Article pubs.acs.org/OPRD
Sequential Nitration/Hydrogenation Protocol for the Synthesis of Triaminophloroglucinol: Safe Generation and Use of an Explosive Intermediate under Continuous-Flow Conditions David Cantillo,† Markus Damm,† Doris Dallinger,† Marcus Bauser,‡ Markus Berger,‡ and C. Oliver Kappe*,† †
Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria Global Drug Discovery, Medicinal Chemistry, Bayer HealthCare, D-13353 Berlin, Germany
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‡
S Supporting Information *
ABSTRACT: A continuous-flow process for the synthesis of triaminophloroglucinol has been developed. The synthetic procedure is based on a sequential nitration/reduction protocol which uses phloroglucinol as an inexpensive substrate. During the initial exothermic nitration step employing a combination of ammonium nitrate and sulfuric acid, the temperature was controlled through the enhanced heat transfer derived from the high surface-to-volume ratio of the utilized capillary tubing. Clogging of the tubing due to precipitation of trinitrophloroglucinol (TNPG) was avoided by immersing the tubular reactor in an ultrasound bath during the process. The nitration mixture was diluted with water and immediately subjected to catalytic hydrogenation of the nitro groups using a commercially available continuous-flow reactor and PtO2 as heterogeneous catalyst, thus avoiding the isolation of the highly unstable and explosive TNPG intermediate.
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INTRODUCTION Derivatives of 1,3,5-triamino-1,3,5-trideoxy-cis-inositol (TACI) are an important class of tailored chelating agents with widespread application in medicine and industrial processes.1 Their high affinity for specific metal cations (Figure 1) makes
Preparation of TACI in the (all-cis)-configuration can be carried out by selective transition-metal-catalyzed hydrogenation of triaminophloroglucinol (TAPG) (Scheme 1).7 This compound, which is air-sensitive in its free base form, can be readily isolated and stored as a stable sulfate salt (TAPG × 1.5 H2SO4).7a TAPG, in turn, can be synthesized by nitration of phloroglucinol (PG) followed by catalytic nitro group reduction using hydrogen and PtO2 as catalyst.7,8 This process is very convenient as it is atom-economic and inexpensive and uses PG as a cheap and readily available starting material. It does, however, involve the preparation and handling of the hazardous trinitrophloroglucinol (TNPG) intermediate. TNPG is a highly unstable and explosive compound often used as active ingredient or additive in the explosives industry.9 Its high impact and friction sensitivity, as well as the high amount of energy liberated during its decomposition (similar to 2,4,6trinitrotoluene, TNT), makes this material a useful ingredient for detonation compositions9c but also an extremely hazardous material, especially when prepared or stored in large amounts. In fact, the safety risks handling isolated crystalline TNPG are well-known and have caused serious accidents in the past.10 Nitration reactions are typically highly exothermic, especially those involving a very rapid nitration step such as in the (poly)nitration of phenols, where autocatalytic processes may occur.11 Therefore, nitrations constitute one the most hazardous industrial processes.12 Safety risks are even more significant when the produced nitro compound is explosive as in the case of TNPG. Continuous-flow processing and microreactor
Figure 1. Typical “sandwich-type” structures for TACI−metal complexes.
them excellent ligands for the treatment of metal intoxications (chelation therapy)2 such as iron overload, lead poisoning, or Wilson’s disease, in which copper accumulates in tissues. Stabilized metal cations in complexes with selective chelating agents based on TACI are also used in diagnostic radiopharmaceuticals and paramagnetic contrast agents.3 Utilization of this type of chelating agents in medicine requires a specific set of properties of the TACI−metal complexes such as stability, appropriate biodistribution, and high selectivity of the ligand towards the target metal.1a Therefore, the design and preparation of suitable derivatives of TACI has been the subject of intense research in the past two decades.4,5 In addition, TACI−metal complexes in combination with copper or rare earth metals have demonstrated to be useful catalysts for the hydrolysis of phosphodiesters in DNA cleavage.6 © 2014 American Chemical Society
Special Issue: Continuous Processes 14 Received: May 1, 2014 Published: June 10, 2014 1360
dx.doi.org/10.1021/op5001435 | Org. Process Res. Dev. 2014, 18, 1360−1366
Organic Process Research & Development
Article
Scheme 1. Retrosynthesic Scheme for the Preparation of TACI from Phloroglucinol
salts/sulfuric acid solutions do not generate NOx gases upon heating.19,20 Following a modified procedure of a literature protocol (see Experimental Section for details),19 a 1 M solution of PG in sulfuric acid was added to a solution containing 1.5 M NH4NO3 (in a 1:2 v/v ratio in order to obtain 3 equiv of nitrating agent). The addition was carried out slowly with external ice bath cooling in order to keep the temperature below 10 °C. The reaction mixture was then stirred at room temperature. After about 5 min, precipitation of copious amounts of a yellow solid corresponding to TNPG was observed. HPLC analysis revealed that the reaction was completed within 10 min. It should be noted that, when the solutions containing the reactants were mixed without external cooling, a significant exotherm was observed, and at 3 mmol scale, the temperature of the solution increased approximately 30 °C within 5 s (see Figure S1 in the Supporting Information). Clearly, batch experiments on larger scale could lead to dangerous temperature levels with a high risk of explosion.11 As mentioned above, continuous-flow processing can overcome the problems associated with highly exothermic reactions by readily controlling the released exotherm.13,14 We therefore decided to translate the ammonium nitrate/sulfuric acid nitration procedure of PG to continuous-flow conditions. Our flow setup consisted of two separate feeds containing solutions of PG (1.0 M) and ammonium nitrate (1.5 M) in concentrated sulfuric acid, which were pumped through the reactor using glass syringe pumps (Figure 2 and Figure S2 in
