NO318054B1 - Procedure for manufacturing the bicycle - Google Patents
Procedure for manufacturing the bicycle Download PDFInfo
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- NO318054B1 NO318054B1 NO20012703A NO20012703A NO318054B1 NO 318054 B1 NO318054 B1 NO 318054B1 NO 20012703 A NO20012703 A NO 20012703A NO 20012703 A NO20012703 A NO 20012703A NO 318054 B1 NO318054 B1 NO 318054B1
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- carbonate
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 49
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 22
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 229940015043 glyoxal Drugs 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GBBZLMLLFVFKJM-UHFFFAOYSA-N 1,2-diiodoethane Chemical compound ICCI GBBZLMLLFVFKJM-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 239000007859 condensation product Substances 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- QJNULWKDWXIXLJ-UHFFFAOYSA-N 1,2-bis(methylsulfonyl)ethane Chemical compound CS(=O)(=O)CCS(C)(=O)=O QJNULWKDWXIXLJ-UHFFFAOYSA-N 0.000 claims description 2
- ATPZFDFVYMLXFX-UHFFFAOYSA-N 1-methyl-4-[2-(4-methylphenyl)sulfonylethylsulfonyl]benzene Chemical compound C1=CC(C)=CC=C1S(=O)(=O)CCS(=O)(=O)C1=CC=C(C)C=C1 ATPZFDFVYMLXFX-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Chemical group 0.000 claims description 2
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical group [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 claims description 2
- 239000002370 magnesium bicarbonate Chemical group 0.000 claims description 2
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 claims description 2
- 235000014824 magnesium bicarbonate Nutrition 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Chemical group 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 239000011736 potassium bicarbonate Chemical group 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- RRBYUSWBLVXTQN-UHFFFAOYSA-N tricyclene Chemical compound C12CC3CC2C1(C)C3(C)C RRBYUSWBLVXTQN-UHFFFAOYSA-N 0.000 abstract 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
- 239000007787 solid Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 16
- 235000019502 Orange oil Nutrition 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 239000010502 orange oil Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 3
- CASDNPHWJOQUQX-UHFFFAOYSA-N 1-benzylaziridine Chemical compound C=1C=CC=CC=1CN1CC1 CASDNPHWJOQUQX-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 235000014676 Phragmites communis Nutrition 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- OAEGRYMCJYIXQT-UHFFFAOYSA-N dithiooxamide Chemical compound NC(=S)C(N)=S OAEGRYMCJYIXQT-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 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
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- RTWNYYOXLSILQN-UHFFFAOYSA-N methanediamine Chemical compound NCN RTWNYYOXLSILQN-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- -1 preferred i DMF Chemical compound 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000039 preparative column chromatography Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 239000002699 waste material 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
Abstract
Description
Foreliggende oppfinnelse gjelder gjenstanden beskrevet i patentkravene, dvs. en ny fremgangsmåte for fremstilling av syklen. The present invention relates to the object described in the patent claims, i.e. a new method for manufacturing the bicycle.
Syklen er et hyppig anvendt utgangsmateriale for fremstilling av makrosykliske kompleksdannere og benyttes fremfor alt innenfor området kjerneresonanstomograi som ligand for gadolinium. Med "ProHance" for Bristol-Myers-Squibb og "Dotarem" fra Guerbet er allerede to preparater kommersielt tilgjengelige. Også spesielle forsknings- og utviklingsprosjekter anvender syklen som utgangsmateriale. Det foreligger derfor et behov for en bekvem og kostnadsgunstig fremgangsmåte for fremstilling av dette produkt. The cycle is a frequently used starting material for the production of macrocyclic complex formers and is used above all in the area of nuclear resonance tomography as a ligand for gadolinium. With "ProHance" for Bristol-Myers-Squibb and "Dotarem" from Guerbet, two preparations are already commercially available. Special research and development projects also use the bicycle as starting material. There is therefore a need for a convenient and cost-effective method for producing this product.
En av de første publiserte fremgangsmåter (Richman og Atkins, J. Am. Chem. Soc. 1974, 96, s. 2268) benytter seg av syklisering av et natriumbissulfonamid med et tilsvarende funksjonalisert dietylensulfonamid. Weisman og Reed (J. Org. Chem. 1996, 61, s. 5186-5187) benytter i sin syntese reaksjonen mellom en bistioimidoester og trietylentetramin for oppbygging av et trisyklisk bisimin som til slutt etter reduksjon hydro-lyseres til syklen. One of the first published methods (Richman and Atkins, J. Am. Chem. Soc. 1974, 96, p. 2268) utilizes the cyclization of a sodium bissulfonamide with a correspondingly functionalized diethylenesulfonamide. Weisman and Reed (J. Org. Chem. 1996, 61, pp. 5186-5187) use in their synthesis the reaction between a bisthioimidoester and triethylenetetramine to build up a tricyclic bisimine which is finally hydrolyzed to the cycle after reduction.
