DE102019129221A1 - Process for the synthesis of ortho-nitrobenzoyl-DOPA and intermediates for its preparation - Google Patents

Process for the synthesis of ortho-nitrobenzoyl-DOPA and intermediates for its preparation Download PDF

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DE102019129221A1
DE102019129221A1 DE102019129221.2A DE102019129221A DE102019129221A1 DE 102019129221 A1 DE102019129221 A1 DE 102019129221A1 DE 102019129221 A DE102019129221 A DE 102019129221A DE 102019129221 A1 DE102019129221 A1 DE 102019129221A1
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nitrobenzyl
char
benzyl
azlactone
dopa
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Stephan Quint
Ralf Zuhse
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Chiracon GmbH
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    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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Abstract

Die Erfindung betrifft Verfahren zur Synthese von ortho-Nitrobenzyl-DOPA und Zwischenstufen zu dessen Herstellung.wobei R bevorzugt Nitrobenzyl istThe invention relates to processes for the synthesis of ortho-nitrobenzyl-DOPA and intermediate stages for its preparation, where R is preferably nitrobenzyl

Description

Die Erfindung betrifft Verfahren zur Synthese von ortho-Nitrobenzyl-DOPA und Zwischenstufen zu dessen Herstellung.The invention relates to processes for the synthesis of ortho-nitrobenzyl-DOPA and intermediates for its preparation.

In der Human- und Veterinärmedizin existieren verschiedene Klebstoffe zur Wundbehandlung oder Hämostase, während z.B. für die Behandlung von Knochenbrüchen keine Klebstoffe zur Verfügung stehen. Allerdings weisen die am Markt erhältlichen Produkte gravierende Nachteile auf. Dazu zählen insbesondere das Toxizitätspotential der Klebstoffe (z. B. Cyanacrylat), die teilweise ungenügende Kontrolle der Klebewirkung mit der Folge von unerwünschter Verklebung von Gewebe und Instrumentarien, hohe Behandlungskosten sowie die Gefahr der Übertragung infektiöser Agentien bei Stoffen humanen und tierischen Ursprungs (z.B. Fibrin). Miesmuscheln stellen einen biologischen Peptid-basierten Klebstoff her, der ihnen das Kleben auf verschiedenen Oberflächen im Wasser ermöglicht - eine Umgebung in der die meisten Klebstoffe nicht funktionieren - und dabei den marinen Gezeitenkräften zu widerstehen. Entscheidend für die Klebewirkung der Proteine ist der hohe Anteil der nicht-kanonischen Aminosäure DOPA (L-3,4-Dihydroxyphenylalanin). Setzt man DOPA mit einer fotolabilen ONB-Schutzgruppe, wie sie schon in zahlreichen Studien verwendet wurde, ein, ermöglicht es die Produktion photoaktivierbarer Proteine oder hier genauer photoaktivierbarer Protein-Klebstoffe, wobei eine Abspaltung durch Bestrahlung mit Licht der Wellenlänge 365 nm erfolgt. Diese Strategie hat folgende Vorteile: 1) Die unerwünschte Oxidation von DOPA wird verhindert. 2) Die Klebewirkung kann bei Bedarf durch Lichtbestrahlung aktiviert werden, indem die fotolabile ONB-Schutzgruppe abgespalten wird.In human and veterinary medicine there are various adhesives for treating wounds or hemostasis, while no adhesives are available for treating bone fractures, for example. However, the products available on the market have serious disadvantages. These include in particular the toxicity potential of the adhesives (e.g. cyanoacrylate), the sometimes inadequate control of the adhesive effect with the consequence of undesired adhesion of tissue and instruments, high treatment costs and the risk of the transmission of infectious agents in substances of human and animal origin (e.g. fibrin ). Mussels make a biological peptide-based adhesive that allows them to stick to various surfaces in the water - an environment in which most adhesives do not work - while resisting the forces of the marine tides. The high proportion of the non-canonical amino acid DOPA (L-3,4-dihydroxyphenylalanine) is decisive for the adhesive effect of the proteins. If DOPA is used with a photolabile ONB protective group, as it has already been used in numerous studies, it enables the production of photoactivatable proteins or, more precisely, photoactivatable protein adhesives, which are split off by irradiation with light with a wavelength of 365 nm. This strategy has the following advantages: 1) The undesired oxidation of DOPA is prevented. 2) If necessary, the adhesive effect can be activated by exposure to light by cleaving off the photolabile ONB protective group.

Bisher ist nur eine Synthese für diese Komponente beschrieben. Sie umfasst 8 Stufen mit einer Gesamtausbeute von 4%. Auf der letzten Stufe erfolgt eine enzymatische Racematspaltung, was aus pharmakologischer Sicht ein Problem bedeuten könnte.So far, only one synthesis has been described for this component. It comprises 8 stages with an overall yield of 4%. The last stage is an enzymatic resolution, which could be a problem from a pharmacological point of view.

