalyzátora sa reakčná zmes zahustí a produkt sa rekryštalizuje z toluénu. Takto sa získa 15,9 g (výťažok 58 %) cyklénu vo forme bezfarebných kryštálov. Teplota topenia 111 až 113 °C.the mixture was mixed with a solution of 9.5 g NaOH in 20 ml water. The product thus formed is filtered and recrystallized from 600 ml of a 2: 1 mixture of ethanol-THF. The tetrabenzylcyclene (55.7 g) thus obtained was dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd / C (10%) at 80 ° C and a H 2 pressure of 20 bar. After filtering off the catalyst, the reaction mixture is concentrated and the product is recrystallized from toluene. 15.9 g (58% yield) of cyclene are thus obtained as colorless crystals. Mp 111-113 ° C.
Príklad 3Example 3
Ako v príklade 1, len tetramerizácia sa vykonáva s 0,33 ekvivalentmi kyseliny metánsulfónovej. Výťažok 52 % cyklénu. Teplota topenia 110 až 112 °C.As in Example 1, only tetramerization was performed with 0.33 equivalents of methanesulfonic acid. Yield 52% cyclene. Mp 110-112 ° C.
Tabuľka 1 Porovnávací prehľad reakčných podmienok a výťažkov syntézy cyklénu cyklotetramerizáciou benzylaziridínuTable 1 Comparative overview of reaction conditions and yields of cyclic synthesis by cyclotetramerization of benzylaziridine
* Lit. 1: J. Heterocyclic Chem. 1968,305* Lit. 1: J. Heterocyclic Chem. 1968.305
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Nasledujúce príklady majú za úlohu objasniť predmet vynálezu bez toho, aby ho týmto spôsobom obmedzovali.The following examples are intended to illustrate the invention without limiting it.
Príklad 1Example 1
K roztoku s 95 ml benzyletanolamínu v 690 ml toluénu sa pridá 53 ml koncentrovanej kyseliny sírovej. Vzniknutá suspenzia sa zahrieva dve hodiny do varu. Voda (14 ml), ktorá pri tom vznikne, sa oddelí pomocou odlučovača vody. Po ochladení na 20 °C sa reakčná zmes zmieša s 1 300 ml vody, 10 minút sa mieša a organická fáza sa oddelí. Hneď potom sa vodná fáza plynulo pridá k roztoku 92,2 g NaOH v 95 ml vody pripraveného v druhej reakčnej nádobe. Reakčná zmes sa privedie zahrievaním do varu. Destilačným mostíkom sa 880 g vodnej N-benzylaziridínovej emulzie oddestiluje do tretej reakčnej nádoby. Emulzia sa zmieša s 880 ml etanolu a zahrieva sa na 60 °C. K nej sa pridáva dávkovacím čerpadlom v priebehu 8 hodín roztok 38,0 g p-TsOH v 19 ml vody. Po skončenom pridávaní sa zmes dve hodiny zahrieva na teplotu spätného toku. Hneď potom sa reakčná zmes zmieša s roztokom 12,0 g NaOH v 20 ml vody. Takto vzniknutý produkt sa filtruje a rekryštalizuje sa zo 600 ml zmesi 2 : 1 etanol - THF. Takto získaný tetrabenzylcyklén (53 g) sa rozpustí v 500 ml izopropanolu a hydrogenuje sa s 10 g Pd/C (10 %) pri 80 °C a tlaku H2 2,0 MPa. Po odfiltrovaní katalyzátora sa reakčný roztok zahustí a produkt sa rekryštalizuje z toluénu. Takto sa získa 15,9 g (výťažok 55 %) cyklénu, vo forme bezfarebných kryštálov. Teplota topenia 110 až 112 °C.To a solution of 95 ml of benzylethanolamine in 690 ml of toluene is added 53 ml of concentrated sulfuric acid. The resulting suspension was heated to boiling for two hours. The resulting water (14 ml) was separated using a water separator. After cooling to 20 ° C, the reaction mixture is treated with 1300 ml of water, stirred for 10 minutes and the organic phase is separated. Immediately thereafter, the aqueous phase is added continuously to a solution of 92.2 g of NaOH in 95 ml of water prepared in the second reaction vessel. The reaction mixture is brought to reflux by heating. By distillation, 880 g of an aqueous N-benzylaziridine emulsion was distilled off into a third reaction vessel. The emulsion is mixed with 880 ml of ethanol and heated to 60 ° C. A solution of 38.0 g of p-TsOH in 19 ml of water was added via metering pump over 8 hours. After the addition was complete, the mixture was heated to reflux for two hours. Immediately thereafter, the reaction mixture was treated with a solution of 12.0 g of NaOH in 20 ml of water. The product thus formed is filtered and recrystallized from 600 ml of a 2: 1 mixture of ethanol - THF. The tetrabenzylcyclene (53 g) thus obtained was dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd / C (10%) at 80 ° C and a H 2 pressure of 20 bar. After filtering off the catalyst, the reaction solution is concentrated and the product is recrystallized from toluene. 15.9 g (yield 55%) of cyclene are thus obtained in the form of colorless crystals. Mp 110-112 ° C.