Fremgangsmåten til V. Pånetta et al. {Tetrahedron Lett. 1992, vol. 33, nr. 38, s. 5505-5508) benytter en indirekte vei til syklen, idet den gjennomfører en syklisering av et tetra-trifluormetansulfonsyreamid av trietylentetramin med 1,2-dibrometan. Det siste reaksjonstrinn omfatter frisetting av syklen. Fremgangsmåten til firmaet Nycomed (WO 96/28433) for fremstilling av tribenzylsyklen bygger også på en tilsvarende fremgangsmåte. Syntesen forløper over reaksjonen mellom et egnet triamin og et monoamin eller mellom to egnede diaminer. Fremgangsmåten publisert i DE 19608307, fører også til tetrabenzyl-syklen og omfatter en tetramerisering av N-benzylaziridin som det viktigste trinn. The procedure of V. Pånetta et al. {Tetrahedron Easy. 1992, vol. 33, no. 38, pp. 5505-5508) uses an indirect route to the cycle, carrying out a cyclization of a tetra-trifluoromethanesulfonic acid amide of triethylenetetramine with 1,2-dibromoethane. The last reaction step involves releasing the bike. The method of the company Nycomed (WO 96/28433) for the production of the tribenzyl cycle is also based on a similar method. The synthesis proceeds via the reaction between a suitable triamine and a monoamine or between two suitable diamines. The process published in DE 19608307 also leads to the tetrabenzyl cycle and comprises a tetramerization of N-benzylaziridine as the most important step.
Firmaet Dow Chemical benytter, som beskrevet i WO 97/31005 og US 5 587 451 et bisimidazolin dannet fra trietylentetramin som intermediat. Ringslutning til det tetrasykliske mellom-produkt skjer med 1,2-dibrometan. Påfølgende hydrolyse frigir syklen. The company Dow Chemical uses, as described in WO 97/31005 and US 5,587,451, a bisimidazoline formed from triethylenetetramine as an intermediate. Ring closure to the tetracyclic intermediate occurs with 1,2-dibromoethane. Subsequent hydrolysis releases the cycle.
Firmaet Bracco benytter, som beskrevet i WO 97/49691, en direkte vei til syklen som begynner med kondensasjon av trietylentetramin med glyoksal - som allerede beskrevet av Weisman et al. (Tetrahedron Lett. 1980, bind 21, s. 335-338). Deretter overføres dette ved reaksjon med 1,2-dibrometan til en tetra-syklisk mellomforbindelse. Fjerning av etylenbroen som er forbundet med de fire heteroatomer, skjer ved oksidasjon med brom og påfølgende hydrolyse (eller også ved hydrolyse med et primært diamin, WO 98/49151). Totalutbyttet oppgis til 25%. The company Bracco uses, as described in WO 97/49691, a direct route to the cycle starting with the condensation of triethylenetetramine with glyoxal - as already described by Weisman et al. (Tetrahedron Lett. 1980, vol. 21, pp. 335-338). This is then transferred by reaction with 1,2-dibromoethane to a tetracyclic intermediate compound. Removal of the ethylene bridge connected to the four heteroatoms occurs by oxidation with bromine and subsequent hydrolysis (or also by hydrolysis with a primary diamine, WO 98/49151). The total yield is stated at 25%.
Reaksjonsskjema 1: Synteserekkefølge til firmaet Reaction scheme 1: Synthesis sequence for the company
Bracco (WO 97/49691) Bracco (WO 97/49691)
Den i WO 96/28432 offentliggjorte syntese til firmaet Nycomed ligner den ovenfor beskrevne sekvens, med den avgjørende forskjell i hydrolysen av den sentrale etylenbro. Her oppnås omsetningen ved tilsetning av hydroksylamin i etanolisk løsning under oppvarming. Totalutbyttet for denne reaksjonssekvens ligger rundt 45%. The synthesis published in WO 96/28432 by the company Nycomed is similar to the sequence described above, with the decisive difference in the hydrolysis of the central ethylene bridge. Here, the conversion is achieved by adding hydroxylamine in ethanolic solution while heating. The total yield for this reaction sequence is around 45%.
