NO310870B1 - Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives - Google Patents
Process for the preparation of 1,4,7,10-tetraazacyclododecane and its derivatives Download PDFInfo
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- NO310870B1 NO310870B1 NO19983901A NO983901A NO310870B1 NO 310870 B1 NO310870 B1 NO 310870B1 NO 19983901 A NO19983901 A NO 19983901A NO 983901 A NO983901 A NO 983901A NO 310870 B1 NO310870 B1 NO 310870B1
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- Prior art keywords
- derivative
- benzylaziridine
- tetraazacyclododecane
- derivatives
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- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title description 5
- CASDNPHWJOQUQX-UHFFFAOYSA-N 1-benzylaziridine Chemical compound C=1C=CC=CC=1CN1CC1 CASDNPHWJOQUQX-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- RRBYUSWBLVXTQN-UHFFFAOYSA-N tricyclene Chemical compound C12CC3CC2C1(C)C3(C)C RRBYUSWBLVXTQN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- -1 sulfuric acid ester Chemical class 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- JIIXMZQZEAAIJX-UHFFFAOYSA-N 1-amino-3-phenylpropan-2-ol Chemical class NCC(O)CC1=CC=CC=C1 JIIXMZQZEAAIJX-UHFFFAOYSA-N 0.000 claims 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- RRBYUSWBLVXTQN-VZCHMASFSA-N tricyclene Natural products C([C@@H]12)C3C[C@H]1C2(C)C3(C)C RRBYUSWBLVXTQN-VZCHMASFSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- XNIOWJUQPMKCIJ-UHFFFAOYSA-N 2-(benzylamino)ethanol Chemical compound OCCNCC1=CC=CC=C1 XNIOWJUQPMKCIJ-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PJXWCRXOPLGFLX-VIFPVBQESA-N (2s)-2-(benzylamino)propan-1-ol Chemical compound OC[C@H](C)NCC1=CC=CC=C1 PJXWCRXOPLGFLX-VIFPVBQESA-N 0.000 description 2
- MVAWRWBZHDXWSL-UHFFFAOYSA-N 1-benzyl-2-methylaziridine Chemical compound CC1CN1CC1=CC=CC=C1 MVAWRWBZHDXWSL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 150000001541 aziridines Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 2
- MXZROTBGJUUXID-UHFFFAOYSA-K gadobenic acid Chemical compound [H+].[H+].[Gd+3].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)C(C([O-])=O)COCC1=CC=CC=C1 MXZROTBGJUUXID-UHFFFAOYSA-K 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- PGFBTQBTIYCCFJ-NSHDSACASA-N (2s)-2-(benzylamino)butan-1-ol Chemical compound CC[C@@H](CO)NCC1=CC=CC=C1 PGFBTQBTIYCCFJ-NSHDSACASA-N 0.000 description 1
- VXOJKUWHCFFUCO-UHFFFAOYSA-N 1,4,7,10-tetrabenzyl-1,4,7,10-tetrazacyclododecane Chemical compound C=1C=CC=CC=1CN(CCN(CC=1C=CC=CC=1)CCN(CC=1C=CC=CC=1)CC1)CCN1CC1=CC=CC=C1 VXOJKUWHCFFUCO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XRAGHRJPISUIDG-UHFFFAOYSA-N 1-benzyl-2-ethylaziridine Chemical compound CCC1CN1CC1=CC=CC=C1 XRAGHRJPISUIDG-UHFFFAOYSA-N 0.000 description 1
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960003411 gadobutrol Drugs 0.000 description 1
- 229960005451 gadoteridol Drugs 0.000 description 1
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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
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- 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
Teknikkens stand State of the art
1,4,7,10-tetraazasyklododekan (syklen) har stor anvendelse, både som makrosyklisk ligand og som edukt ved fremstillingen av forskjellige metallholdige farmasøytisk benyt-tede komplekser, som f.eks. gadobutrol (INN), gadobenat (INN) eller gadoteridol (INN). 1,4,7,10-tetraazacyclododecane (the cyclen) is widely used, both as a macrocyclic ligand and as an educt in the preparation of various metal-containing pharmaceutically used complexes, such as e.g. gadobutrol (INN), gadobenate (INN) or gadoteridol (INN).
