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Synthesis of the Caffeine Metabolites 5-Acetylamino-6-Formylamino- 3-Methyluracil (AFMU) and 5-Acetylamino-6-Amino-3-Methyluracil (AAMU) on a Preparative Scale R

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Synthesis of the Caffeine Metabolites 5-Acetylamino-6-Formylamino- 3-Methyluracil (AFMU) and 5-Acetylamino-6-Amino-3-Methyluracil (AAMU) on a Preparative Scale R Synthesis of the Caffeine Metabolites 5-Acetylamino-6-formylamino- 3-methyluracil (AFMU) and 5-Acetylamino-6-amino-3-methyluracil (AAMU) on a Preparative Scale R. Röhrkasten3, P. Raatz3, R. P. Kreher3*, M. Blaszkewiczb a Lehrstuhl für Organische Chemie II, Fachbereich Chemie, Universität Dortmund. D-44227 Dortmund b Institut für Arbeitsphysiologie an der Universität Dortmund, ZWE Analytische Chemie, Ardeystraße 67, D-44139 Dortmund Z. Naturforsch. 52b, 1526-1532 (1997); received April 7, 1995 Pyrimidine-diones, Caffeine Metabolites, Synthesis 5-Acetylamino-6-amino-3-methyluracil (AAMU) and 5-acetylamino-6-formylamino-3- methyluracil (AFMU) have been prepared by simple chemical transformations starting from thiourea and ethyl cyanoacetate. These compounds AAMU and AFMU are required as standard materials for qualitative identification and quantitative determination in connection with the metabolism of caffeine. Introduction procedures are applied to obtain weighable amounts. The first method consisted in the con­ The N-acetyltransferase plays an important role sumption of a caffeinated beverage and the extrac­ in the metabolism of many xenobiotics; the pro­ tion of the metabolites from the urine; but the duction of the enzyme is genetically controlled. In­ yields are low [10]. A very expensive synthetic dividuals differ in the amount of the acetylated procedure is based on a procedure of Khmelevskii metabolites and can be classified as slow or rapid et al. [3] modified by Tang et al. [10] using 1-MU acetylators. The acetylator status is connected with instead of uric acid. After acylation with formic some diseases such as diabetes mellitus and blad­ acid/acetic anhydride the yield was only 19% pro­ der cancer and the knowledge of it is for the bene­ ducing 2 mg of AFMU 9. fit of therapeutics. In recent years, caffeine has been used as a non- invasive probe for the phenotyping of the acetyla­ Synthesis tor status. The metabolism of caffeine comprises a Pfleiderer and co-workers [1,6,7] have estab­ variety of reactions, such as oxidative demethyla- lished a synthesis of eight steps for AAMU 8 with tion, ring hydroxylation, ring-opening and acetyla­ an overall yield of 10%. While working on pyrimi­ tion. The ratios of the molar concentrations of uri­ dines, we have recognized a general interest in nary caffeine metabolites, like 5-acetylamino-6- some of our pyrimidine derivatives; AAMU 8 was formylamino-3-methvluracil (AFMU) (9), 5-ace- one of it. After analyzing the fundamental synthe­ tylamino-6-amino-3-methyluracil (AAMU) (8), 1- sis of Pfleiderer and co-workers [7] we were suc­ methylxanthine (1-MX) or 1-methyluric acid (1- cessful in shortening the sequence to six steps and MU) enable the determination of the acetylator in increasing the yield by modification of the reac­ status. tion conditions up to 42% ( cf. Scheme 1). For quantitative analytical determinations, Cyclization of thiourea (1) (NCN-compound) AFMU 9 or AAMU 8 are required as standard and ethyl cyanoacetate (2) (CCC-compound) - materials. Both metabolites are not available com­ based on a modified procedure of Taylor and mercially. Therefore biochemical and synthetic Cheng [12] and of Traube [13] - affords 99% of 6-amino-2-thiouracil (3) after treatment with base (NaOEt/EtOH/3h/reflux). The procedure is very simple and using an optimized work-up method it * Reprint requests to Prof. Dr. R. P. Kreher. is possible after complete removal of solvents to 0932-0776/97/1200-1526 $06.00 © 1997 Verlag der Zeitschrift für Naturforschung. All rights reserved. D Dieses Werk wurde im Jahr 2013 vom Verlag Zeitschrift für Naturforschung This work has been digitalized and published in 2013 by Verlag Zeitschrift in Zusammenarbeit mit der Max-Planck-Gesellschaft zur Förderung der für Naturforschung in cooperation with the Max Planck Society for the Wissenschaften e.V. digitalisiert und unter folgender Lizenz veröffentlicht: Advancement of Science under a Creative Commons Attribution Creative Commons Namensnennung 4.0 Lizenz. 4.0 International License. R. Röhrkasten et al. ■ Synthesis of the Caffeine Metabolites 1527 h3c h3c N N N T A O'A, N O ^N nh2 I H Scheme 1. rt: NaOEt / EtOH (3 h; reflux) - 99%; r2: (H3C0)2S02 / 2N NaOH (1 h; H3Cv 40 °C) - 62%; r3; 1 N NaOH (2 h; reflux) - HsC'NJ Y NH 91%; r4; NaOAc / HOAc / H.O / NaN02 (65 min; 100 °C) - 95%; r5: Pd;C / H2 / NaOH NI NH2 H A, (6-12 h; 20 °C) - 82%; r6: NaOAc / Xc20 (3 h; reflux) - 97%; r7: H C O -O -C O C H , / HCOOH (7 d; 20 °C) - 60-80%. separate water insoluble compounds easily. Neu­ o c h 3 tralization with acetic acid instead of mineral acids N seems to be more effective, because the sodium JL + 4 h3cs n nh2 h3cs Ln nh2 acetate formed a buffer and therefore organic salts aren’t formed. 