Príklad 2 ml benzyletanolamínu sa pripraví tak, ako je opísané v príklade 1, pomocou kyseliny sírovej a potom s NaOH. Vzniknutá vodná emulzia N-benzylaziridínu sa zmieša s 2,6 1 etanolu a zahrieva na 50 °C. K tomu sa pridá dávkovacím čerpadlom v priebehu 8 hodín roztok 29,3 g p-TsOH v 15 ml vody. Po skončení pridávania sa zmes dve hodiny zahrieva pri teplote spätného toku. Hneď potom sa reakčnáExample 2 ml of benzylethanolamine was prepared as described in Example 1 with sulfuric acid and then with NaOH. The resulting aqueous N-benzylaziridine emulsion was mixed with 2.6 L of ethanol and heated to 50 ° C. To this was added a solution of 29.3 g of p-TsOH in 15 ml of water over 8 hours via a metering pump. After the addition was complete, the mixture was heated at reflux for two hours. Immediately after the reaction
PATENTOVÉ NÁROKYPATENT CLAIMS
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19608307A DE19608307C1 (en) | 1996-02-26 | 1996-02-26 | Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives |
| PCT/EP1997/000927 WO1997031905A1 (en) | 1996-02-26 | 1997-02-26 | Process for preparing 1,4,7,10-tetraazacyclododecane and its derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SK117298A3 SK117298A3 (en) | 1999-01-11 |
| SK281972B6 true SK281972B6 (en) | 2001-09-11 |
Family
ID=7787168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1172-98A SK281972B6 (en) | 1996-02-26 | 1997-02-26 | Process for preparing alkylsubstituted cyclene derivatives |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0883610B1 (en) |
| JP (2) | JP4745469B2 (en) |
| KR (1) | KR100453668B1 (en) |
| CN (1) | CN1081186C (en) |
| AT (1) | ATE194602T1 (en) |
| AU (1) | AU717720B2 (en) |
| CA (1) | CA2247265C (en) |
| CZ (1) | CZ290128B6 (en) |
| DE (2) | DE19608307C1 (en) |
| DK (1) | DK0883610T3 (en) |
| ES (1) | ES2148837T3 (en) |
| GR (1) | GR3034468T3 (en) |
| HK (1) | HK1018618A1 (en) |
| IL (1) | IL125419A (en) |
| NO (1) | NO310870B1 (en) |
| NZ (1) | NZ331520A (en) |
| PL (1) | PL185927B1 (en) |
| PT (1) | PT883610E (en) |
| SK (1) | SK281972B6 (en) |
| WO (1) | WO1997031905A1 (en) |
| ZA (1) | ZA971672B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19608307C1 (en) * | 1996-02-26 | 1997-08-28 | Schering Ag | Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives |
| CZ2005653A3 (en) * | 2005-10-17 | 2007-01-10 | Azacycles S. R. O. | Process for preparing 1,4,7,10-tetraazacyclododecane and N-acyl derivatives thereof |
| DE102009057274B4 (en) | 2009-12-02 | 2011-09-01 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrol preparation using trioxobicyclo-octane |
| DE102010013833A1 (en) | 2010-03-29 | 2011-09-29 | Bayer Schering Pharma Aktiengesellschaft | Producing gadolinium complex of N-(hydroxymethyl-dihydroxypropyl)-triscarboxymethyl-tetraazacyclododecane useful as magnetic resonance imaging contrast agent, comprises e.g. reacting cyclic compound with dimethylformamide dimethylacetal |
| CN101845112B (en) * | 2010-06-02 | 2011-09-14 | 华东理工大学 | Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles |
| DE102010023105A1 (en) | 2010-06-04 | 2011-12-08 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrol preparation in a one-pot process using DMF-acetal and N-methylimidazole |
| PE20141325A1 (en) | 2011-04-21 | 2014-10-08 | Bayer Ip Gmbh | HIGH PURITY GADOBUTROL PREPARATION |