Reaksjonsskjerna 2: Syntesesekvensen til firmaet Nycomed (WO 96/28432) Reaction core 2: The synthesis sequence of the company Nycomed (WO 96/28432)
Vurdering av fremgangsmåtene Assessment of the procedures
Fremgangsmåten ifølge WO 97/4 9691 viser noen fremtredende ulemper som understøttes av eksperimentell etterbearbeidelse og som i det påfølgende kort sammenfattes: Fremstillingen av den trisykliske forbindelse som den er beskrevet, er ikke reproduserbar, da: The method according to WO 97/4 9691 shows some prominent disadvantages which are supported by experimental post-processing and which are briefly summarized below: The production of the tricyclic compound as described is not reproducible, then:
- Kalsiumhydroksidet kan ikke fjernes kvantitativt. - The calcium hydroxide cannot be removed quantitatively.
- Større mengder vann må avdestiUeres. - Larger quantities of water must be distilled.
- Produktet foreligger ikke som angitt som en olje. - The product is not available as an oil as indicated.
Opprensingen av den tetrasykliske forbindelse er svært kostbar: - Ekstraksjonen av produktet fra et fast stoff redus-erer utbyttet. The purification of the tetracyclic compound is very expensive: - The extraction of the product from a solid reduces the yield.
Hydrolysen til syklen viser seg å være svært vanskelig: The hydrolysis of the bicycle turns out to be very difficult:
- Det må gjennomføres en autoklavreaksjon ved pH = 14 og ved 185 °C. - Produktet krystalliserer dårlig og bare svært forurenset fra reaksjonsløsningen. - An autoclave reaction must be carried out at pH = 14 and at 185 °C. - The product crystallizes poorly and only very contaminated from the reaction solution.
Også fremgangsmåten ifølge WO 96/28432 gir grunn til kritikk. De vesentlige ulemper er sammenstilt nedenfor. The method according to WO 96/28432 also gives rise to criticism. The significant disadvantages are summarized below.
- Alle syntesetrinn omfatter lange omrøringstider. - All synthesis steps involve long stirring times.
- Opprensing av den tetrasykliske forbindelse skjer ved en preparativ kolonnekromatografi. - Hydrolysen til syklen varer svært lenge, og den angitte opprensingsfremgangsmåt gir ikke produktet i den ønskede renhet. - The tetracyclic compound is purified by preparative column chromatography. - The hydrolysis of the cycle lasts a very long time, and the specified purification procedure does not give the product the desired purity.
Alle øvrige fremgangsmåter omfatter syntesesekvenser i flere trinn hvor mellomprodukter isoleres, noe som som regel er tid- og råstoffkrevende. Fremgangsmåten til Weisman og Reed utelukker en kommersiell syntese da den er avhengig av rubean-hydrogen (tilnærmet DM 400,-/100 g) som et av utgangsmateri-alene. Ved fremgangsmåten til Richman og Atkins så vel som fremgangsmåten til V. Pånetta må først tilsvarende beskyttede aminer fremstilles. Etter avsluttet reaksjon er så, som også i fremgangsmåtene til firmaene Dow Chemical, Nycomed (WO 96/28433) og Schering (DE19608307), avspalting av disse beskyttelses-grupper nødvendig som et ekstra reaksjonstrinn, noe som gir en dårligere stoffbalanse med hensyn til det ønskede produkt. Ved tetråmeriseringen av benzylaziridin må det arbeides med store mengder karsinogene stoffer. All other methods include synthesis sequences in several steps where intermediate products are isolated, which is usually time- and raw material-consuming. The method of Weisman and Reed precludes a commercial synthesis as it depends on rubean hydrogen (approximately DM 400/100 g) as one of the starting materials. In the method of Richman and Atkins as well as the method of V. Pånetta, correspondingly protected amines must first be prepared. After completion of the reaction, as in the methods of the companies Dow Chemical, Nycomed (WO 96/28433) and Schering (DE19608307), removal of these protective groups is necessary as an additional reaction step, which results in a poorer material balance with regard to the desired product. During the tetramerization of benzylaziridine, large quantities of carcinogenic substances must be used.
En lønnsom fremgangsmåte bør bygge på billigst mulige, mest mulig miljøbevarende og lett tilgjengelige råstoffer. Videre bør reaksjonstidene være korte og forløpe ved lav energi-tilsetning. I tillegg bør stoffmengdene under totalsyntesen være lavest mulige. A profitable method should be based on the cheapest possible, most environmentally friendly and easily available raw materials. Furthermore, reaction times should be short and proceed with low energy addition. In addition, the amounts of substances during the total synthesis should be as low as possible.
