DD271903A1 - PROCESS FOR THE PRODUCTION OF STABILIZED, 2-UNSUBSTITUTED IMIDAZOLE-3-OXIDE - Google Patents
PROCESS FOR THE PRODUCTION OF STABILIZED, 2-UNSUBSTITUTED IMIDAZOLE-3-OXIDE Download PDFInfo
- Publication number
- DD271903A1 DD271903A1 DD31582688A DD31582688A DD271903A1 DD 271903 A1 DD271903 A1 DD 271903A1 DD 31582688 A DD31582688 A DD 31582688A DD 31582688 A DD31582688 A DD 31582688A DD 271903 A1 DD271903 A1 DD 271903A1
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- acid
- aliphatic
- imidazole
- aromatic
- unsubstituted imidazole
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 7
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- -1 aromatic amino acids Chemical class 0.000 claims abstract description 11
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- GIFGMEWQGDEWKB-UHFFFAOYSA-N 2-(4-aminophenoxy)acetic acid Chemical compound NC1=CC=C(OCC(O)=O)C=C1 GIFGMEWQGDEWKB-UHFFFAOYSA-N 0.000 description 1
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Abstract
Das Verfahren zur Herstellung stabiler, 2-unsubstituierter Imidazol-3-oxide besteht in der Cyclokondensation von a-Hydroxyiminoketonen mit Formaldehyd und einer Aminocarbonsaeure in einem mit Wasser mischbaren organischen Loesungsmittel. Als Aminocarbonsaeuren sind aliphatische, araliphatische und cycloaliphatische D,L-, D- und L-a-Aminosaeuren, aliphatische b-, g, d-, e- und v-Aminosaeuren sowie aliphatisch-aromatische, aromatisch-aliphatische und rein aromatische Aminosaeuren einsetzbar.The process for preparing stable, 2-unsubstituted imidazole-3-oxides consists in the cyclocondensation of α-hydroxyiminoketones with formaldehyde and an aminocarboxylic acid in a water-miscible organic solvent. Suitable aminocarboxylic acids are aliphatic, araliphatic and cycloaliphatic D, L, D and L-α-amino acids, aliphatic b-, g-, d-, e- and v-amino acids as well as aliphatic-aromatic, aromatic-aliphatic and purely aromatic amino acids.
Description
Die nach dem erfindungsgemäßen Verfahren zugänglichen 2-unsubstituierten lmidazol-3-oxide sind als Zwischenprodukte für die Herstellung biologisch wirksamer Verbindungen von Bedeutung. Die D-Enantiomeren sind selbst antiphytoviral wirksam.The 2-unsubstituted imidazole-3-oxides obtainable by the process according to the invention are important as intermediates for the preparation of biologically active compounds. The D-enantiomers are themselves antiphytoviral effective.
Die Synthese 2-substituierter, insbesondere 2-arylsubstituierter 1 -Alkyl(aryl7-imidazol-3-oxide ist aus a-Hydroxyiminoketonen (a-Diketonmonoximen), primären Aminen und Aldehyden (besonders aromatischen Aldehyden! leicht möglich (ϊ. B. Z. Chem. 10/1970/431); dabei werden die Reaktionskomponenten gewöhnlich in Eisessig oder wasserhaltigem Ethanol einige Stunden erhitzt.The synthesis of 2-substituted, in particular 2-aryl-substituted, 1-alkyl (aryl-7-imidazole-3-oxides is readily possible from α-hydroxyiminoketones (α-diketone monoximes), primary amines and aldehydes (especially aromatic aldehydes) (Benz Chem / 1970/431), the reaction components are usually heated in glacial acetic acid or aqueous ethanol for a few hours.
Setzt man bei dieser grundsätzlichen Synthese an Stelle eines beliebigen anderen, in der Regel aber aromatischen Aldehyds Formaldehyd ein, so erhält man keine 2-unsubstituierten 1-Alkyl(aryl)-imidazol-3-oxide, sondern 1 -Alkyl(aryl)-2(3H)-imidazolone oder Gemische beider (Z. Chem. 10/1970/462).Substituting in this fundamental synthesis in place of any other, but usually aromatic aldehyde formaldehyde, we obtain no 2-unsubstituted 1-alkyl (aryl) -imidazole-3-oxides, but 1-alkyl (aryl) -2 (3H) -imidazolones or mixtures of both (Z. Chem. 10/1970/462).