| KR102067551B1 (en) * | 2018-04-12 | 2020-01-17 | (주) 에프엔지리서치 | Compounds for remediating the contaminated soil or water |
| CN108794417A (en) * | 2018-08-04 | 2018-11-13 | 许昌恒生制药有限公司 | A kind of preparation method of medical diagnosis contrast agent intermediate |
| EP4335461A1 (en) | 2022-09-09 | 2024-03-13 | Bayer AG | Combinations of contrast agents |
| EP4335840A1 (en) | 2022-09-09 | 2024-03-13 | Bayer Aktiengesellschaft | New contrast agents for use in diagnostic imaging |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3828023A (en) * | 1971-09-13 | 1974-08-06 | Dow Chemical Co | Process for preparing cyclic oligomers of n-substituted aziridines |
| US6693190B1 (en) * | 1994-05-11 | 2004-02-17 | Bracco International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
| EP0813523A2 (en) * | 1995-03-10 | 1997-12-29 | Nycomed Salutar, Inc. | Preparation of n-arylmethyl aziridine derivatives, 1,4,7,10-tetraazacyclododecane derivatives obtained therefrom and n-arylmethyl-ethanol-amine sulphonate esters as intermediates |
| DE19608307C1 (en) * | 1996-02-26 | 1997-08-28 | Schering Ag | Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives |
-
1996
- 1996-02-26 DE DE19608307A patent/DE19608307C1/en not_active Expired - Fee Related
-
1997
- 1997-02-26 WO PCT/EP1997/000927 patent/WO1997031905A1/en active IP Right Grant
- 1997-02-26 CA CA002247265A patent/CA2247265C/en not_active Expired - Lifetime
- 1997-02-26 PL PL97328468A patent/PL185927B1/en unknown
- 1997-02-26 EP EP96946361A patent/EP0883610B1/en not_active Expired - Lifetime
- 1997-02-26 CZ CZ19982721A patent/CZ290128B6/en not_active IP Right Cessation
- 1997-02-26 PT PT96946361T patent/PT883610E/en unknown
- 1997-02-26 AU AU18772/97A patent/AU717720B2/en not_active Expired
- 1997-02-26 CN CN97192459A patent/CN1081186C/en not_active Expired - Lifetime
- 1997-02-26 IL IL12541997A patent/IL125419A/en not_active IP Right Cessation
- 1997-02-26 ZA ZA9701672A patent/ZA971672B/en unknown
- 1997-02-26 DE DE59702009T patent/DE59702009D1/en not_active Expired - Lifetime
- 1997-02-26 NZ NZ331520A patent/NZ331520A/en not_active IP Right Cessation
- 1997-02-26 JP JP53059297A patent/JP4745469B2/en not_active Expired - Lifetime
- 1997-02-26 ES ES96946361T patent/ES2148837T3/en not_active Expired - Lifetime
- 1997-02-26 SK SK1172-98A patent/SK281972B6/en not_active IP Right Cessation
- 1997-02-26 DK DK96946361T patent/DK0883610T3/en active
- 1997-02-26 AT AT96946361T patent/ATE194602T1/en active
- 1997-02-26 KR KR10-1998-0706649A patent/KR100453668B1/en not_active IP Right Cessation
-
1998
- 1998-08-25 NO NO19983901A patent/NO310870B1/en not_active IP Right Cessation
-
1999
- 1999-08-27 HK HK99103678A patent/HK1018618A1/en not_active IP Right Cessation
-
2000
- 2000-09-21 GR GR20000402157T patent/GR3034468T3/en unknown
-
2009
- 2009-05-27 JP JP2009127490A patent/JP2009185077A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| PL185927B1 (en) | 2003-09-30 |
| AU1877297A (en) | 1997-09-16 |
| PL328468A1 (en) | 1999-02-01 |
| SK117298A3 (en) | 1999-01-11 |
| JP4745469B2 (en) | 2011-08-10 |
| ES2148837T3 (en) | 2000-10-16 |
| NZ331520A (en) | 2000-01-28 |
| CA2247265C (en) | 2005-06-21 |
| CN1081186C (en) | 2002-03-20 |
| NO983901L (en) | 1998-08-25 |
| IL125419A0 (en) | 1999-03-12 |
| NO310870B1 (en) | 2001-09-10 |
| KR100453668B1 (en) | 2004-12-16 |