Aufgabe der Erfindung ist es daher, ein Verfahren zur enantioselektiven Herstellung von ortho-Nitrobenzyl-DOPA zur Verfügung zu stellen.The object of the invention is therefore to provide a process for the enantioselective production of ortho-nitrobenzyl-DOPA.

Die Aufgabe der Erfindung wird gelöst durch ein Verfahren nach Anspruch 1.The object of the invention is achieved by a method according to claim 1.

Nachfolgend wird das Verfahren nach Anspruch 1 in seiner bestmöglichen Ausprägung vorgestellt, nämlich eine vollsynthetische, enantioselektive Synthese, die 5 Stufen umfasst und das Produkt in einer Gesamtausbeute von 5-7% erzeugt. Schlüsselschritt ist eine asymmetrische Hydrierung mit einer chiralen Rhodiumspezies.In the following, the method according to claim 1 is presented in its best possible form, namely a fully synthetic, enantioselective synthesis which comprises 5 stages and produces the product in an overall yield of 5-7%. The key step is an asymmetric hydrogenation with a chiral rhodium species.

Allgemeine Syntheseroute:General synthesis route:

Figure DE102019129221A1_0002
Figure DE102019129221A1_0003
Figure DE102019129221A1_0004
wobei R ausgesucht ist aus der Gruppe bestehend aus:
Figure DE102019129221A1_0005
Figure DE102019129221A1_0006
Figure DE102019129221A1_0007
Figure DE102019129221A1_0008
wobei die Cumarin-Abkömmlinge für R den besonderen Vorteil haben, dass diese beim photoinduzierten Austritt beim Einsatz am Patienten keine toxischen Nebenprodukte bilden.
Figure DE102019129221A1_0002
Figure DE102019129221A1_0003
Figure DE102019129221A1_0004
 where R is selected from the group consisting of:
Figure DE102019129221A1_0005
Figure DE102019129221A1_0006
Figure DE102019129221A1_0007
Figure DE102019129221A1_0008
 The coumarin derivatives for R have the particular advantage that they do not form any toxic by-products when they are photo-induced when used on patients.

Bevorzugte Syntheseroute:Preferred synthesis route:

Figure DE102019129221A1_0009
Figure DE102019129221A1_0009
Figure DE102019129221A1_0010
Figure DE102019129221A1_0010
Figure DE102019129221A1_0011
Figure DE102019129221A1_0011

Beschreibung der EinzelschritteDescription of the individual steps

Einführung der lichtempfindlichen Austrittsgruppe RIntroduction of the light-sensitive leaving group R

Figure DE102019129221A1_0012
Figure DE102019129221A1_0012

Bevorzugt Einführung der Nitrobenzyl Gruppe als lichtempfindliche Austrittsgruppe

Figure DE102019129221A1_0013
30,9 g Natriumhydrid (774 mmol; 2,03 eq. 60% in Mineralöl) werden dreimal mit je 100 ml Hexan gewaschen und unter Feinvakuum getrocknet. Man suspendiert in 500 ml DMF (abs.) und kühlt im Eisbad. 52,6 g Dihydroxybenzaldehyd (381 mmol) werden innerhalb von 15 Minuten portionsweise addiert und werden 30 Minuten im Eisbad nachgerührt. 82,3 g o-Nitrobenzylbromid (381 mmol; 1eq.) werden in 160 ml DMF (abs.) gelöst und innerhalb von 25 Minuten zugetropft. Nach 20 Minuten wird ein Gemisch aus 1,95 ml Wasser und 250 ml 2M Salzsäure eingegossen und mit 700 ml Essigsäureethylester versetzt. Man rührt einige Minuten nach und filtriert dann über eine G3 Fritte. Die Phasen werden getrennt und die wässrige Phase noch dreimal mit je 700 ml Essigsäureethylester extrahiert. Die vereinten organischen Phasen werden dreimal mit je 700 ml Wassergewaschen, sowie über Natriumsulfat getrocknet.
Nach Filtration und Einengen erhält man 99,95 g gelboranges Öl.Preference is given to introducing the nitrobenzyl group as the light-sensitive leaving group
Figure DE102019129221A1_0013
 30.9 g of sodium hydride (774 mmol; 2.03 eq. 60% in mineral oil) are washed three times with 100 ml of hexane each time and dried under fine vacuum. It is suspended in 500 ml of DMF (abs.) And cooled in an ice bath. 52.6 g of dihydroxybenzaldehyde (381 mmol) are added in portions over the course of 15 minutes and the mixture is subsequently stirred in an ice bath for 30 minutes. 82.3 g of o-nitrobenzyl bromide (381 mmol; 1eq.) Are dissolved in 160 ml of DMF (abs.) And added dropwise over the course of 25 minutes. After 20 minutes, a mixture of 1.95 ml of water and 250 ml of 2M hydrochloric acid is poured in, and 700 ml of ethyl acetate are added. The mixture is stirred for a few minutes and then filtered through a G3 frit. The phases are separated and the aqueous phase is extracted three times with 700 ml of ethyl acetate each time. The combined organic phases are washed three times with 700 ml of water each time and dried over sodium sulfate.
After filtration and concentration, 99.95 g of yellow-orange oil are obtained.