1,4,7,10-tetraazasyklododekan blir som regel fremstilt i en flertrinnssyntese ved syklokondensering av to lineære forløpere (J. Chem. Rev. 1989, 929; The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, U.K. 1989). 1,4,7,10-tetraazacyclododecane is usually prepared in a multistep synthesis by cyclocondensation of two linear precursors (J. Chem. Rev. 1989, 929; The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, U.K. 1989).
Ulempen med denne metode er de store antall trinn, et dårlig totalutbytte, så vel som store avfallsmengder av uor-ganiske salter som oppstår under syntesen. The disadvantage of this method is the large number of steps, a poor overall yield, as well as large waste quantities of inorganic salts that occur during the synthesis.
En i prinsippet tilsynelatende enkel metode for fremstilling av 1,4,7,10-tetraazasyklododekan er syklotetrameriseringen av N-substituerte aziridiner. I litteraturen er det beskrevet forskjellige varianter av denne reaksjon. Ved denne blir det først fra benzyletanolamin fremstilt og isolert det tilsvarende N-substituerte aziridin. Aziridinet blir deretter syklotetramerisert i lavt utbytte i nærvær av Bronsted-syrer som f.eks. p-TsOH (J. Heterocyclic Chem. 1968, 305) eller Lew:is-syrer som trialkylaluminium (US patentskrift 3 828 023) ellfji BF3-eterat (Tatrahedron Letters, 1970. 1367). Skjønt fremgangsmåten for fremstilling av små mengder (< 5 g) er gjennomførbar, er den teknikkens stand selv 16 år etter den første publikasjon (WO 95/31444). An apparently simple method in principle for the preparation of 1,4,7,10-tetraazacyclododecane is the cyclotetramerization of N-substituted aziridines. Different variants of this reaction are described in the literature. With this, the corresponding N-substituted aziridine is first prepared and isolated from benzylethanolamine. The aziridine is then cyclotetramerized in low yield in the presence of Bronsted acids such as p-TsOH (J. Heterocyclic Chem. 1968, 305) or Lewis acids such as trialkylaluminum (US Patent 3,828,023) or BF 3 etherate (Tatrahedron Letters, 1970. 1367). Although the method for the preparation of small quantities (< 5 g) is feasible, the state of the art is still 16 years after the first publication (WO 95/31444).
Alle hittil beskrevne syklotetrameriseringsreaksjoner krever anvendelsen av rene aziridiner, og disse har som be-kjent sterk mutagen og cancerogen virkning (Roth, Giftliste, VCH Weinheim). Av denne grunn har syklotetrameriseringen av aziridiner som synes å være den enkleste metode for fremstilling av 1,4,7,10-tetraazasyklododekan, ingen praktisk anvendelse i industriell skala. Det er derfor stor interesse for en teknisk brukbar, lite miljøbelastende og stort sett ufarlig fremgangsmåte for fremstilling av 1, 4,7,10-tetraazasyklododekan . All cyclotetramerization reactions described so far require the use of pure aziridines, and these are known to have strong mutagenic and carcinogenic effects (Roth, Giftliste, VCH Weinheim). For this reason, the cyclotetramerization of aziridines, which appears to be the simplest method for the preparation of 1,4,7,10-tetraazacyclododecane, has no practical application on an industrial scale. There is therefore great interest in a technically usable, low environmental impact and mostly harmless method for the production of 1, 4,7,10-tetraazacyclododecane.
Oppgaven til foreliggende oppfinnelse er derfor å skaffe til veie en brukbar fremgangsmåte for fremstilling av 1.4.7.10- tetraazasyklododekan i industriell skala slik at man overvinner de ovenfor nevnte ulemper, og særlig å unngå at menneskene utsettes for fare på grunn av mutagene og cancero-gene mellomtrinn. The task of the present invention is therefore to provide a usable method for the production of 1.4.7.10-tetraazacyclododecane on an industrial scale so that the above-mentioned disadvantages are overcome, and in particular to avoid human exposure to danger due to mutagens and carcinogens intermediate stage.