2-Thio-4-amino-6-hydroxy-pyrimi- 10 dine is alkylated by means of methyl iodide or di­ Scheme 2. methyl sulphate at the sulfur atom [2], Regioselec- tive S- and N-alkylation of 3 at 1-position can be readily achieved with dimethyl sulfate in NaOH. the 2-methylthio group; with a 2-methoxy group The first step is the formation of a thiolate anion; O-alkylation did not occur. its enhanced reactivity is responsible for the for­ The methylthio group in 2-position represents a mation of 6-amino-2-methylthio-uracil (10). The favorite center for nucleophilic attack of hydrox­ rate of this step and the following reaction are al­ ide anions. 6-Amino-2-methylthio-3-methyluracil most the same. If not enough alkylating reagent is (4) reacts with 1 N NaOH (2 h/reflux) to give 91% used, starting material 3 is isolated beside of 6- of 6-amino-3-methyluracil (5). After neutraliza­ amino-2-methylthio-3-methyluracil (4) and 6- tion with acetic acid 5 can be isolated as colorless amino-4-methoxy-2-methylthio-uracil (11). Using solid. a 2.5fold excess of the alkylating reagent the py­ The nitrosation of 6-amino-3-methyluracil (5) rim idines 4 (62% ) and 11 (17%) can be synthe­ was carried out in diluted acetic acid with sodium sized (cf. Scheme 2). A direct synthesis of 10 can­ nitrite (65 min/100 °C). To increase yield and pro­ not be realized in this way. Alkylation of duct quality (microcrystals) the use of sodium ace­ independently synthesized 10 leads to the result tate as buffer seems to be advantageous. The that 4 and 11 were generated in the same ratio. higher reaction temperature is necessary because The unusual O-alkylation must be dependent on the starting material is almost insoluble. The insol- 1528 R. Röhrkasten et al. • Synthesis of the Caffeine Metabolites üble violet 6-amino-5-nitroso-3-methyluracil (6) Formylation of AAMU 8 to prepare 6-ace- was collected and washed extensively with water tylamino-5-formylamino-3-methyluracil (AFMU) and carefully dried (48 h over P20 5; yield 95% (9) was achieved by Tang and co-workers [10] with with m.p. >350 °C). The main advantage of func- a mixture of formic acid/acetic anhydride (4:1). tionalizing with a nitroso group is the effective This method (yield: 19%) was not effective on a work-up procedure as well as the considerable preparative scale; therefore it seemed to be advan­ yield and the remarkable regioselectivity; the ena- tageous to use the mixed anhydride of formic and mine structure permits only nitrosation at 5- acetic acid, which can be synthesized as an reagent position. on a preparative scale [4], In earlier literature Raney-Nickel [5,11] was AAMU 8 was suspended and stirred in a 1:1 used to perform catalytic hydrogenation of the ni­ mixture of formic acid and acetic formic anhydride tro group at 5 position. Remarkable amounts of (7 d/20 °C). Thereby the turnover of AAMU 8 is the catalyst are required and lower yields can be not complete, because the resulting AFMU 9 is caused by adsorption of the product on surface. decomposed to AAMU 8, which can be reused. Using palladium [8] only small amounts of catalyst An indication for the increased reactivity of are required. Because of increased reactivity, the AFMU 9 is the formation of 5,6-diacetylamino-3- decision for an appropiate solvent is important: methyluracil (DAMU) (12) ( cf. Scheme 3). This The conversion of nitroso-pyrimidines in water transformation can be described as a transamida- leads presumably to the hydration of the CC- tion of the 6-formylamino-group. An analytical double bond, in methanol no transformation takes pure sample of DAMU 12 was isolated by semi­ place, because of the poor solubility of the nitroso preparative HPLC, so that characterization and compound 6. The sodium salt of the starting identification were possible. material is more polar then the free base and therefore soluble in methanol. For this reason so­ dium hydroxide was added with 10% excess to the mixture. Hydrogenation is successful with 10% palladium on charcoal in a mixture of methanol/ aqueous sodium hydroxide at 20 °C in 6-12 h; the 12 reaction is completed after the red solid has disap­ Scheme 3. peared. Work up must be performed rapidly and under an argon atmosphere. The neutralization AAMU 8 could be excluded as a source for the with hydrochloric acid have to be carried out ex­ formation of DAMU 12, because it cannot be de­ actly to pH = 7.0 (pH-electrode; otherwise the pre­ tected during the synthesis of AAMU 8 with acetic cipitate is very unstable); after this the precipitate anhydride under forced conditions. was filtered off and dried. The isolated 5,6-dia- Attempts to suppress the competitive reaction mino-3-methyluracil (7) is relative stable and can are not successful, because the turnover of be stored for a longer period at 20 °C without A A M U 8 is negligible below -5 °C.
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