Denne oppgave løses ved foreliggende oppfinnelse. This task is solved by the present invention.
Det har overraskende nok blitt funnet at en fremgangsmåte for fremstilling av syklen som kjennetegnes ved at i en éhkolbefremgangsmåte omsettes trietylentetramin med 4 0% glyoksal ved 20 °C til 80 °C i et polart, protisk løsemiddel, fortrinnsvis metanol, etanol, isopropanol, butanol, glykol, vann eller blandinger av disse, spesielt foretrukket etanol, i løpet av 4 til 40 timer, fortrinnsvis 15 til 20 timer, at den således dannede, intermediære, trisykliske forbindelse etter fjerning av løsemidlet alkyleres på begge de sekundære aminnitrogener med et 1,2-difunksjonalisert alkyleringsmiddel X(CHa)2X, hvori X står for en nukleofil gruppe, fortrinnsvis med 1,2-dibrometan, 1,2-dikloretan, 1,2-ditosyletan, 1,2-dimesyletan eller 1,2-dijodetan, spesielt foretrukket med 1,2-dikloretan, i et polart, aprotisk løse-middel, fortrinnsvis i N,N-dimetylformamid (DMF), N,N-dimetylacetamid (DMAC), N-metylpyrrolidon (NMP), tetrametylurea, formamid eller dimetylpropylenurea (DMPU), spesielt foretrukket i DMF, eventuelt i nærvær av en hjelpebase, fortrinnsvis natriumkarbonat, kaliumkarbonat, kalsiumkarbonat, natriumhydrogenkarbonat, kaliumhydrogenkarbonat, maganesiumkarbonat, magnesiumhydrogenkarbonat, litiumhydroksid eller litiumkarbonat, spesielt foretrukket uten hjelpebase, ved 20 til 120 °C, fortrinnsvis 30 til 70 °C, i løpet av 2 til 24 timer, fortrinnsvis 6 til 10 timer, at det således erholdte kondensasjonsprodukt etter fjerning av løsemidlet behandles med hydrazinhydrat i et polart, protisk løsemiddel, fortrinnsvis metanol, etanol, isopropanol, butanol, glykol, vann eller blandinger av disse, spesielt foretrukket etanol, ved en pH fra 3 til 6, fortrinnsvis fra 3 til 4, i 12 til 48 timer, fortrinnsvis 25 til 35 timer, ved reflukstemperatur, hvoretter syklen frisettes fra syklensaltet ved tilsetning av en base, fortrinnsvis natriumhydroksid, kaliumhydroksid, kalsiumhydroksid eller en basisk ionebytter, spesielt foretrukket natriumhydroksid og kaliumhydroksid, og isoleres etter inndamping av reaksjonsløsningen til tørrhet, løser den ovenfor nevnte oppgave. It has surprisingly been found that a method for the production of the cycle which is characterized by reacting triethylenetetramine with 40% glyoxal at 20°C to 80°C in a polar, protic solvent, preferably methanol, ethanol, isopropanol, butanol, in a single flask process . 2-difunctionalized alkylating agent X(CHa)2X, in which X stands for a nucleophilic group, preferably with 1,2-dibromoethane, 1,2-dichloroethane, 1,2-ditosylethane, 1,2-dimesylethane or 1,2-diiodoethane, particularly preferred with 1,2-dichloroethane, in a polar, aprotic solvent, preferably in N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), tetramethylurea, formamide or dimethylpropyleneurea (DMPU), particularly preferred i DMF, optionally in the presence of an auxiliary base, preferably sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate, magnesium hydrogen carbonate, lithium hydroxide or lithium carbonate, particularly preferably without an auxiliary base, at 20 to 120 °C, preferably 30 to 70 °C, during 2 to 24 hours, preferably 6 to 10 hours, that the condensation product thus obtained, after removal of the solvent, is treated with hydrazine hydrate in a polar, protic solvent, preferably methanol, ethanol, isopropanol, butanol, glycol, water or mixtures thereof, particularly preferred ethanol , at a pH from 3 to 6, preferably from 3 to 4, for 12 to 48 hours, preferably 25 to 35 hours, at reflux temperature, after which the cycle is released from the cycle salt by the addition of a base, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide or a basic ion exchangers, particularly preferred sodium hydroxide and potassium hydroxide, and isolated after in evaporation of the reaction solution to dryness, solves the above-mentioned task.