| CN1211975A (en) | 1999-03-24 |
| ZA971672B (en) | 1997-08-29 |
| JP2000505467A (en) | 2000-05-09 |
| HK1018618A1 (en) | 1999-12-30 |
| CA2247265A1 (en) | 1997-09-04 |
| ATE194602T1 (en) | 2000-07-15 |
| GR3034468T3 (en) | 2000-12-29 |
| JP2009185077A (en) | 2009-08-20 |
| DK0883610T3 (en) | 2000-09-25 |
| IL125419A (en) | 2001-01-11 |
| CZ290128B6 (en) | 2002-06-12 |
| KR19990087248A (en) | 1999-12-15 |
| DE59702009D1 (en) | 2000-08-17 |
| CZ272198A3 (en) | 2000-02-16 |
| PT883610E (en) | 2000-10-31 |
| NO983901D0 (en) | 1998-08-25 |
| WO1997031905A1 (en) | 1997-09-04 |
| EP0883610A1 (en) | 1998-12-16 |
| DE19608307C1 (en) | 1997-08-28 |
| EP0883610B1 (en) | 2000-07-12 |
| AU717720B2 (en) | 2000-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2009185077A (en) | Method for producing 1,4,7,10-tetraazacyclododecane | |
| IE842652L (en) | 2-mercapto-imidazoles | |
| WO2007144512A2 (en) | Diazeniumdiolate derivatives, method for the preparation thereof, pharmaceutical compositions thereof, and use of same in the fields of hypertension and cardiovascular pathologies | |
| EP0307303A1 (en) | 1-[(2-Pyrimidinyl)-aminoalkyl] piperidines, their preparation and their use in therapy | |
| NO128569B (en) | ||
| NO309567B1 (en) | Process for the preparation of 1,1 '- [1,4-phenylene bis | |
| SU1021342A3 (en) | Process for preparing derivatives of piperidine propyl or their pharmacologically acceptable salts | |
| Simay et al. | Oxidation of aryloxyaminoalcohols with activated dimethylsulfoxide; a novel CN oxidation facilitated by neighboring group effect | |
| EP0252353B1 (en) | 4-benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, preparation and use | |
| NO123529B (en) | PROCEDURE FOR THE PREPARATION OF 1-SUBSTITUTED 5-NITROIMIDAZOLE-2-YLALKYL CARBAMATES | |
| US5744616A (en) | Process for the production of 1,4,7,10-tetraazacyclododecane and its derivatives | |
| FI61880B (en) | EXAMINATION OF N-ARYL SULPHONYL-N '- (3-AZABICYCLOALKYL) -URINAEMNEN | |
| US3201406A (en) | Pyridylcoumarins | |
| AU2018374838B2 (en) | Process for preparing acylated amphetamine derivatives | |
| EP0293814A1 (en) | Mono- and polyhydroxyacyl derivatives of polyoxygenated labdanes, a process for their production and their use as drugs | |
| Fülöp et al. | Synthesis of stereoisomers 2-phenylimino-3, 1-perhydro-benzoxazines and 3, 1-perhydrobenzothiazines | |
| KR940009533B1 (en) | Process for preparing ammoniun salts derived from hexahydrodi-benzodioxane | |
| RU2207340C2 (en) | Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazole-4-one or its pharmaceutically acceptable salts | |
| EP0230127A1 (en) | Synthesis of nizatidine | |
| US3822252A (en) | 3-azetidinols | |
| JPS6213953B2 (en) | ||
| BE571366A (en) | ||
| CH505828A (en) | Heterocyclic cpds C.N.S. active | |
| CS252587B1 (en) | Cis-1-(2-(2,4-dichlorophenyl)-4-(2-alkyl-thio-5-pyrimidinyloxymethyl)-1,3-dioxolane-2-ylmethyl)-1h-imidazoles and their salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC4A | Assignment and transfer of rights |
Owner name: BAYER INTELLECTUAL PROPERTY GMBH, MONHEIM AM R, DE Free format text: FORMER OWNER: BAYER PHARMA AKTIENGESELLSCHAFT, BERLIN, DE Effective date: 20130226 |
|
| TC4A | Change of owner's name |
Owner name: BAYER PHARMA AKTIENGESELLSCHAFT, BERLIN, DE Effective date: 20130502 |
|
| MK4A | Patent expired |
Expiry date: 20170226 |