Dieses Öl wird in 300 ml warmem Methanol gelöst. 500 ml Wasser werden addiert und man erwärmt für 15 Minuten auf 80-85°C. Die entstehende kaugummiartige Masse wird durch Filtration über eine G3 Fritte abgetrennt, bei 40°C am Rotationsverdampfer getrocknet, sowie mit Methanol abgeraucht. 79,83 g einer harzartigen Masse werden isoliert.This oil is dissolved in 300 ml of warm methanol. 500 ml of water are added and the mixture is heated to 80-85 ° C. for 15 minutes. The resulting chewing gum-like mass is separated off by filtration through a G3 frit, dried at 40 ° C. on a rotary evaporator and smoked with methanol. 79.83 g of a resinous mass are isolated.

150 ml Dichlormethan werden addiert und man erwärmt zum Sieden. Man lässt bei 4°C kristallisieren. Es wird über eine G3 Fritte filtriert und fünfmal mit je 20 ml kaltem Dichlormethan gewaschen.150 ml of dichloromethane are added and the mixture is heated to the boil. It is left to crystallize at 4 ° C. It is filtered through a G3 frit and washed five times with 20 ml of cold dichloromethane each time.

Man erhält 23,26 g Produkt (85 mmol, 22%, 09-19-11-08 P8571) als weißen Feststoff.
1H-NMR-Daten für R gleich Nitrobenzyl
1H (DMSO): s 10,38 (1H, OH); s 9,76 (1H, CHO); dd 8,15(8,2/1,1 Hz, 1H, CHar NO2 Benzyl); d 7,92 (7,4 Hz, 1H, CHar NO2 Benzyl), dt 7,82 (7,6-7,7/1-1,2 Hz, 1H, CHar NO2 Benzyl), m 7,61-7,66 (1H, CHar NO2 Benzyl); m 7,45-7,49, 2H, 2xCHar); m 7,01-7,05 (1H, CHar); s 5,53 (2H, CH2 Benzyl)23.26 g of product (85 mmol, 22%, 09-19-11-08 P8571) are obtained as a white solid.
1 H-NMR data for R equal to nitrobenzyl
1 H (DMSO): 10.38 s (1H, OH); s 9.76 (1H, CHO); dd 8.15 (8.2 / 1.1 Hz, 1H, CH ar NO 2 benzyl); d 7.92 (7.4 Hz, 1H, C Har benzyl NO 2), dt 7.82 (7.6-7.7 / 1-1.2 Hz, 1H, CH ar NO 2 benzyl), m 7, 61 - 7.66 (1H, CH ar NO 2 benzyl); m 7.45-7.49, 2H, 2xCHar); m 7.01-7.05 (1H, CHar); s 5.53 (2H, CH 2 benzyl)