Oppgaven blir løst ved hjelp av fremgangsmåten ifølge oppfinnelsen slik som det fremgår av patentkravene. Det dreier seg derved om en fremgangsmåte for fremstilling av syklenderivater ved syklotetramerisering av benzylaziridinderivater, og som er karakterisert ved at benzylaziridinderivatet oppnås in situ og uten isolering under tilsetning av en sterk syre blir tetramerisert til et tetrabenzyisyklenderivat, og deretter fjernes benzylgruppen ved hydrering. The task is solved with the help of the method according to the invention as it appears from the patent claims. It is thereby a process for the production of cyclene derivatives by cyclotetramerization of benzylaziridine derivatives, and which is characterized by the fact that the benzylaziridine derivative is obtained in situ and, without isolation, is tetramerized to a tetrabenzycycline derivative with the addition of a strong acid, and then the benzyl group is removed by hydration.
Innenfor rammen av foreliggende oppfinnelse skal begrepet syklenderivater omfatte både 1,4,7,10-tetraazasyklododekan, så vel som slike derivater som har alkylsubstituenter på etylenbroene. Således vedrører begrepet syklenderivat f.eks. også forbindelsene [2S-( 2a,5a,8a,lia)]-2,5,8,11-tetra-metyl-1, 4,7,10-tetraazasyklododekan og [2S-(2a,5a,8a,lia)]-2.5.8.11- tetraetyl-l,4,7,10-tetraazasyklododekan. Within the framework of the present invention, the term cyclene derivatives shall include both 1,4,7,10-tetraazacyclododecane, as well as such derivatives which have alkyl substituents on the ethylene bridges. Thus, the term cycle derivative relates to e.g. also the compounds [2S-(2a,5a,8a,lia)]-2,5,8,11-tetra-methyl-1,4,7,10-tetraazacyclododecane and [2S-(2a,5a,8a,lia) ]-2.5.8.11-tetraethyl-1,4,7,10-tetraazacyclododecane.
På analog måte skal begrepet tetrabenzylsykienderi-vater innenfor rammen av foreliggende oppfinnelse omfatte både 1,4,7,10-tetrabenzyl-l,4,7,10-tetraazasyklododekan, så vel som slike derivater som har alkylsubstituenter på etylenbroene. Begrepet benzylaziridinderivat skal innenfor rammen av foreliggende oppfinnelse omfatte benzylaziridin, så vel som slike derivater hvor aziridinringen har alkylsubstituenter. Således vedrører begrepet benzylaziridinderivat f.eks. også forbindelsene (S )-l-benzyl-2-metylaz-iridin og (S)-l-benzyl-2-etylaziri-din. Analogously, the term tetrabenzylcycle derivatives within the scope of the present invention shall include both 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane, as well as such derivatives which have alkyl substituents on the ethylene bridges. Within the scope of the present invention, the term benzylaziridine derivative shall include benzylaziridine, as well as such derivatives where the aziridine ring has alkyl substituents. Thus, the term benzylaziridine derivative relates to e.g. also the compounds (S)-1-benzyl-2-methylaziridine and (S)-1-benzyl-2-ethylaziridine.
Oppfinnelsen vedrører derfor en fremgangsmåte for fremstilling av eventuelt substituerte 1,4,7,10-tetraazasyk-lododekanderivater ved tetramerisering av tilsvarende edukter. Oppfinnelsen vedrører fortrinnsvis fremstillingen av 1,4,7,10-tetraazasyklododekan . The invention therefore relates to a method for producing optionally substituted 1,4,7,10-tetraazacyclododecane derivatives by tetramerization of corresponding educts. The invention preferably relates to the production of 1,4,7,10-tetraazacyclododecane.