Isolering av syklen skjer fortrinnsvis ved krystallisering av toluen, trifluormetylbenzen eller dietoksymetan av hvilke den siste forbindelse er spesielt foretrukket. Isolation of the cycle preferably takes place by crystallization of toluene, trifluoromethylbenzene or diethoxymethane, of which the last compound is particularly preferred.
Reaksjonsskjema 3 tydeliggjør som et eksempel igjen for-løpet av syntesen ifølge oppfinnelsen: Reaction scheme 3 clarifies as an example again the course of the synthesis according to the invention:
Fordeler ved fremgangsmåten Advantages of the procedure
Fremgangsmåten ifølge oppfinnelsen for fremstilling av syklen viser tydelige fordeler fremfor fremgangsmåtene ifølge teknikkens stand, siden den utføres som en enkolbefremgangsmåte. - Det kreves ingen tid- og råstoffkrevende isoleringstrinn av mellomprodukter. - Omsetningen med aminet skjer uten at det dannes nevne-verdige mengder av biprodukter. The method according to the invention for manufacturing the bicycle shows clear advantages over the methods according to the state of the art, since it is carried out as a one-piston method. - No time- and raw material-consuming isolation step of intermediate products is required. - The reaction with the amine takes place without significant amounts of by-products being formed.
- Råstoffene er prisgunstige og lett tilgjengelige. - The raw materials are inexpensive and easily available.
- Det dannes lite avfall. - Little waste is produced.
- Den totale syntesetid er kort. - The total synthesis time is short.
- Det anvendes en ny, prisgunstig rensefremgangsmåte for syklen. - Utbyttet er høyere enn ved fremgangsmåtene ifølge teknikkens stand. - A new, cost-effective cleaning method is used for the bicycle. - The yield is higher than with the methods according to the state of the art.
De påfølgende eksempler er ment å ytterligere belyse oppfinnelsen. The following examples are intended to further illustrate the invention.
Ekfifrmp<p>l Ekfifrmp<p>l
1 4 7 f 1 n-tPtr-aa^afiyklodndekan f= syklen) 1 4 7 f 1 n-tPtr-aa^afiyklodndekan f= the bicycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som løses i 400 ml dimetylformamid og tilsettes 81,2 ml (101,5 g = 1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 4 0 °C inndampes reak-sjonsblandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til tilnærmet pH = 3-4 med 37% saltsyre i vann. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum, løses igjen i 100 ml etanol og løsemidlet fjernes. Restmaterialet tilsettes 25 g aktivt kull og 100 ml formaldehyddietylacetal og oppvarmes i en tid under refluks før den varme løsning filtreres gjennom en membran. Etter avkjøling av løs-ningen isoleres produktet ved filtrering. Det erholdes 3 8,3 g syklen (0,222 mol = 65% av teoretisk utbytte) som et krystallinsk, fast stoff. 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is dissolved in 400 ml of dimethylformamide and 81.2 ml (101.5 g = 1.026 mol) of 1,2-dichloroethane is added. After stirring for 8 hours at 40 °C, the reaction mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to approximately pH = 3-4 with 37% hydrochloric acid in water. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum, dissolved again in 100 ml of ethanol and the solvent is removed. 25 g of activated charcoal and 100 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 8.3 g of the cycle are obtained (0.222 mol = 65% of theoretical yield) as a crystalline solid.
EkSAinpAl 2 Example 2
1.4,7,10-tetraazasyklododekan f= syklen) 1.4,7,10-tetraazacyclododecane f= the cycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylformamid og tilsettes 88,5 ml (192,8 g = 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylformamide and 88.5 ml (192.8 g =
1,026 mol) 1,2-dibrometan. Etter 6 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettses 166 ml (171 g = 3,42 mol) 1.026 mol) 1,2-dibromoethane. After 6 hours of stirring at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. This reaction solution is added to 166 ml (171 g = 3.42 mol)
hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres med fast kaliumhydroksid til pH = 13. Deretter inndampes reaksjonsløsningen under vakuum og løses igjen i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 39,5 g syklen (67% av teoretisk utbytte) som et krystallinsk, fast stoff. hydrazine hydrate at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted with solid potassium hydroxide to pH = 13. The reaction solution is then evaporated under vacuum and dissolved again in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated carbon and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 39.5 g of the cycle (67% of theoretical yield) are obtained as a crystalline solid.