Bildung des AzlactonsFormation of azlactone

Figure DE102019129221A1_0014
Bevorzugt Bildung des Azlactons mit R gleich Nitrobenzyl
Figure DE102019129221A1_0015
23,26 g Produkt der Vorstufe (85 mmol), 9,08 g Natriumacetat (111 mmol, 1,3 eq.) und 11,98 g N-Acetylglycin (102 mmol, 1,2 eq.) werden trocken vorgemischt und in 40 ml Essigsäureanhydrid (426 mmol, 5 eq.) suspendiert. Man erwärmt 4 Stunden auf 120°C. Zunächst bildet sich eine gut rührbare Mischung, dann eine gelbe Suspension. Nach Abkühlen werden 70 ml Wasser addiert und man zerkleinert mechanisch, um Rührbarkeit zu erreichen. Es wird über eine G3 Fritte filtriert und sechsmal mit je 23 ml eines 1:1 Gemisches aus Wasser und Ethanol gewaschen, sowie bei 40°C getrocknet.
31,4 g eines gelben Feststoffes (79 mmol, 93%, 09-19-11-15 P8579) werden als Produkt isoliert.
1H-NMR-Daten für R gleich Nitrobenzyl
1H (DMSO): dd 8,18 (0,7/8,2 Hz, 1H, CHar NO2 Benzyl); d 8,03 (1,7 Hz, 1H, CHar); dd 7,83 (1,7/8,3 Hz, 1H, CHar); dt 7,80 (1/7,5-7,7 Hz, 1H, CHar NO2 Benzyl); d 7,73 (6,9 Hz, 1H, CHar NO2 Benzyl); m 7,6-7,66 (wohl dt, 1H, CHar NO2 Benzyl); d 7,28 (8,3 Hz, 1H, CHar); s 7,18 (1H; CHolef); s 5,57 (2H, CH2 Benzyl); s 2,37 (3H; CH3); s 2,31 (3H; CH3COO-)
Figure DE102019129221A1_0014
 Preferred formation of the azlactone where R is nitrobenzyl
Figure DE102019129221A1_0015
 23.26 g of the product of the precursor (85 mmol), 9.08 g of sodium acetate (111 mmol, 1.3 eq.) And 11.98 g of N-acetylglycine (102 mmol, 1.2 eq.) Are premixed dry and in 40 ml of acetic anhydride (426 mmol, 5 eq.) Suspended. The mixture is heated to 120 ° C. for 4 hours. First a well-stirrable mixture forms, then a yellow suspension. After cooling, 70 ml of water are added and the mixture is crushed mechanically in order to achieve stirrability. It is filtered through a G3 frit and washed six times with 23 ml each of a 1: 1 mixture of water and ethanol, and dried at 40 ° C.
31.4 g of a yellow solid (79 mmol, 93%, 09-19-11-15 P8579) are isolated as the product.
1 H-NMR data for R equal to nitrobenzyl
1 H (DMSO): dd 8.18 (0.7 / 8.2 Hz, 1H, CHar NO 2 benzyl); d 8.03 (1.7 Hz, 1H, CHar); dd 7.83 (1.7 / 8.3 Hz, 1H, CHar); dt 7.80 (1 / 7.5-7.7 Hz, 1H, CHar NO 2 benzyl); d 7.73 (6.9 Hz, 1H, CHar NO 2 benzyl); m 7.6-7.66 (probably dt, 1H, CHar NO 2 benzyl); d 7.28 (8.3 Hz, 1H, CHar); s 7.18 (1H; CH olef ); s 5.57 (2H, CH 2 benzyl); s 2.37 (3H; CH 3); s 2.31 (3H; CH 3 COO-)

Öffnung des AzlactonsOpening of the azlactone

Figure DE102019129221A1_0016
Figure DE102019129221A1_0016

Bevorzugt Öffnung des Azlactons mit R gleich Nitrobenzyl

Figure DE102019129221A1_0017
31,4 g Produkt der Vorstufe werden in 184 ml Ethanol suspendiert und mit 56 ml Triethylamin versetzt und erwärmt 28h unter Rückfluss. Reaktionskontrolle ist nach Verdünnen mit DCM mit dem Gemisch EE/PE 2:1 möglich. Man nimmt in 1,6 I Essigester auf und addiert 1 I Wasser und 1 I Kochsalzlösung. Mit 56 ml Salzsäure (25%) bringt man auf pH 1 und trennt die Phasen. Die wässrige Phase wird noch viermal mit je 800 ml Essigsäureethylester extrahiert. Die vereinten organischen Phasen werden mit 600 ml Kochsalzlösung gewaschen, sowie über Natriumsulfat getrocknet. Nach Filtration und Einengen werden 32,15 g Rohprodukt als rot-gelber Feststoff isoliert. Man löst in der Wärme in 200 ml Ethanol, lässt kurz abkühlen und addiert 3,57 g Aktivkohle. Es wird aufgekocht und warm über Celite filtriert. Mit 250 ml warmem Ethanol wird nachgespült. Man destilliert soviel Ethanol ab bis eine dicke Suspension entstanden ist (ca. 60 ml) und lässt sie bei 8°C kristallisieren. Der ausgefallene Feststoff wird abfiltriert, mit insgesamt 70 ml kaltem Ethanol gewaschen, sowie bei 40°C getrocknet. 18,08 g Produkt (58%) werden als blassgelber Feststoff (09-19-11-19 P8598) erhalten.Preference is given to opening the azlactone where R is nitrobenzyl
Figure DE102019129221A1_0017
 31.4 g of the product of the precursor are suspended in 184 ml of ethanol, 56 ml of triethylamine are added and the mixture is heated under reflux for 28 h. The reaction can be checked after dilution with DCM with the EE / PE 2: 1 mixture. It is taken up in 1.6 l of ethyl acetate and 1 l of water and 1 l of sodium chloride solution are added. The pH is brought to 1 with 56 ml of hydrochloric acid (25%) and the phases are separated. The aqueous phase is extracted four times with 800 ml of ethyl acetate each time. The combined organic phases are washed with 600 ml of sodium chloride solution and dried over sodium sulfate. After filtration and concentration, 32.15 g of crude product are isolated as a red-yellow solid. It is dissolved in 200 ml of ethanol in the heat, allowed to cool briefly and 3.57 g of activated charcoal are added. It is boiled and filtered warm through Celite. Rinse with 250 ml of warm ethanol. Sufficient ethanol is distilled off until a thick suspension has formed (approx. 60 ml) and it is left to crystallize at 8 ° C. The precipitated solid is filtered off, washed with a total of 70 ml of cold ethanol and dried at 40.degree. 18.08 g of product (58%) are obtained as a pale yellow solid (09-19-11-19 P8598).