En foretrukket utførelsesform av fremgangsmåten utgår fra lett tilgjengelig benzyletanolamin som ved oppvarmning (80-150 °C, fortrinnsvis 90-110 °C) med 1-1,4 ekvivalenter konsentrert svovelsyre i et organisk løsningsmiddel (f.eks. toluen, sykloheksan, heptan o.a., konsentrasjon: 10-20%) og azeotrop destillasjon av det derved dannede vann blir overført i den tilsvarende svovelsyreester. Reaksjonstiden utgjør derved 2-10 timer. Denne blir oppvarmet med 2-5 ekvivalenter vandig lut (f.eks. NaOH, KOH), og det fremstilte benzylaziridin i et andre reaksjonskar, som sammen med det første danner et lukket system, blir kontinuerlig avdestillert azeotropt med vann. Den således dannede, vandige benzylaziridinemulsjon kan, etter fortynning med et organisk løsningsmiddel (f.eks. etanol, metanol, THF), ved kontinuerlig tilsetning av minst 0,25-0. 4 mol (fortrinnsvis 0,25-0,35 mol) av en sterk syre pr. mol benzylaziridin (dvs. ekvivalent mengde syre beregnet på produktet) overraskende bli omsatt fullstendig til tetrabenzylsyklen. Som organisk løsningsmiddel kan det anvendes f.eks. etanol, metanol eller tetrahydrofuran (THF). Som sterk syre kan det f.eks. anvendes para-toluensulfonsyre (pTsOH), metansulfonsyre (MsOH), svovelsyre eller BF3-eterat. Produktet blir utvunnet etter alkalisering (0,2-0,5 ekvivalenter base, f.eks. NaOH, KOH) av reaksjonsblandingen ved krystallisasjon fra polare løsningsmidler (f.eks. THF, etanol, aceton, isopropan-01, dietyleter, etylacetat, furan, dioksan, vann eller blan-dinger derav) og deretter hydrert i et organisk løsningsmiddel (etanol, metanol, isopropanol, THF) ved hjelp av en katalysa-tor (Pd/C, mengde 5-20% beregnet på tetrabenzylsyklenderi-vatet, trykk: 1-20 bar). Ved filtrering av katalysatoren og avdestillering av løsningsmidlet får man 1,4,7,10-tetraazasyklododekan i et utbytte på 45-60% av det teoretiske totalutbytte. A preferred embodiment of the method starts from readily available benzylethanolamine which, when heated (80-150 °C, preferably 90-110 °C) with 1-1.4 equivalents of concentrated sulfuric acid in an organic solvent (e.g. toluene, cyclohexane, heptane o.a., concentration: 10-20%) and azeotropic distillation of the resulting water is transferred into the corresponding sulfuric acid ester. The reaction time is therefore 2-10 hours. This is heated with 2-5 equivalents of aqueous lye (e.g. NaOH, KOH), and the produced benzylaziridine in a second reaction vessel, which together with the first forms a closed system, is continuously azeotropically distilled off with water. The aqueous benzylaziridine emulsion thus formed can, after dilution with an organic solvent (e.g. ethanol, methanol, THF), by continuous addition of at least 0.25-0. 4 mol (preferably 0.25-0.35 mol) of a strong acid per mol of benzylaziridine (i.e. equivalent amount of acid calculated on the product) surprisingly be converted completely to the tetrabenzylcycle. As an organic solvent, e.g. ethanol, methanol or tetrahydrofuran (THF). As a strong acid, it can e.g. para-toluenesulfonic acid (pTsOH), methanesulfonic acid (MsOH), sulfuric acid or BF3 etherate are used. The product is recovered after alkalization (0.2-0.5 equivalents of base, e.g. NaOH, KOH) of the reaction mixture by crystallization from polar solvents (e.g. THF, ethanol, acetone, isopropane-01, diethyl ether, ethyl acetate, furan, dioxane, water or mixtures thereof) and then hydrated in an organic solvent (ethanol, methanol, isopropanol, THF) with the help of a catalyst (Pd/C, amount 5-20% calculated on the tetrabenzyl cycle derivative, pressure: 1-20 bar). By filtering the catalyst and distilling off the solvent, 1,4,7,10-tetraazacyclododecane is obtained in a yield of 45-60% of the theoretical total yield.