Eksempel 3 Example 3
1. 4. 7. 10- tetraazasyklododekan (= syklen) 1. 4. 7. 10- tetraazacyclododecane (= the cycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylformamid og tilsettes 82,6 ml (274,8 g = 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylformamide and 82.6 ml (274.8 g =
1,026 mol) 1,2-dijodetan. Etter 5 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses igjen i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes en tid under refluks før den varme løsning filtreres gjennom en membran. Etter av-kjøling av løsningen isoleres produktet ved filtrering. Det erholdes 37,1 g syklen (63% av teoretisk utbytte) som et krystallinsk, fast stoff. 1.026 mol) 1,2-diiodoethane. After 5 hours of stirring at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and dissolved again in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated carbon and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for some time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.1 g of the cycle (63% of theoretical yield) are obtained as a crystalline solid.
Eksempel 4 Example 4
1, 4, 7, 10- tetraazasyklododekan (= syklen) 1, 4, 7, 10- tetraazacyclododecane (= the cycle)
50 g trietylentetramin (0,342 mol) løses ill metanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 50 g of triethylenetetramine (0.342 mol) are dissolved in methanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After 20 hours of stirring, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in
400 ml dimetylformamid og tilsettes 81,2 ml (101,5 g = 400 ml of dimethylformamide and add 81.2 ml (101.5 g =
1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses igjen i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks, før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 37,7 g syklen (64% av teoretisk utbytte) som et krystallinsk, fast stoff. 1.026 mol) 1,2-dichloroethane. After stirring for 8 hours at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and dissolved again in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated charcoal and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux, before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.7 g of the cycle (64% of theoretical yield) are obtained as a crystalline solid.
Eksempel 5 Example 5
1 . A , 7 . ln- t- P- tY- aazasyklodndpkan (= syklen) 1. A, 7. ln- t- P- tY- aazacyclodndpkan (= the cycle)
50 g trietylentetramin (0,342 mol) ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylacetamid og tilsettes 81,2 ml (101,5 g = 1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjons-løsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjons-løsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses igjen i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks, før den varme løsning filtreres gjennom en membran. Etter avkjøling av løs-ningen isoleres produktet ved filtrering. Det erholdes 37,7 g syklen (64% av teoretisk utbytte) som et krystallinsk, fast stoff. 50 g of triethylenetetramine (0.342 mol) in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylacetamide and 81.2 ml (101.5 g = 1.026 mol) of 1,2-dichloroethane is added. After stirring for 8 hours at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and dissolved again in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated charcoal and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux, before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.7 g of the cycle (64% of theoretical yield) are obtained as a crystalline solid.
1.4r7riri-tetraazaByklododfikan ( = syklen) 1.4r7riri-tetraazaByklododfican ( = the cycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml tetrametylurea og tilsettes 81,2 ml (101,5 g = 1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 40 °C inndampes reaksjonblandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses på ny i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 37,1 g syklen (63% av teoretisk utbytte) som et krystallinsk, fast stoff. 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of tetramethylurea and 81.2 ml (101.5 g = 1.026 mol) of 1,2-dichloroethane is added. After stirring for 8 hours at 40 °C, the reaction mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and re-dissolved in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated carbon and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.1 g of the cycle (63% of theoretical yield) are obtained as a crystalline solid.
Eksempel 7 Example 7
1.4 r 7f 1 n - tet raa 7.a sykl odnriftkan f= syklen) 1.4 r 7f 1 n - tet raa 7.a cycle odnriftkan f= the cycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 4 00 ml tetrametylurea og tilsettes 88,5 ml (192,8 g = 1,026 mol) 1,2-dibrometan. Etter 6 timers omrøring ved 4 0 °C inndampes blandingen under vakuum, og restmaterialet løses i 4 00 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reak-sjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reak-sjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses på ny i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks, før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 37,6 g syklen (64% av maksimalt utbytte) som et krystallinsk, fast stoff. 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of tetramethylurea and 88.5 ml (192.8 g = 1.026 mol) of 1,2-dibromoethane is added. After stirring for 6 hours at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and re-dissolved in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated charcoal and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux, before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.6 g of the cycle (64% of maximum yield) are obtained as a crystalline solid.
Eksempel 8 Example 8
1 r4r7.in-tPl-raa?:aKyk1ndr>dekan f = syklen) 1 r4r7.in-tPl-raa?:aKyk1ndr>dekan f = the bike)
50 g trietylentetramin (0,342 mol) løses ill metanol og tilsettes 3 9 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylformamid og tilsettes 88,5 ml (192,8 g = 50 g of triethylenetetramine (0.342 mol) are dissolved in methanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylformamide and 88.5 ml (192.8 g =
1,026 mol) 1,2-dibrometan, Etter 6 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses på ny i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks, før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 35,9 g syklen (61% av teoretisk utbytte) som et krystallinsk, fast stoff. 1.026 mol) 1,2-dibromoethane, After 6 hours of stirring at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and re-dissolved in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated charcoal and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux, before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 35.9 g of the cycle (61% of theoretical yield) are obtained as a crystalline solid.