Die 1-Alkyl(aryl)-imidazol-3-oxide ohne Substituenten in der 2-Stelluny erhält man nur dann, wenn die Reaktion mit einem 1,3,5·substituierten Hexahydro-1,3,5-triazin (dem Kondensationsprodukt aus Formaldehyd und Amin) in wasserfreien organischen Lösungsmitteln durchgeführt wird (J. Chem. Soc, Perkin Trans. 1/1975/275; Roczn. Chem. 51/1977/49). Von den Autoren dieser Synthesevariante wird angegeben, daß die Gegenwart von Wasser die Bildung der 2(3H)-lmidazolone begünstigt. Die Arbeit mit wasserfreien Lösungsmitteln ist technisch aufwendig und unbequem, die notwendige Herstellung der Hoxahydro-1,3,5-triazine eine zusätzliche Veif ahrensstufe, die durch die geringe Kristallisationsneigung dieser Verbindungen einen besonderen Aufwand erfordert.The 1-alkyl (aryl) -imidazole-3-oxides without substituents in the 2-Stelluny is obtained only if the reaction with a 1,3,5 · substituted hexahydro-1,3,5-triazine (the condensation product of Formaldehyde and amine) in anhydrous organic solvents (J.Chem.Soc, Perkin Trans. 1/1975/275; Roczn. Chem. 51/1977/49). The authors of this synthetic variant state that the presence of water favors the formation of the 2 (3H) -imidazolones. The work with anhydrous solvents is technically complicated and inconvenient, the necessary preparation of Hoxahydro-1,3,5-triazines an additional Veir Ahrensstufe, which requires due to the low tendency to crystallize these compounds a special effort.
Die Erfindung hat das Ziel, ein Syntheseverfahren zu erarbeiten, das unter technisch einfach zu realisierenden Bedingungen, insbesondere unter Einsatz von Wasser oder wasserhaltigen organischen Lösungsmitteln als Reaktionsmedium, die Herstellung von stabilen 1-substituierten lmidazol-3-oxideii ermöglicht, die in der 2-SteIlung keiner, Substituenten tragen.The object of the invention is to develop a synthesis process which, under conditions which are technically easy to implement, in particular using water or aqueous organic solvents as the reaction medium, enables the preparation of stable 1-substituted imidazole-3-oxideii, which is described in US Pat. Steplessness, no substituents.
Der Erfindung liegt die Aufgabe zugrunde, entweder durch die Entwicklung eines neuartigen Herstellungsverfahrens oder durch Variation des an sich bekannten Verfahrens hinsichtlich der Reaktionsbedingungen oder hinsichtlich der Reaktionskomponenten 2-unsubstituierte 1-Alkyl(aryl, aralkyl)-imidazol-3-oxide unter technisch einfachen Bedingungen zugänglich zu machen. Überraschenderweise wurde festgestellt, daß zur Lösung der Aufgabe kein grundsätzlich neues Herstellungsverfahren erforderlich ist. Es wurde gefunden, daß von nahezu beliebigen a-Hydroxyiminoketonen, aliphatischen, araliphatischen, cycloaliphatischen oder aromatischen primären Aminen und wäßriger Formaldehydlösung ausgehend immer dann stabile 2-unsubstituierte lmidazol-3-oxide und keine 2(3 Hl-Imidazolone entstehen, wenn die Aminkomponente eine oder mehrere freie Carboxylgruppen enthält. In all diesen Fällen ist die Anwendung wasserfreier organischer Reaktionsmedien eher störend als förderlich, da die als Aminkomponente fungierende Aminosäure in diesen Medien in der Regel wenig löslich ist; sofern das σ-Diketonmonoxim eine ausreichende Wasserlöslichkeit besitzt (z. B. Diacetylmonoxim), kann die Herstellung der 2-unsubstituierten lmidazol-3-oxide auch direkt in Wasser erfolgen. Zahlreiche Aminocarbonsäuretypen sind einsetzbar:The invention is based on the object, either by the development of a novel preparation process or by varying the known method with respect to the reaction conditions or with respect to the reaction components 2-unsubstituted 1-alkyl (aryl, aralkyl) -imidazol-3-oxides under technically simple conditions to make accessible. Surprisingly, it was found that no fundamentally new manufacturing process is required to solve the problem. It has been found that starting from almost any a-Hydroxyiminoketonen, aliphatic, araliphatic, cycloaliphatic or aromatic primary amines and aqueous formaldehyde starting always stable 2-unsubstituted imidazole-3-oxides and no 2 (3 Hl imidazolones arise when the amine component In all these cases, the use of anhydrous organic reaction media is more troublesome than beneficial, since the amino acid acting as the amine component is generally sparingly soluble in these media, provided that the σ-diketone monoxime has sufficient water solubility (e.g. Diacetylmonoxime), the preparation of the 2-unsubstituted imidazole-3-oxides can also be carried out directly in water.