Analogt med denne syntese kan det også anvendes Analogous to this synthesis, it can also be used
alkylsubstituert benzyletanolamin, f.eks. L-2-benzylaminopro-panol eller L-2-benzylaminobutanol, for å oppnå syklenderivat som har forgreninger i etylenbroene. Ved en foretrukken utfør-elsesform av syntesen blir (S)-l-benzyl-2-metylaziridin analogt med den ovenfor angitte fremgangsmåte fremstilt fra L-2-benzylaminopropanol og uten isolering omsatt ved tetramerisering til [2S-(2a, 5a,8a, lia)]-2,5,8,11-tetrametyl-l,4,7,10-tetraaza(benzyl)-l,4,7,10-tetraazasyklododekan, hvorfra man ved hydrering oppnår [2S-(2a,5a,8a,lia)]-2, 5,8,11-tetrametyl- alkyl substituted benzylethanolamine, e.g. L-2-benzylaminopropanol or L-2-benzylaminobutanol, to obtain a cyclene derivative which has branches in the ethylene bridges. In a preferred embodiment of the synthesis, (S)-1-benzyl-2-methylaziridine is prepared analogously to the above-mentioned method from L-2-benzylaminopropanol and converted without isolation by tetramerization to [2S-(2a, 5a,8a, lia)]-2,5,8,11-tetramethyl-1,4,7,10-tetraaza(benzyl)-1,4,7,10-tetraazacyclododecane, from which by hydrogenation one obtains [2S-(2a,5a, 8a,lia)]-2, 5,8,11-tetramethyl-
1,4,7,10-tetraazasyklododekan. 1,4,7,10-tetraazacyclododecane.
Fremgangsmåten ifølge oppfinnelsen for syklotetramerisering av benzylaziridinderivatet skiller seg fra fremgangs-måter som er kjent fra teknikkens stand ved at det ikke er nødvendig å isolere aziridinet i ren form. Den omtalte fremgangsmåte tillater dermed at man gjennomfører prosessen i et lukket system og dermed unngår å utsette mennesker og miljø for fare på grunn av cancerogent aziridin. The method according to the invention for cyclotetramerization of the benzylaziridine derivative differs from methods known from the prior art in that it is not necessary to isolate the aziridine in pure form. The described method thus allows the process to be carried out in a closed system and thus avoids exposing people and the environment to danger due to carcinogenic aziridine.
I motsetning til metoder som er kjent fra teknikkens stand for syklotetramerisering av benzylaziridin, blir det istedenfor en katalytisk mengde av en syre (p-TsOH, MsOH, svovelsyre, BF3-eterat eller trialkylaluminium) anvendt en støkiometrisk mengde (0,25-0,35 mol beregnet på 1 mol benzylaziridin). Ved forsøk som ble gjort for å øke målestokken for derved å kunne fremstille større mengder av 1,4,7,10-tetraazasyklododekan, ble det ved anvendelse av katalytiske mengder p-TsOH ved omsetningen av den in situ fremstilte benzylaziridinemulsjon kun oppnådd 12-25% av teoretisk utbytte. Det ble nå overraskende funnet at ved kontinuerlig tilsetning av fra 0,25 til 0,35 ekvivalenter p-TsOH (beregnet på benzylaziridin) ved 60-78 °C i løpet av 6 til 9 timer til den azeotrope, avdestil-lerte benzylaziridinemulsjon kan utbyttet av 1,4, 7,10-tetraazasyklododekan forbedres til 60-65% av teoretisk utbytte. In contrast to methods known from the prior art for the cyclotetramerization of benzylaziridine, instead of a catalytic amount of an acid (p-TsOH, MsOH, sulfuric acid, BF3 etherate or trialkylaluminum) a stoichiometric amount (0.25-0, 35 mol calculated on 1 mol of benzylaziridine). When attempts were made to increase the scale in order to thereby be able to produce larger amounts of 1,4,7,10-tetraazacyclododecane, using catalytic amounts of p-TsOH in the reaction of the in situ produced benzylaziridine emulsion only obtained 12-25 % of theoretical yield. It was now surprisingly found that by continuous addition of from 0.25 to 0.35 equivalents of p-TsOH (calculated on benzylaziridine) at 60-78 °C during 6 to 9 hours to the azeotropic, distilled off benzylaziridine emulsion can be obtained of 1,4,7,10-tetraazacyclododecane is improved to 60-65% of theoretical yield.