Es werden 4,26 g Produkt (09-19-1-47 P8459, 95%) als rot-brauner Feststoff isoliert.
1H-NMR-Daten für R gleich Nitrobenzyl
1H (DMSO): s 9,73 (1H; NH 1); s 9,41 (1H, OH 2); dd 8,17 (1-2/8,2 Hz, 1H, CHar NO2 Benzyl 3); d 7,91 (7,4 Hz, 1H, CHar NO2 Benzyl 4); dt 7,82 (1,2-1,4/7,4-7,6 Hz, CHar NO2 Benzyl 5); m 7,60-7,66 (wohl dt, 1H, CHar NO2 Benzyl 6); d 7,37 (1,9 Hz, 1H, CHar 7); dd 7,14 (1,8-1,9/8,3 Hz, 1H, CHar8); s 7,10 (1H, CHolef 9); d 6,89 (8,3 Hz, 1H, CHar 10); s 5,50 (2H, CH2 Benzyl 11), q 4,14 (7,1 Hz, CH2-O 12); s 1,93 (3H, CH3COO 13); t 1,22 (7,11 Hz, 3H, CH3-CH2O 14)

Figure DE102019129221A1_0018
4.26 g of product (09-19-1-47 P8459, 95%) are isolated as a red-brown solid.
1 H-NMR data for R equal to nitrobenzyl
1 H (DMSO): s 9.73 (1H; NH 1); s 9.41 (1H, OH 2); dd 8.17 (1-2 / 8.2 Hz, 1H, CH ar NO 2 benzyl 3); d 7.91 (7.4 Hz, 1H, CHar NO 2 benzyl 4); dt 7.82 (1.2-1.4 / 7.4-7.6 Hz, CHar NO 2 benzyl 5); m 7.60-7.66 (probably dt, 1H, CHar NO 2 benzyl 6); d 7.37 (1.9 Hz, 1H, CH ar 7); dd 7.14 (1.8-1.9 / 8.3 Hz, 1H, CHar8); s 7.10 (1H, CH olef 9); d 6.89 (8.3 Hz, 1H, CHar 10); s 5.50 (2H, CH 2 benzyl 11), q 4.14 (7.1 Hz, CH 2 -O 12); s 1.93 (3H, CH 3 COO 13); t 1.22 (7.11 Hz, 3H, CH 3 -CH 2 O 14)
Figure DE102019129221A1_0018

Asymmetrische HydrierungAsymmetric hydrogenation

Figure DE102019129221A1_0019
Figure DE102019129221A1_0019

Bevorzugt Asymmetrische Hydrierung mit R gleich Nitrobenzyl

Figure DE102019129221A1_0020
220 ml Methanol werden durch Durchperlen von Stickstoff entgast. 23 mg S,S Et-Duphos (0,15m1%) werden in einem ausgeheizten Kolben zweimal entgast und in 14 ml entgastem Methanol gelöst, sowie nochmals zweimal entgast. 23,1 mg Bisoctadienyl Rhodiumtetrafluoroborat (0,55 mol%) werden addiert und man entgast zweimal. Die Lösung wird eine Stunde bei Raumtemperatur gerührt. 4,53 g Produkt der Vorstufe werden in 205 ml entgastem Methanol suspendiert, mit der Katalysatorlösung versetzt, sowie im Autoklav verschlossen. Man spült dreimal mit Stickstoff, dreimal mit Wasserstoff und rührt schließlich bei 5 bar bei Raumtemperatur unter Wasserstoff. Nach 17 Stunden wird der Autoklav geöffnet. Reaktionskontrolle ist mit dem Gemisch EE/PE 10:1 möglich. Man filtriert über etwa 32 g Kieselgel und spült das Kieselgel mit Methanol nach. Produkt enthaltende Fraktionen werden vereint und eingeengt. Man erhält 4,68 g Rohprodukt. In den 4 Durchläufen werden insgesamt 18,36 g Produkt isoliert.Preference is given to asymmetric hydrogenation where R is nitrobenzyl
Figure DE102019129221A1_0020
 220 ml of methanol are degassed by bubbling nitrogen through them. 23 mg of S, S Et-Duphos (0.15m1%) are degassed twice in a heated flask and dissolved in 14 ml of degassed methanol, and again degassed twice. 23.1 mg of bisoctadienyl rhodium tetrafluoroborate (0.55 mol%) are added and the mixture is degassed twice. The solution is stirred for one hour at room temperature. 4.53 g of product from the preliminary stage are suspended in 205 ml of degassed methanol, the catalyst solution is added and the product is sealed in the autoclave. It is flushed three times with nitrogen and three times with hydrogen and finally stirred at 5 bar at room temperature under hydrogen. The autoclave is opened after 17 hours. Reaction monitoring is possible with the EE / PE 10: 1 mixture. It is filtered through about 32 g of silica gel and the silica gel is rinsed with methanol. Fractions containing product are combined and concentrated. 4.68 g of crude product are obtained. A total of 18.36 g of product are isolated in the 4 runs.