(A) aliphatische, araliphatisnhe und cycloaliphatische α-Aminocarbonsäuren wie Glycin, Alanin, Valin, Norvalin, a-Aminobuttersäure, Leucin, Isoleucin, Phenylalanin und Phenylglycin, auch solche, die weitere funktioneile Gruppen besitzen wie Serin, Methionin, Asparaginsäure, Glutaminsäure, a-Aminoadipinsäure und Tyrosin, sowie solche, die zusätzlich α-verzweigt sind wie a-Aminoisobuttersäure, Isovalin, a-Methylphenylglycin und 1-Aminocyclohexan-i-carbonsäure,(A) aliphatic, araliphatic and cycloaliphatic α-aminocarboxylic acids such as glycine, alanine, valine, norvaline, α-aminobutyric acid, leucine, isoleucine, phenylalanine and phenylglycine, including those having other functional groups such as serine, methionine, aspartic acid, glutamic acid, a -Aminoadipinsäure and tyrosine, as well as those which are additionally α-branched such as a-aminoisobutyric acid, isovalin, a-methylphenylglycine and 1-aminocyclohexane-i-carboxylic acid,
(B) aliphatische β-, γ-, δ-, ε- und andere ω-Aminocarbonsäuren, die zusätzlich durch Alkyl-, Aralkyl-, Cycloalkyl- oder Arylgruppen C-substituiert sein können wie ß-Alanin, ß-Aminobuttersäure, γ-Aminobuttersäure, ε-Aminocapronsäure, ω-Amino-onanthsäure, a-(p-Chlorphenyl)-ß-aminopropionsäure (Baclofen) und ß-Amino-ß-phenylpropionsäure,(B) aliphatic β-, γ-, δ-, ε- and other ω-aminocarboxylic acids which may additionally be C-substituted by alkyl, aralkyl, cycloalkyl or aryl groups, such as β-alanine, β-aminobutyric acid, γ- Aminobutyric acid, ε-aminocaproic acid, ω-aminoanthic acid, a- (p-chlorophenyl) -β-aminopropionic acid (baclofen) and β-amino-β-phenylpropionic acid,
(C) aliphatisch-aromatische Aminocarbonsäuren, bei denen der Aromat die Aminogruppe trägt und die Carboxylgruppe Bestandteil des aliphatischen Moleküls ist, z.B. p-Amino-phenylessigsäure, p-Aminophenoxyessigsäure und o-, m- und p-Aminozimtsäure,(C) aliphatic-aromatic aminocarboxylic acids in which the aromatic carries the amino group and the carboxyl group is part of the aliphatic molecule, e.g. p-amino-phenylacetic acid, p-aminophenoxyacetic acid and o-, m- and p-aminocinnamic acid,
(O) aliphatisch-aromatische Aminocarbonsäuren, bei denen umgekehrt der aliphatische Molekülteil die Amino- und der(O) aliphatic-aromatic aminocarboxylic acids in which, conversely, the aliphatic moiety of the amino and the
aromatische Teil die Carboxylgruppe trägt, z. B. p-Aminomethyl-benzoesäure, (E) aromatische Aminocarbonsäuren wie o-, m- und p-Aminobenzoesäure und 4-Aminosalicylsäure. Als a-Diketonmonoxime sind u.a. Butan-2,3-dion-2-oxim (Diacetylmonoxim), 4-Methyl-pentan-2,3-dion-3-oxim, Heptan-2,3-dion-2-oxim, Octan-2,3-dion-3-oxim, 1-Phenyl-propan-1,2-dion-2-oxim (a-lsonitrosopropiophenom), 1-(4-Methylphenylipropan-1,2dion-2-oxim, 1-(4-Bromphenyl)-propan-1,2-dion-2-oxim, Pentan-2,3,4-trion-3-oxim (Isonitrosoacetylacetori), 2-Hydroxyimino-3-oxo-butansäureethylester(a-lsonitrosoacetessigester), 2-Hydroxyimino-3-oxo-butansäure-diethylamid, 2-Hydroxyimino-3-oxo-bi'tansäure-3-methylanilid und 4-(2 Hydroxyimino-3· oxo-butanoyl3mino)-benzoesäure einsetzbar. Mit den unter (A) genannten Aminocarbonsäuren und den vorstehenden a-Diketonmonoximen werden lmidazol-3-oxide des Typs 1 erhalten (Tabelle 1), mit den untei (B) aufg'iführten Aminosäuren lmidazol-3-oxide des Typs 2 (Tabelle 2), mit den unter (C) genannten Aminosäuren solche des Typs 3 (Tabslle 3), mit den unter (O) enthaltenen Aminosäuren die N-Oxide 4 (Tabelle 3) und mit den aromatischen Aminosäuren unter (E) die lmidazol-3-oxide 5 (Tabelle 3).aromatic part bears the carboxyl group, for. B. p-aminomethyl-benzoic acid, (E) aromatic aminocarboxylic acids such as o-, m- and p-aminobenzoic acid and 4-aminosalicylic acid. As a-diketone monoximes are u.a. Butane-2,3-dione-2-oxime (diacetylmonoxime), 4-methyl-pentane-2,3-dione-3-oxime, heptane-2,3-dione-2-oxime, octane-2,3-dione 3-oxime, 1-phenyl-propane-1,2-dione-2-oxime (α-iso-nitrosopropiophene), 1- (4-methyl-phenyl-propane-1,2-dione-2-oxime, 1- (4-bromophenyl) -propane 1,2-dione-2-oxime, pentane-2,3,4-trione-3-oxime (isonitrosoacetylacetyl), 2-hydroxyimino-3-oxo-butanoic acid ethyl ester (α-isoisonoacetate), 2-hydroxyimino-3-oxo butanoic acid diethylamide, 2-hydroxyimino-3-oxo-bi'-tanoic acid 3-methylanilide and 4- (2-hydroxyimino-3-oxo-butanoyl-3-amino) -benzoic acid can be used with the aminocarboxylic acids mentioned under (A) and the abovementioned Diketone monoximes are given imidazole-3-oxides of type 1 (Table 1), with the untei (B) aufg'iführt amino acids imidazole-3-oxide of type 2 (Table 2), with the amino acids mentioned under (C) of the type 3 (Table 3), with the amino acids contained under (O), the N-oxides 4 (Table 3) and with the aromatic amino acids under (E) the imidazole-3-oxides 5 (Tab 3).