Eksempel 9 Example 9
1, 4 f7. 10- tetraazasyklododekan ( = syklen) 1, 4 f7. 10- tetraazacyclododecane ( = the cycle)
50 g trietylentetramin (0,342 mol) løses ill etanol og tilsettes 3 9 ml 4 0% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylformamid og tilsettes 81,2 ml (101,5 g = 50 g of triethylenetetramine (0.342 mol) are dissolved in ethanol and 39 ml of 40% glyoxal in water (0.342 mol) are added at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylformamide and 81.2 ml (101.5 g =
1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,42 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under 1.026 mol) 1,2-dichloroethane. After stirring for 8 hours at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.42 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under
refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses på ny i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 200 ml toluen og oppvarmes i en tid under refluks før den varme løsning filtreres gjennom en membran. Etter avkjøling av løs-ningen isoleres produktet ved filtrering. Det erholdes 35,8 g syklen (61% av teoretisk utbytte) som et krystallinsk, fast stoff. reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and re-dissolved in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated charcoal and 200 ml of toluene are added to the residual material and heated for a time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 35.8 g of the cycle (61% of theoretical yield) are obtained as a crystalline solid.
Eksempel 10 Example 10
1 f4f7r10- tetraa7:asyk1<->dndekan ( = <g>ykl<p>n) 1 f4f7r10- tetraa7:asyk1<->dndecane ( = <g>ykl<p>n)
50 g trietylentetramin (0,342 mol) løses ill 2-propanol og tilsettes 39 ml 40% glyoksal i vann (0,342 mol) ved romtemperatur. Etter 20 timers omrøring avdestilleres løsemidlet under vakuum, og det erholdes en orange olje som deretter løses i 400 ml dimetylformamid og tilsettes 81,2 ml (101,5 g = Dissolve 50 g of triethylenetetramine (0.342 mol) in 2-propanol and add 39 ml of 40% glyoxal in water (0.342 mol) at room temperature. After stirring for 20 hours, the solvent is distilled off under vacuum, and an orange oil is obtained which is then dissolved in 400 ml of dimethylformamide and 81.2 ml (101.5 g =
1,026 mol) 1,2-dikloretan. Etter 8 timers omrøring ved 40 °C inndampes blandingen under vakuum, og restmaterialet løses i 400 ml etanol og surgjøres til pH = 3-4 med 37% vandig saltsyre. Denne reaksjonsløsning tilsettes 166 ml (171 g = 3,4 2 mol) hydrazinhydrat ved romtemperatur og oppvarmes i 30 timer under refluks. Reaksjonsløsningen justeres til pH = 13 med fast kaliumhydroksid. Deretter inndampes reaksjonsløsningen under vakuum og løses på ny i 100 ml etanol, og løsemidlet fjernes på ny under vakuum. Restmaterialet tilsettes 25 g aktivt kull og 150 ml formaldehyddietylacetal og oppvarmes i en tid under refluks før den varme løsning filtreres gjennom en membran. Etter avkjøling av løsningen isoleres produktet ved filtrering. Det erholdes 37,2 g syklen (63% av teoretisk utbytte) som et krystallinsk, fast stoff. 1.026 mol) 1,2-dichloroethane. After stirring for 8 hours at 40 °C, the mixture is evaporated under vacuum, and the residual material is dissolved in 400 ml of ethanol and acidified to pH = 3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g = 3.4 2 mol) of hydrazine hydrate are added to this reaction solution at room temperature and heated for 30 hours under reflux. The reaction solution is adjusted to pH = 13 with solid potassium hydroxide. The reaction solution is then evaporated under vacuum and re-dissolved in 100 ml of ethanol, and the solvent is removed again under vacuum. 25 g of activated carbon and 150 ml of formaldehyde diethyl acetal are added to the residual material and heated for a time under reflux before the hot solution is filtered through a membrane. After cooling the solution, the product is isolated by filtration. 37.2 g of the cycle (63% of theoretical yield) are obtained as a crystalline solid.