technology have been demonstrated to be safe alternatives for the preparation of nitro compounds, and in the past years, a number of continuous-flow nitrations have been reported in the literature.13 The enhanced heat transfer experienced in microfluidic devices14 can control the exotherm generated during nitration reactions. Therefore, these hazardous processes can be carried out in a safe, controlled, and scalable manner using flow devices. In this context, several nitrating agents and solvent systems have been successfully combined with continuous-flow reactors to prepare nitro compounds.13 A typical experimental setup for continuous nitration of aromatic compounds consist of two feeds, containing the substrate and the nitrating agent. The two feeds are mixed in a micromixing device under thermostated conditions, followed by a residence time unit.13 Catalytic hydrogenations using batch conditions, especially when carried out on large scale, are also inherently hazardous as pressurized hydrogen gas can cause explosions. Thus, pressureresistant autoclave reactors and special safety precautions are typically required.15 Continuous-flow hydrogenation is a common technique in modern organic synthesis,16 and specially designed reactors for catalytic hydrogenations are commercially available. In addition to the safe (on demand) generation of hydrogen gas characteristics for these types of devices, prepacked catalyst cartridges are typically employed, thus avoiding the handling of often pyrophoric metal catalysts.16 Owing to a high demand for TACI for the above-mentioned medicinal applications,4 a convenient procedure for the largescale preparation of the TAPG precursor is highly desirable. However, the safety issues associated with the preparation and storage of the explosive TNPG intermediate are a significant weakness of this most direct route using PG as starting material (Scheme 1). To overcome these problems, we envisaged a continuous-flow protocol for the synthesis of TAPG, in which PG is subjected to a sequential continuous-flow nitration/ hydrogenation sequence. The hazardous TNPG generated in solution is immediately consumed without the need for isolation or purification, thus avoiding the handling of this dangerous material as a solid. Herein, we present the details on the development of a two-step, continuous-flow preparation of TAPG from PG on laboratory scale.
Figure 2. Schematic diagram of the setup utilized for the continuousflow nitration of phloroglucinol. Coil 1: 75 μL, 0.8 mm inner diameter PFA coil. Coil 2: 1 mL, 1.6 mm inner diameter PFA coil. For a graphical representation of the reactor, see Figure S2 in the Supporting Information.
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RESULTS AND DISCUSSION Nitration of Phloroglucinol. Batch Experiments and Continuous-Flow Optimization. The first synthesis of TNPG from PG via a nitrosation/oxidation procedure was described in the 19th century by Benedikt.17 More recently, the direct nitration using HNO3/H2SO4 has been reported,18 as well as procedures which use NH4NO3 in stoichiometric amounts, thus avoiding the use of excess fuming nitric acid.19 Nitrate salt solutions in sulfuric acid have some advantages over the more common sulfonitric mixed acid, such as the more economical and safe use of nitrate salts and the fact that nitrate
the Supporting Information). After the two feeds were introduced into a standard T-mixer, the reaction mixture entered a short ca. 75 μL volume PFA coil (0.8 mm inner diameter). In this capillary tube (coil 1, Figure 2), efficient mixing of the two streams takes place, and the initial exotherm is properly released. As precipitation of TNPG is expected during the reaction,21 the initial capillary tube was connected to a larger 1.6 mm inner diameter PFA coil (residence time unit) immersed into a thermostated ultrasound bath (coil 2). The 1361
dx.doi.org/10.1021/op5001435 | Org. Process Res. Dev. 2014, 18, 1360−1366
Organic Process Research & Development
Article
and to assist the rapid solubilization of the product after the dilution with water. Gratifyingly, a mild increase of the reactor temperature of coil 2 to 40 °C (entry 3) resulted in excellent results comparable to the batch experiments. Further increase of the temperature produced a black solution, and side products were detected by HPLC analysis. It should be noted that this simple reactor design based on readily available PFA tubing with two different inner diameters enabled us to perform the nitration of PG in a safe and controllable manner. Thus, in the first section of the reactor (coil 1), the initial exotherm was controlled by an efficient heat transfer derived from the high surface-to-volume ratio of the capillary (0.8 mm inner diameter, residence time