XCOOH )=/ y^.CoOHXCOOH) = / y ^ .CoOH
Die in den Tabellen 1 und 2 aufgeführten lmidazol-3-oxide 1 (R' Φ R2) und 2 (R1 Φ H! wurden jeweils mit den R,S-bzw. D1L-Aminosäuren erhalten. Man kann die entsprechenden 1 und 2 aber auch mit den reinen R- und S-Enantiomeren herstellen; diese lmidazol-3-oxide sind dann optisch aktiv (Tabelle 4).The imidazole-3-oxides 1 (R ' Φ R 2 ) and 2 (R 1 Φ H 2 ) listed in Tables 1 and 2 were each obtained with the R, S or D 1 L amino acids 1 and 2 but also with the pure R and S enantiomers, these imidazole-3-oxides are then optically active (Table 4).
Fortsetzung Tabelle 1 Nr. R1 Continuation Table 1 No. R 1
R4 R 4
3.1 3.2 3.3 3.4 3.5 3.6 3.7 4.1 4.2 4.3 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.93.1 3.2 3.3 3.4 3.5 3.6 3.7 4.1 4.2 4.3 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9
CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3
CH3 CH 3
CH3 CH 3
CH3 CH 3
CH3 CH 3
C6H6 C 6 H 6
CH3 CH 3
C6H6 C 6 H 6
CH3 CH 3
C6H6 C 6 H 6
4-CIC6H4 4-CIC 6 H 4
CH3 CH 3
C6H6 C 6 H 6
4-CIC8H4 4-CIC 8 H 4
CH3 CH 3
C6H6 C 6 H 6
4-CIC6H4 4-CIC 6 H 4
CH3 CH 3
C6H6 C 6 H 6
4-CIC6H4 4-CIC 6 H 4
CH2 CH 2
CH=CHCH = CH
CH=CHCH = CH
CH=CHCH = CH
CH=CHCH = CH
OCH2 OCH 2
OCH2 OCH 2
CH2 CH 2
CH2 CH 2
CH2 CH 2
4 2 3 4 4 4 4 4 4 4 2 2 2 3 3 3 4 4 44 2 3 4 4 4 4 4 4 4 2 2 2 3 3 3 4 4 4
273-77273-77
194-98194-98
163-67163-67
217-21217-21
244-45244-45
360360
360360
269-73269-73
157-62157-62
254-56254-56
187-91187-91
248-52248-52
268-72268-72
184-89184-89
273-77273-77
178-83178-83
277-79277-79
168-70168-70
221-28221-28
63 53 83 62 77 84 91 68 83 73 82 73 75 65 73 44 59 68 3763 53 83 62 77 84 91 68 83 73 82 73 75 65 73 44 59 68 37
Tabelle 4. D-undL-i-a-CarboxyalkyKaralkyl.cycloalkyO-imidazol-S-oxide 1 (R2 = H)"Table 4. D- and L-ia-CarboxyalkyKaralkyl.cycloalkyO-imidazole S-oxides 1 (R 2 = H) "
Konf.Conf.
/a/g'/ A / g '
F. (0C) Zers.F. ( 0 C) Zers.
1) Drehweribestimmung: C = 3.1 N HCI1) rotation determination: C = 3.1 N HCI
2) n.b. = nie! 'bestimmt2) n.b. never! 'certainly
Ausb.(%)Yield. (%)
AusführungsbolspieleAusführungsbolspiele
Die nachfolgenden Beispiele erläutern die Erfindung, ohne sie einzuschränken.The following examples illustrate the invention without limiting it.