Claims (10)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19856481A DE19856481C1 (en) | 1998-12-02 | 1998-12-02 | Process for the production of cycles |
| PCT/EP1999/009089 WO2000032581A1 (en) | 1998-12-02 | 1999-11-17 | Method of producing cyclene |
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| Publication Number | Publication Date |
|---|---|
| NO20012703D0 NO20012703D0 (en) | 2001-06-01 |
| NO20012703L NO20012703L (en) | 2001-06-01 |
| NO318054B1 true NO318054B1 (en) | 2005-01-24 |
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| NO20012703A NO318054B1 (en) | 1998-12-02 | 2001-06-01 | Procedure for manufacturing the bicycle |
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| JP (1) | JP4636690B2 (en) |
| KR (1) | KR100639270B1 (en) |
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| AT (1) | ATE250042T1 (en) |
| AU (1) | AU764260B2 (en) |
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| CZ (1) | CZ300157B6 (en) |
| DE (2) | DE19856481C1 (en) |
| DK (1) | DK1135376T3 (en) |
| ES (1) | ES2209530T3 (en) |
| HK (1) | HK1044148B (en) |
| IL (1) | IL143079A (en) |
| NO (1) | NO318054B1 (en) |
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| FR2830253B1 (en) | 2001-09-28 | 2005-02-04 | Air Liquide | NOVEL PROCESS FOR THE PREPARATION OF C-FUNCTIONALIZED NITROGEN MACROCYCLES AND NOVEL INTERMEDIATES OBTAINED |
| CN103360333B (en) * | 2013-07-22 | 2016-03-30 | 厦门市华兴化工有限公司 | A kind of preparation method of high purity methyl-isochondodendrine |
| CN106490298B (en) * | 2016-11-28 | 2020-05-22 | 华南理工大学 | High-dispersity plant protein and preparation method thereof |
| US10344115B2 (en) | 2017-05-25 | 2019-07-09 | International Business Machines Corporation | Amine glyoxal resins |
| KR20190108383A (en) | 2018-03-14 | 2019-09-24 | 주식회사 지에이치바이오텍 | Novel synthesis of cyclen using oxamide and lithium aluminium hydride |
| EP4067348A1 (en) | 2021-03-30 | 2022-10-05 | Bracco Imaging SPA | Process for the preparation of cyclen |
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| IT1284046B1 (en) * | 1996-06-21 | 1998-05-08 | Bracco Spa | PROCESS FOR THE PREPARATION OF TETRAAZAMACROCYCLES |
| IT1290457B1 (en) * | 1997-04-04 | 1998-12-03 | Bracco Spa | PROCESS FOR THE PREPARATION OF TETRAAZAMACROCYCLES |
| IT1291673B1 (en) * | 1997-04-28 | 1999-01-19 | Bracco Spa | PROCESS FOR THE PREPARATION OF 1,4,7,10 - TETRAAZACICLODODECANO |
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| NZ512051A (en) | 2003-10-31 |
| JP4636690B2 (en) | 2011-02-23 |
| EP1135376B1 (en) | 2003-09-17 |
| HK1044148B (en) | 2005-04-01 |
| CN1155583C (en) | 2004-06-30 |
| ES2209530T3 (en) | 2004-06-16 |
| PT1135376E (en) | 2004-02-27 |
| KR20010080648A (en) | 2001-08-22 |
| SK7242001A3 (en) | 2001-12-03 |
| EP1135376A1 (en) | 2001-09-26 |
| AU764260B2 (en) | 2003-08-14 |
| ATE250042T1 (en) | 2003-10-15 |
| SK285372B6 (en) | 2006-12-07 |
| KR100639270B1 (en) | 2006-10-27 |
| HK1044148A1 (en) | 2002-10-11 |
| DK1135376T3 (en) | 2004-01-19 |
| NO20012703D0 (en) | 2001-06-01 |
| DE59907056D1 (en) | 2003-10-23 |
| ZA200105406B (en) | 2002-07-25 |
| IL143079A (en) | 2005-08-31 |
| CA2353680C (en) | 2008-09-09 |
| AU1654300A (en) | 2000-06-19 |
| WO2000032581A1 (en) | 2000-06-08 |
| CA2353680A1 (en) | 2000-06-08 |
| CZ20011915A3 (en) | 2001-09-12 |
| JP2003522114A (en) | 2003-07-22 |
| NO20012703L (en) | 2001-06-01 |
| IL143079A0 (en) | 2002-04-21 |
| CN1329603A (en) | 2002-01-02 |
| DE19856481C1 (en) | 2000-07-06 |
| CZ300157B6 (en) | 2009-02-25 |
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