Ytterligere fordeler ved denne fremgangsmåte er det høye totalutbytte og de lave avfallsmengder (Na-suifat ved aziridinfremstillingen og toluen ved hydreringen) sammenlignet med kjente metoder. Further advantages of this method are the high total yield and the low amounts of waste (Na sulfate during the aziridine production and toluene during the hydrogenation) compared to known methods.
Utførelseseksempler Execution examples
De følgende eksempler skal belyse oppfinnelsesgjen-standen uten å begrense denne. The following examples shall illustrate the object of the invention without limiting it.
Eksempel 1 Example 1
Til en løsning av 95 ml benzyletanolamin i 690 ml toluen ble det tilsatt 53 ml konsentrert svovelsyre. Den oppnådde suspensjon ble oppvarmet til kokning i 2 timer.- Det derved dannede vann (14 ml) blir fraskilt ved hjelp av en vann-utskiller. Etter avkjøling til 20 °C blir reaksjonsblandingen tilsatt 1 300 ral vann, omrørt i 10 minutter, og den organiske fase blir fraskilt. Deretter blir den vandige fase hurtig tilsatt til et andre reaksjonskar hvori det befinner seg 92,2 g NaOH i 95 ml vann. Reaksjonsblandingen ble oppvarmet til kokning. Ved hjelp av en destillasjonsbro blir 880 g vann-N-benzylaziridinemulsjon avdestillert i et tredje reaksjonskar. Emulsjonen ble tilsatt 880 ml etanol og oppvarmet til 60 "C. Deretter blir det i løpet av 8 timer tilsatt en løsning av 38,0 g p-TsOH i 19 ml vann ved hjelp av en doseringspumpe. To a solution of 95 ml of benzylethanolamine in 690 ml of toluene was added 53 ml of concentrated sulfuric acid. The resulting suspension was heated to boiling for 2 hours. - The resulting water (14 ml) is separated by means of a water separator. After cooling to 20 °C, 1,300 ral of water are added to the reaction mixture, stirred for 10 minutes, and the organic phase is separated. The aqueous phase is then quickly added to a second reaction vessel in which there are 92.2 g of NaOH in 95 ml of water. The reaction mixture was heated to boiling. Using a distillation bridge, 880 g of water-N-benzylaziridine emulsion is distilled off in a third reaction vessel. The emulsion was added to 880 ml of ethanol and heated to 60 °C. Then, in the course of 8 hours, a solution of 38.0 g of p-TsOH in 19 ml of water is added using a dosing pump.
"V "W
Etter avsluttet tilsetning blir det kokt i 2 timer under til-bakeløp. Deretter blir reaksjonsblåndingen tilsatt en løsning av 12,0 g NaOH i 20 ml vann. Det utfelte produkt ble filtrert" bg omkrystallisert fra 600 ml 2:1 etanol-THF-blanding. Det således oppnådde tetrabenzylsyklen (53 g) blir oppløst i 500 ml isopropanol og hydrert med lb" g Pd/C (10%) ved 80 "C og et H2-trykk på 20 bar. Etter frafiltrering av katalysatoren blir reaksjonsløsningen konsentrert og produktet omkrystallisert fra toluen. Man får 15,9 g (55% av teoretisk) syklen som fargeløse krystaller. Smp. 110-112 °C. After the addition is finished, it is boiled for 2 hours under reflux. A solution of 12.0 g of NaOH in 20 ml of water is then added to the reaction mixture. The precipitated product was filtered" bg recrystallized from 600 ml of 2:1 ethanol-THF mixture. The thus obtained tetrabenzylcycle (53 g) is dissolved in 500 ml of isopropanol and hydrated with lb" g of Pd/C (10%) at 80 " C and an H2 pressure of 20 bar. After filtering off the catalyst, the reaction solution is concentrated and the product recrystallized from toluene. 15.9 g (55% of theory) of the cycle are obtained as colorless crystals. Mp. 110-112 °C.