1) 4-n-Butyl-1-carboxymethyl-5-methyl-imidazol-3-oxid (1.7). Die Lösung von 4,29g (0,03mol) Heptan-2,3-dion-3-oxim, 2,37g (0,03mol) Glycin und 5g (0,05mol) 30%ige wäßrige Formaldehydlösuny in 80ml 80%igem Ethanol wird 3 Std. unter Rückfluß gekocht, abgekühlt, filtriert und im Rotationsverdampfer eingedampft. Der Rückstand wird 2-3mal mit je 50 ml Aceton behandelt, jeweils erneut eingedampft und schließlich mit Ether zur Kristallisation gebracht. Aus Chlorcform/Methanol/Benzin farblose Kristalle, F.2*2-24°C (Zers.); Ausb. 4,77g (75%). Analyse für C10H16N2O3 (212,2): C 56,32% (ber. 56,58%), H 7,56 (7,60), N 13,08 (13,20)1) 4-n-butyl-1-carboxymethyl-5-methyl-imidazole-3-oxide (1.7). The solution of 4.29 g (0.03 mol) heptane-2,3-dione-3-oxime, 2.37 g (0.03 mol) glycine and 5 g (0.05 mol) of 30% aqueous Formaldehydlösuny in 80 ml of 80% ethanol is refluxed for 3 hours, cooled, filtered and evaporated in a rotary evaporator. The residue is treated 2-3 times with 50 ml of acetone, in each case re-evaporated and finally brought to crystallization with ether. From Chloroform / Methanol / Petrol Colorless Crystals, F.2 * 2-24 ° C (dec.); Y. 4,77g (75%). Analysis for C 10 H 16 N 2 O 3 (212.2): C 56.32% (calc. 56.58%), H 7.56 (7.60), N 13.08 (13.20)
IR-Spektrum (KBr); 645,745,900,960,1025,1100,1155,1 205 (θΝ0). 1 260,1325,1375,1420,1455,1540,1680 (Oco) 2065 (θ0Η0). 2400 (θοΗΟ), 2860,2925,2955,3040,3105cm"1 (θ0Η) 80 MHr-'HNMR-Spektrum (DMSO-d6): δ = 8,56ppm (s, 1H, Im-2H), 4,59ppm (s,2H,CH2),4,03ppm („s", breit,6H,3CH2), 2,07ppm (s,3H, ImCH3), 0,90ppm (s, 3H, CH3)IR spectrum (KBr); 645,745,900,960,1025,1100,1155,1205 (θ Ν0 ). 1,260,1325,1375,1420,1455,1540,1680 (O co ) 2065 (θ 0Η0 ). 2400 (θοΗΟ), 2860.2925,2955,3040,3105cm " 1 (θ 0Η ) 80 MHr-'HNMR spectrum (DMSO-d6): δ = 8.56ppm (s, 1H, Im-2H), 4, 59ppm (s, 2H, CH 2 ), 4.03ppm ("s", broad, 6H, 3CH 2 ), 2.07ppm (s, 3H, ImCH 3 ), 0.90ppm (s, 3H, CH 3 )
2) D.L-i-a-Carboxyethyl-S-p-chlorphenyl^-rnethylimidazol-S-oxidd.n). Die Lösung von 3,95g I0,02mol) 1-(4-Chlorphenyl)-1,2-propandion-2-oxim, 1.78g (0,02 mol) D,L-Alanin und 3g (0,03mol) 30%ige Formaldehydlösung in 100ml Methanol wird 4 Stdn. unter Rückfluß gekocht. Beim Abkühlen kristallisieren 5,6g (78%). Aus verdünntem Ethanol farblose Kristalle, F. 199-202°C (Zers.). Analyse für C13H13CI N2O3 (280,7): C 54,89% (ber. 55,62%), H 4.81 (4,67), N 9,79 (9,98), Cl 12,99 (12,63). IR-Spektrum (Nujol): 755,855,870,950-1000 (breit), 1100,1210 (SN0), 1305,1341,1715 (θ£0), 3125crrr' (θ0Η).2) DL-ia-carboxyethyl-Sp-chlorophenyl-methyl-imidazole-S-oxide-d). The solution of 3.95 g of I0.02 mol) of 1- (4-chlorophenyl) -1,2-propanedione-2-oxime, 1.78 g (0.02 mol) of D, L-alanine and 3 g (0.03 mol) of 30% Formaldehyde solution in 100 ml of methanol is boiled under reflux for 4 hrs. Upon cooling, 5.6 g (78%) crystallize. From dilute ethanol colorless crystals, mp 199-202 ° C (dec.). Analysis for C 13 H 13 Cl N 2 O 3 (280.7): C 54.89% (calc. 55.62%), H 4.81 (4.67), N 9.79 (9.98), Cl 12.99 (12.63). IR spectrum (Nujol): 755,855,870,950-1,000 (wide), 1100,1210 (S N0 ), 1305,1341,1715 (θ £ 0 ), 3125crrr '(θ 0Η ).
80 MHz — 1HNMR-Spektrum (DMSO-d6): δ = 8,98ppm (s, 1H, lm-2h), 7,55ppm (m, 4H, Ar-H), 4,48ppm (9,1 H, J = 7,38 Hz, CH), 2,04 ppm (s, 3 H, ImCH3I, i ,60 ppm (d, 3 H, J = 7,26 Hz, Q-CH3).80 MHz - 1 HNMR spectrum (DMSO-d 6 ): δ = 8.98 ppm (s, 1H, lm-2h), 7.55 ppm (m, 4H, Ar-H), 4.48 ppm (9.1 H , J = 7.38 Hz, CH), 2.04 ppm (s, 3 H, 3 IMCH I, i, 60 ppm (d, 3 H, J = 7.26 Hz, Q-CH 3).