Diese werden vereint, mit 3,61 g Aktivkohle versetzt und kurz zum Sieden erhitzt. Man filtriert in der Hitze über Cellite und spült mit 150 bis 200 warmem Methanol. Die Lösung wird bei 40°C eingeengt. 17,79 g heller Feststoff werden isoliert (09-19-11-38 P8623, 98%)
1H-NMR-Daten für R gleich Nitrobenzyl
1H (DMSO): s 8,17 (1H, NH 1); dd 8,15 (1,2/8,2 Hz, 1H, CHar NO2 Benzyl 2); dd 7,93 (0,7-0,8/7,7 Hz, 1H, CHar NO2 Benzyl 3); dt 7,80 (1,2/7,5-7,7 Hz, 1H, CHar NO2 Benzyl 4); m 7,59-7,66 (1H, wohl eigentlich dt, CHar NO2 Benzyl 5); d 6,85 (1,9 Hz; 1H, CHar 6); d 6,75 (8 Hz, 1H, CHar 7); dd 6,65 (1,9/8,1 Hz, 1H, CHar 8); s 5,43 (2H, CH2 Benzyl 9); m 4,30-4,37 (1H; CH-N 10); q 4,02 (7,1 Hz, 2 H, CH2-O 11); dd 2,85 (5,8/13,8 Hz, 1H, CH2-Ar 12); dd 2,74 (8,8/13,8 Hz, 1H, CH2-Ar 13); s 1,76 (3H; CH3CO 14); 1 1,12 (7,1 Hz, 3H, CH3CH2 15)

Figure DE102019129221A1_0021
These are combined, mixed with 3.61 g of activated charcoal and briefly heated to the boil. It is filtered while hot through Celite and rinsed with 150 to 200 warm methanol. The solution is concentrated at 40 ° C. 17.79 g of pale solid are isolated (09-19-11-38 P8623, 98%)
1 H-NMR data for R equal to nitrobenzyl
1 H (DMSO): s 8.17 (1H, NH 1); dd 8.15 (1.2 / 8.2 Hz, 1H, CHar NO 2 benzyl 2); dd 7.93 (0.7-0.8 / 7.7 Hz, 1H, CHar NO 2 benzyl 3); dt 7.80 (1.2 / 7.5-7.7 Hz, 1H, CHar NO 2 benzyl 4); m 7.59-7.66 (1H, probably actually dt, CHar NO 2 benzyl 5); d 6.85 (1.9 Hz; 1H, CHar 6); d 6.75 (8 Hz, 1H, CHar 7); dd 6.65 (1.9 / 8.1 Hz, 1H, CHar 8); s 5.43 (2H, CH 2 benzyl 9); m 4.30-4.37 (1H; CH-N10); q 4.02 (7.1 Hz, 2 H, CH 2 -O 11); dd 2.85 (5.8 / 13.8 Hz, 1H, CH 2 -Ar 12); dd 2.74 (8.8 / 13.8 Hz, 1H, CH 2 -Ar 13); s 1.76 (3H; CH 3 CO 14); 1 1.12 (7.1 Hz, 3H, CH 3 CH 2 15)
Figure DE102019129221A1_0021