Eksempel 2 Example 2
95 ml benzyletanolamin ble som beskrevet i eksempel 1 omsatt med svovelsyre og deretter med NaOH. Den oppnådde, vandige N-benzylaziridinemulsjon blir tilsatt 2,6 1 etanol og oppvarmet til 50 °C. Til denne blir det i løpet av 8 timer" tilsatt en løsning av 29,3 g p-TsOH i 15 ml vann ved hjelp av en doseringspumpe. Etter avsluttet tilsetning blir det kokt i 2 timer under tilbakeløp. Deretter blir reaksjonsblandingen tilsatt en løsning av 9,5 NaOH i 20 ml vann. Det utfelte produkt blir filtrert og omkrystallisert fra 600 ml 2:1 etanol-THF-blanding. Det således oppnådde tetrabenzylsyklen (55,7 g) blir oppløst i 500 ml isopropanol og hydrert med 10 g Pd/C (10%) ved 80 °C og et H2-trykk på 20 bar. Etter f raf iltrering av katalysatoren blir reaksjonsløsningen konsentrert og produktet omkrystallisert fra toluen. Man får 15,9 g (58% av teoretisk) syklen som fargeløse krystaller. Smp. 111-113 °C. 95 ml of benzylethanolamine was, as described in example 1, reacted with sulfuric acid and then with NaOH. The obtained aqueous N-benzylaziridine emulsion is added to 2.6 1 of ethanol and heated to 50°C. A solution of 29.3 g of p-TsOH in 15 ml of water is added to this over the course of 8 hours using a dosing pump. After completion of the addition, it is boiled for 2 hours under reflux. Then the reaction mixture is added with a solution of 9.5 NaOH in 20 ml water. The precipitated product is filtered and recrystallized from 600 ml 2:1 ethanol-THF mixture. The tetrabenzylcycle thus obtained (55.7 g) is dissolved in 500 ml isopropanol and hydrated with 10 g Pd /C (10%) at 80 °C and an H2 pressure of 20 bar. After filtration of the catalyst, the reaction solution is concentrated and the product recrystallized from toluene. 15.9 g (58% of theory) of the cycle are obtained as colorless crystals .Mp 111-113 °C.
Eksempel 3 Example 3
Som i eksempel 1, bare at tetrameriseringen ble gjen-nomført med 0,33 ekv. metansulfonsyre. Utbytte 52% syklen. Smp. 110-112 °C. As in Example 1, only that the tetramerization was carried out with 0.33 equiv. methanesulfonic acid. Yield 52% cycle. Temp. 110-112 °C.
Claims (5)
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| 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 |
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| NO983901L NO983901L (en) | 1998-08-25 |
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| 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 |
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| 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 |
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| PL185927B1 (en) | 2003-09-30 |
| AU1877297A (en) | 1997-09-16 |
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| 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 |
| KR100453668B1 (en) | 2004-12-16 |
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| HK1018618A1 (en) | 1999-12-30 |
| CA2247265A1 (en) | 1997-09-04 |
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| GR3034468T3 (en) | 2000-12-29 |
| JP2009185077A (en) | 2009-08-20 |
| DK0883610T3 (en) | 2000-09-25 |
| IL125419A (en) | 2001-01-11 |
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| SK281972B6 (en) | 2001-09-11 |
| 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 |
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