3) D.L-1 -a.ß-Dicarboxyethyl^-ethoxycarbonyl-ö-methyl-imidszol-S-oxid (1.77). Die Lösung von 4,9g (Ο,Γ-3 mol) 2-Hydroxyimino-3-oxo-butansäureethylester,4,0g (0,03mol) D,L-Asparaginsäure und 5g (p,05mol) 30%ige Formaldehydlösung in 80ml 80%igem Ethanol wird 3 Stdn. unter Rückfluß gekocht, abgekühlt und im Rotationsverdampfer eingedampft. Der Rückstand kristallisiert beim Behandeln mit Aceton. Man erhält 6,95g (81 %) eines farblosen Produktes, das aus Chloroform/Ethanol/Benzin umkristallisiert wird; F. 145-^8°C(Zers.).3) D.L-1-α.beta.-dicarboxyethyl ^ -ethoxycarbonyl-.alpha.-methyl-imidazole S-oxide (1.77). The solution of 4.9 g (Ο, Γ-3 mol) of ethyl 2-hydroxyimino-3-oxo-butanoate, 4.0 g (0.03 mol) of D, L-aspartic acid and 5 g (p, 05 mol) of 30% formaldehyde solution in 80 ml 80% ethanol is boiled under reflux for 3 hrs, cooled and evaporated in a rotary evaporator. The residue crystallizes on treatment with acetone. This gives 6.95 g (81%) of a colorless product, which is recrystallized from chloroform / ethanol / gasoline; F. 145-8 ° C (dec.).
Analyse für C11H14N2O7 (286,2): C 45,85% (ber. 46,1B%), H 4,78 (4,93), N 9,69 (9,79).Analysis for C 11 H 14 N 2 O 7 (286.2): C 45.85% (calculated 46.1B%), H 4.78 (4.93), N 9.69 (9.79).
IR-Spektrum (KBr): 605,635,735,760,845; 880,935,960,1005,1080,1180 (θΝ0), 1 235,1 260,1320,1395,1435,1475,1605,1680 Oco), 1695 Oco), 1705 (γεο), 2000 (θΟΗο), 2480 (θ0Η0), 2600 (θΟΗο), 2915, 2965,3220cm-\{»oH)· 80ΜΗζ-1 HNMR-Spektrum (DMSO-d6): δ = 10,46ppm <s, 1H, Irn-2H),4,96ppm (t, 1H, J - 5,32 Hz, CH),4,19ppm (9,2H, J = 6,77Hz, CH2 Me), 3,07 ppm (d, CH, J = 6,11 H, Q-CH2), 2,36 ppm (s, 3 H, ImCH3) 1,;>5ppm (t, 3 H, J = 6,32 Hz, CH3).IR spectrum (KBr): 605,635,735,760,845 ; 880, 935, 960, 1005, 1080, 1180 (θ Ν0 ), 1 235.1, 260, 1320, 1395, 1435, 1475, 1605, 1680 O co ), 1695 Oco), 1705 (γ εο ), 2000 (θ ΟΗ ο), 2480 (θ 0Η0 ), 2600 (θ ΟΗ ο), 2915, 2965,3220cm - \ {»oH) · 80ΜΗζ-1 HNMR spectrum (DMSO-d 6 ): δ = 10.46 ppm <s, 1H, Ir 2H), 4.96ppm (t, 1H, J - 5.32Hz, CH), 4.19ppm (9.2H, J = 6.77Hz, CH 2 Me), 3.07ppm (d, CH, J = 6.11 H, Q-CH 2), 2.36 ppm (s, 3 H, IMCH 3) 1,;> 5 ppm (t, 3 H, J = 6.32 Hz, CH 3).
4) D-i-a-Carboxyisobutyl^.S-dimethyl-irnidazol-S-oxid (1.94). Die Lösung von 5,05g (0,05 mol) Butan-2,3-dion-2-oxim (Diacetylmonoxim), 5,85g (0,05 mol) D-VaIin und 7,0g (0,07 mcl) 30%ige Formaldehydlösung in 100 ml Ethanol wird 4 Stdn. unter Rückfluß gekocht, abgekühlt, filtriert und eingedampft. Der Rückstand kristallisiert beim Behandeln mit Aceton und läßt sich aus Chloroform/Methanol/Benzin Umkristallisieren. Man erhält farblose Nadeln, F. 208-10°C (Zers.), /α/" -35,21°, C = 3,1NHCI; Ausb. 9,97 g (94%).4) D-i-a-Carboxyisobutyl ^. S-dimethyl-iridazole S-oxide (1.94). The solution of 5.05 g (0.05 mol) of butane-2,3-dione-2-oxime (diacetylmonoxime), 5.85 g (0.05 mol) of D-valine and 7.0 g (0.07 mcl) of 30 % Formaldehyde solution in 100 ml of ethanol is boiled under reflux for 4 hrs, cooled, filtered and evaporated. The residue crystallizes on treatment with acetone and can be recrystallized from chloroform / methanol / gasoline. This gives colorless needles, mp 208-10 ° C (dec.), / Α / "-35.21 °, C = 3.1NHCl, yield 9.97 g (94%).