Abspalten der SchutzgruppenCleavage of the protective groups

Figure DE102019129221A1_0022
Bevorzugt Abspalten der Schutzgruppen mir R gleich Nitrobenzyl
Figure DE102019129221A1_0023
17,79 g Produkt der Vorstufe (44,2 mmol) werden in 95 ml Dioxan suspendiert und erwärmt, um eine Lösung zu erhalten. 95 ml 32% Salzsäure werden addiert und man erwärmt 5h unter Rückfluss. Es wird bei 60°C eingeengt und in 140 ml 1M Salzsäure gelöst. Man extrahiert mit 270 ml Essigester und zweimal 230 ml Essigester. Langsam werden 19,81 g Natriumhydrogencarbonat addiert, bis pH 7 erreicht ist. Eine grünliche Suspension bildet sich, die auf 4°C gekühlt wird. Nach 2h filtriert man, wäscht mit viermal 60 ml kaltem Wasser und trocknet bei 50°C. 9,33 g gelber Feststoff werden isoliert (28 mmol, 64%, 09-19-11-42 P8625), der leicht verunreinigt ist.
Figure DE102019129221A1_0022
 Preference is given to splitting off the protective groups with R being nitrobenzyl
Figure DE102019129221A1_0023
 17.79 g of the product of the precursor (44.2 mmol) are suspended in 95 ml of dioxane and heated in order to obtain a solution. 95 ml of 32% hydrochloric acid are added and the mixture is heated under reflux for 5 h. It is concentrated at 60 ° C. and dissolved in 140 ml of 1M hydrochloric acid. It is extracted with 270 ml of ethyl acetate and twice 230 ml of ethyl acetate. 19.81 g of sodium hydrogen carbonate are slowly added until pH 7 is reached. A greenish suspension forms, which is cooled to 4 ° C. After 2 hours, it is filtered, washed four times with 60 ml of cold water and dried at 50.degree. 9.33 g of yellow solid are isolated (28 mmol, 64%, 09-19-11-42 P8625), which is slightly contaminated.

8,10 g werden in 320 ml Methanol suspendiert und bei Raumtemperatur 1h 40 gerührt. Es wird über eine G4 Fritte filtriert und zweimal mit je 80 ml Methanol gewaschen, sowie bei 40°C getrocknet. 5,56 g Produkt (09-19-11-58 P8656, 69%) werden isoliert. Der Enantiomeren-Exzess (ee) beträgt 98%.
1H-NMR-Daten für R gleich Nitrobenzyl
1H (DMSO): s 8,17 (1H, NH 1); dd 8,15 (1,2/8,2 Hz, 1H, CHar NO2 Benzyl 2); dd 7,93 (0,7-0,8/7,7 Hz, 1H, CHar NO2 Benzyl 3); dt 7,80 (1,2/7,5-7,7 Hz, 1H, CHar NO2 Benzyl 4); m 7,59-7,66 (1H, wohl eigentlich dt, CHar NO2 Benzyl 5); d 6,85 (1,9 Hz; 1H, CHar 6); d 6,75 (8 Hz, 1H, CHar 7); dd 6,65 (1,9/8,1 Hz, 1H, CHar 8); s 5,43 (2H, CH2 Benzyl 9); m 4,30-4,37 (1H; CH-N 10); q 4,02 (7,1 Hz, 2 H, CH2-O 11); dd 2,85 (5,8/13,8 Hz, 1H, CH2-Ar 12); dd 2,74 (8,8/13,8 Hz, 1H, CH2-Ar 13); s 1,76 (3H; CH3CO 14); t 1,12 (7,1 Hz, 3H, CH3CH2 15)

Figure DE102019129221A1_0024
8.10 g are suspended in 320 ml of methanol and the mixture is stirred at room temperature for 1 hour. It is filtered through a G4 frit and washed twice with 80 ml of methanol each time and dried at 40.degree. 5.56 g of product (09-19-11-58 P8656, 69%) are isolated. The enantiomer excess (ee) is 98%.
1 H-NMR data for R equal to nitrobenzyl
1 H (DMSO): s 8.17 (1H, NH 1); dd 8.15 (1.2 / 8.2 Hz, 1H, CHar NO 2 benzyl 2); dd 7.93 (0.7-0.8 / 7.7 Hz, 1H, CHar NO 2 benzyl 3); dt 7.80 (1.2 / 7.5-7.7 Hz, 1H, CHar NO 2 benzyl 4); m 7.59-7.66 (1H, probably actually dt, CHar NO 2 benzyl 5); d 6.85 (1.9 Hz; 1H, CHar 6); d 6.75 (8 Hz, 1H, CHar 7); dd 6.65 (1.9 / 8.1 Hz, 1H, CHar 8); s 5.43 (2H, CH 2 benzyl 9); m 4.30-4.37 (1H; CH-N10); q 4.02 (7.1 Hz, 2 H, CH 2 -O 11); dd 2.85 (5.8 / 13.8 Hz, 1H, CH 2 -Ar 12); dd 2.74 (8.8 / 13.8 Hz, 1H, CH 2 -Ar 13); s 1.76 (3H; CH 3 CO 14); t 1.12 (7.1 Hz, 3H, CH 3 CH 2 15)
Figure DE102019129221A1_0024

Zuvor genannte Verbindungen D, E und F sind bisher nicht in der Literatur beschrieben.Compounds D, E and F mentioned above have not yet been described in the literature.