Analyse für C10H16N2O3 (212,2): C 56,38% (ber. 56,58%), H 7,83 (7,60), N 13,01 (13,20).Analysis for C 10 H 16 N 2 O 3 (212.2): C 56.38% (calc. 56.58%), H 7.83 (7.60), N 13.01 (13.20).
IR-Spektrum (KBr): 775,900-1000 (breit), 1190 (θΝ0), 1220,1370,1420,1710 (θεο). 2865,3130,3400cm"1 (8Oh) 200MHz-1HNMR-Spektrum(DjO/NaOD): = 7,92ppm(s,1H,lm-2H),3,81ppm(d,1H,J = 9,49H^CHCOO"), 1,91 ppm (m,1 H, J = 6,72 Hz, CHMe2), 1,75 ppm (s, 3 H, ImCH3), 1,70 ppm (s, 3 H, Im CH3), 0,61 ppm (d, 3 H, J = 6,64 Hz, CH3), 0,43 ppm (d, 3 H, J = 6,58 Hz, CH3) ES-MS (7OeV; 22O°C,VioV); 212 (15,4% B; M+), 196 (95,7; M-16), 97 (B).IR spectrum (KBr): 775.900-1000 (wide), 1190 (θ Ν0 ), 1220, 1370, 1420, 1710 (θ εο ). 2865.3130.3400cm " 1 (8 o h) 200MHz- 1 HNMR spectrum (DjO / NaOD): = 7.92ppm (s, 1H, lm-2H), 3.81ppm (d, 1H, J = 9, 49H ^ CHCOO "), 1.91 ppm (m, 1 H, J = 6.72 Hz, CH Me 2), 1.75 ppm (s, 3 H, IMCH 3), 1.70 ppm (s, 3 H , In CH 3 ), 0.61 ppm (d, 3 H, J = 6.64 Hz, CH 3 ), 0.43 ppm (d, 3 H, J = 6.58 Hz, CH 3 ) ES-MS (7OeV, 22O ° C, VioV); 212 (15.4% B; M + ), 196 (95.7; M-16), 97 (B).
5) 1-<i>-Carboxypentyl-4,5-dimethyl-imidazol-3-oxid (2,2). Die Lösung von 5,05g (0,05mol) Butan-2,3-dion-2-oxim, 6,5Gg (0,05mol) ε-Aminocapronsäure und 7,0g (0,07mol) 30%ige Formaldehydlösung ir. 100ml 95%igem Ethanol wird 5 Stdn. unter Rückfluß gekocht, abgekühlt und im Rotationsverdampfer eingedampft. Beim Behandeln des Rückstandes mit Aceton tritt Kristallisation ein. Das Produkt wird abgesaugt und aus Ethanol/Wasser umkristallisiert. Man erhält farblose Nadeln, F. 166-69°C (Zers.),Ausb. 6,22g (55%).5) 1- (i) -Carboxypentyl-4,5-dimethyl-imidazole-3-oxide (2,2). The solution of 5.05 g (0.05 mol) of butane-2,3-dione-2-oxime, 6.5 g (0.05 mol) of ε-aminocaproic acid and 7.0 g (0.07 mol) of 30% formaldehyde solution ir. 100 ml 95% ethanol is boiled under reflux for 5 hrs, cooled and evaporated in a rotary evaporator. Upon treatment of the residue with acetone, crystallization occurs. The product is filtered off and recrystallized from ethanol / water. This gives colorless needles, mp 166-69 ° C (dec.), Yield. 6.22g (55%).
Analyse für CuHi8N2O3 (226,3): C 57,85% (ber. 58,39%), H 8,14 (8,02), N 12,09 (12,38). ES-MS (7OeV; 170"C, VioV); 210 (89,1 % B, ML16), 110 (B)Analysis for CuHi 8 N 2 O 3 (226.3): C 57.85% (calculated 58.39%), H 8.14 (8.02), N 12.09 (12.38). ES-MS (7OeV; 170 "C, VioV); 210 (89.1% B, ML16), 110 (B)
6) 1-p-Carboxymethylphenyl-4,5-dimethyl-imidazol-3-oxid (3.1). Die Lösung von 3,03g (0,03mol) Butan-2,3-dion-2-oxim, 4,53g (0,03mol) p-Aminophenylessigsäure und 5g (0,05mol) 30%ige Formaldehydlösung in 100ml Methanol wird 4 Stdn. unter Rückfluß gehalten, abgekühlt, filtriert und eingedampft. Der Rückstand kristallisiert beim Anreiben mit Aceton. Aus Ethanol/ Wasser farblose Kristalle, F. 273-77"C (Zers.); Ausb. (63%).6) 1-p-carboxymethylphenyl-4,5-dimethyl-imidazole-3-oxide (3.1). The solution of 3.03 g (0.03 mol) of butane-2,3-dione-2-oxime, 4.53 g (0.03 mol) of p-aminophenylacetic acid and 5 g (0.05 mol) of 30% formaldehyde solution in 100 ml of methanol becomes 4 Stdn. Held under reflux, cooled, filtered and evaporated. The residue crystallizes on trituration with acetone. Colorless crystals from ethanol / water, mp 273-77 "C (dec.); Yield (63%).
3400cm"1 Ooh)·3400cm " 1 ooh) ·
7) 1-p-Carboxybenzyl-4,5-dimethyl-imidazol-3-oxid (4.1). Die Lösung von 2,02g (0,02mol) Bu'.an-2,3-dion-2-oxim, 3,02g (0,02mol) p-Aminomethyl-benzoesäure (PAMBA) und 4g (0,04mol) 30%igo Formaldehydlösung in 70ml Ethanol wird 3 Stdn. unter Rückfluß gekocht, filtriert und auf die Hälfte des Volumens eingedampft. Dabei tritt Kristallisation ein. Man erhält 3,35g (68%) farbloses Produkt, F. 269-730C unter Zers. (Dimethylformamid/Wasser).7) 1-p-Carboxybenzyl-4,5-dimethyl-imidazole-3-oxide (4.1). The solution of 2.02 g (0.02 mol) of Bu'.an-2,3-dione-2-oxime, 3.02 g (0.02 mol) of p-aminomethylbenzoic acid (PAMBA) and 4 g (0.04 mol) of 30 % igo formaldehyde solution in 70 ml of ethanol is boiled under reflux for 3 hours, filtered and evaporated to half the volume. This crystallization occurs. This gives 3.35 g (68%) of colorless product, mp 269-73 0 C under Zers. (Dimethylformamide / water).
3110cm'1 (θΟΗ).3110cm ' 1 (θΟΗ).
8) 1 -p-Carboxyphenyl-4,5-dimethyl-imidazol-3-oxid (5.7). Die Lösung von 3,03g (0,03 mol) Butan-2,3-dion-2-oxim, 4,11 g (0,03mol) p-Aminobenzoesäure und 5g (0,05mol) 30%ige Formaldehydlösung in 50ml Dimethylformamid (DMF) wird unter Rühren'3 Stdn. auf 1000C erhitzt, abgekühlt und portionsweise mit 200ml Wasser verdünnt. Das ausgefallene Produkt wird abgesaugt, mit 50%igem Ethanol gewaschen und aus DMF/Wasser umkristallisiert. Farblose Kristalle, F. 277-790C (Zers.); Ausb. 4,11g (59%).8) 1 -p-Carboxyphenyl-4,5-dimethyl-imidazole-3-oxide (5.7). The solution of 3.03 g (0.03 mol) of butane-2,3-dione-2-oxime, 4.11 g (0.03 mol) of p-aminobenzoic acid and 5 g (0.05 mol) of 30% formaldehyde solution in 50 ml of dimethylformamide (DMF) is heated under Rühren'3 hrs. to 100 0 C, cooled, and diluted portionwise with 200 ml of water. The precipitated product is filtered off, washed with 50% ethanol and recrystallized from DMF / water. Colorless crystals, mp 277-79 0 C (dec.); Y. 4.11g (59%).
3010,3090,3420Cm-1OOH).3010, 3090, 3420 Cm -1 OOH).
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD31582688A DD271903A1 (en) | 1988-05-17 | 1988-05-17 | PROCESS FOR THE PRODUCTION OF STABILIZED, 2-UNSUBSTITUTED IMIDAZOLE-3-OXIDE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD31582688A DD271903A1 (en) | 1988-05-17 | 1988-05-17 | PROCESS FOR THE PRODUCTION OF STABILIZED, 2-UNSUBSTITUTED IMIDAZOLE-3-OXIDE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD271903A1 true DD271903A1 (en) | 1989-09-20 |
Family
ID=5599295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD31582688A DD271903A1 (en) | 1988-05-17 | 1988-05-17 | PROCESS FOR THE PRODUCTION OF STABILIZED, 2-UNSUBSTITUTED IMIDAZOLE-3-OXIDE |
Country Status (1)
| Country | Link |
|---|---|
| DD (1) | DD271903A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0700904A1 (en) * | 1994-09-09 | 1996-03-13 | Hoechst Aktiengesellschaft | Heterocyclic-N-oxide substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic, medicaments containing them as well as intermediates for their preparation |
| JP2007502259A (en) * | 2003-08-14 | 2007-02-08 | グラクソ グループ リミテッド | Inhibitors of matrix metalloproteinases |
-
1988
- 1988-05-17 DD DD31582688A patent/DD271903A1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0700904A1 (en) * | 1994-09-09 | 1996-03-13 | Hoechst Aktiengesellschaft | Heterocyclic-N-oxide substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic, medicaments containing them as well as intermediates for their preparation |
| JP2007502259A (en) * | 2003-08-14 | 2007-02-08 | グラクソ グループ リミテッド | Inhibitors of matrix metalloproteinases |
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