BezugszeichenlisteList of reference symbols

11
Einführung der Nitrobenzyl GruppeIntroduction of the nitrobenzyl group
22
Bildung des AzlactonsFormation of azlactone
33
Öffnen des AzlactonsOpening the azlactone
44th
asymmetrisches Hydrierenasymmetric hydrogenation
55
Abspalten der SchutzgruppenCleavage of the protective groups

Claims (5)

Verfahren zur Synthese von ortho-Nitrobenzyl-DOPA aufweisend die folgenden Schritte - Verethern von Dihydroxybenzaldehyd mit Nitrobenzylbromid nach Reaktionsschema 1 (Einführung der Nitrobenzyl Gruppe) - Umsetzen des Ethers mit N-Acetylglycin zu einem Azlacton nach Reaktionsschema 2 (Bildung des Azlactons), - Öffnen des Azlactons nach Reaktionsschema 3 (Öffnen des Azlactons), - asymmetrisches Hydrieren des geöffneten Azlactons nach Reaktionsschema 4 (asymmetrisches Hydrieren), - Abspalten von Schutzgruppen zu ortho-Nitrobenzyl-DOPA nach Reaktionsschema 5 (Abspalten der Schutzgruppen) A method for the synthesis of ortho-nitrobenzyl-DOPA comprising the following steps - Etherification of dihydroxybenzaldehyde with nitrobenzyl bromide according to reaction scheme 1 (introduction of the nitrobenzyl group) - conversion of the ether with N-acetylglycine to an azlactone according to reaction scheme 2 (formation of the azlactone), - opening of the azlactone according to reaction scheme 3 (opening of the azlactone), - asymmetric hydrogenation of the opened azlactone according to reaction scheme 4 (asymmetric hydrogenation), - splitting off of protective groups to ortho-nitrobenzyl-DOPA according to reaction scheme 5 (splitting off of protective groups) Verbindung mit folgender Struktur
Figure DE102019129221A1_0025
wobei R bevorzugt Nitrobenzyl ist, gemäß folgender Struktur
Figure DE102019129221A1_0026
 Connection with the following structure
Figure DE102019129221A1_0025
 where R is preferably nitrobenzyl, according to the following structure
Figure DE102019129221A1_0026
 Verbindung mit folgender Struktur
Figure DE102019129221A1_0027
wobei R bevorzugt Nitrobenzyl ist, gemäß folgender Struktur
Figure DE102019129221A1_0028
 Connection with the following structure
Figure DE102019129221A1_0027
 where R is preferably nitrobenzyl, according to the following structure
Figure DE102019129221A1_0028
 Verbindung mit folgender Struktur
Figure DE102019129221A1_0029
wobei R bevorzugt Nitrobenzyl ist, gemäß folgender Struktur
Figure DE102019129221A1_0030
 Connection with the following structure
Figure DE102019129221A1_0029
 where R is preferably nitrobenzyl, according to the following structure
Figure DE102019129221A1_0030
 Verbindung nach Anspruch 2, 3 oder 4 dadurch gekennzeichnet, dass R ausgesucht ist aus der Gruppe bestehend aus:
Figure DE102019129221A1_0031
Figure DE102019129221A1_0032
Figure DE102019129221A1_0033
Figure DE102019129221A1_0034
wobei die Cumarin-Abkömmlinge für R den besonderen Vorteil haben, dass diese beim photoinduzierten Austritt beim Einsatz am Patienten keine toxischen Nebenprodukte bilden.Connection after Claim 2 , 3 or 4th characterized in that R is selected from the group consisting of:
Figure DE102019129221A1_0031
Figure DE102019129221A1_0032
Figure DE102019129221A1_0033
Figure DE102019129221A1_0034
 The coumarin derivatives for R have the particular advantage that they do not form any toxic by-products when they are photo-induced when used on patients.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000245A1 (en) * 2000-06-28 2002-01-03 Prana Biotechnology Limited Neurotoxic oligomers
US20140023603A1 (en) * 2011-02-09 2014-01-23 Pusan National University Industry-University Cooperation Foundation Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use therefor

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Publication number Priority date Publication date Assignee Title
WO2002000245A1 (en) * 2000-06-28 2002-01-03 Prana Biotechnology Limited Neurotoxic oligomers
US20140023603A1 (en) * 2011-02-09 2014-01-23 Pusan National University Industry-University Cooperation Foundation Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use therefor

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* Cited by examiner, † Cited by third party
Title
RZEPECKI, Leszek ; WAITE J. Herbert: Quinone chemistry: Applications in bioadhesion. In: Biotechnology and polymers. New York : Plenum Press, 1991. S. 229-243. - ISBN 0-306-44049-0 *
SCHNEIDER, Tobias ; KUBYSHKIN, Vladimir; BUDISA, Nediljko: Synthesis of a photo-caged DOPA derivative by selective alkylation of 3,4-dihydroxybenzaldehyde. In: European journal of organic chemistry, 2018, No. 18, S. 2053-2063. - ISSN 1099-0690 *

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