Andrew R. Bogdan

The Continuous‐Flow Synthesis of Ibuprofen

Organic synthesis is a powerful enterprise that continues to develop more selective and efficient chemical methods and synthetic routes. To synthesize complex molecules, whether in academic laboratories or industrial manufacturing, reactions are often performed iteratively in batch reactors. Although these stepwise methods are effective, they are also very wasteful. The pharmaceutical industry, for example, produces 25–100 kg of waste for every kilogram of a complex molecule synthesized. Though chemists are constantly striving to devise more efficient syntheses, recent reminders of a resource-limited world underscore the need for more sustainable methods and technologies to synthesize molecules of importance. The application of new technologies, such as microreactors, to organic synthesis can be used to achieve this goal. Microreactors are a developing technology used to perform safer, more efficient, and more selective chemical transformations in microchannels or narrow-bore tubing. The many advantages associated with conducting reactions in flow are attributed to large surface-area-to-volume ratios that allow precise reaction control through rapid heat transfer and mixing. The syntheses can be scaled up by running a single reactor for extended periods of time or by the addition of more identical flow reactors in parallel, a process known as numbering up. Although most applications of microreactors in organic synthesis have focused on single-step reactions, recent examples have demonstrated multistep reaction sequences in flow. 28–32] Our group has a long-standing interest in the development of new methodologies that enable the rapid and efficient synthesis of important small molecules. Specifically, we have aimed to run multistep reaction sequences in one pot (i.e. in batch reactors) or in series (i.e. in microreactors). 34] We report herein a three-step, continuous-flow synthesis of ibuprofen, a high-volume, nonsteroidal anti-inflammatory drug (NSAID), using a simplified microreactor that eliminates the need for purification and isolation steps. To achieve this continuous-flow synthesis, a careful retrosynthetic analysis of ibuprofen was performed, considering the synthesis of ibuprofen as an entity, as opposed to a series of independent reactions steps. Reactions therefore had to be designed such that byproducts and excess reagents from one reaction were compatible with downstream reactions. In this way, reactions could be performed in sequence without any breaks in the synthesis. The general three-step synthesis of ibuprofen we investigated is outlined in Scheme 1.

Cerebrospinal fluid pulsation amplitude and its quantitative relationship to cerebral blood flow pulsations : a phase-contrast MR flow imaging study

Abstract Our purpose in this investigation was to explain the heterogeneity in the cerebrospinal fluid (CSF) flow pulsation amplitudes. To this end, we determined the contributions of the cerebral arterial and jugular venous flow pulsations to the amplitude of the CSF pulsation. We examined 21 healthy subjects by cine phase-contrast MRI at the C2–3 disc level to demonstrate the CSF and vascular flows as waveforms. Multiple regression analysis was performed to calculate the contributions of (a) the arterial and venous waveform amplitudes and (b) the delay between the maximum systolic slopes of the arterial and venous waveforms (AV delay), in order to predict the amplitude of the CSF waveform. The contribution of the arterial waveform amplitude was positive (r = 0.61; p = 0.003) to the CSF waveform amplitude and that of the venous waveform amplitude was negative (r = −0.50; p = 0.006). Both in combination accounted for 56 % of the variance in predicting the CSF waveform amplitude (p < 0.0006). The contribution of AV delay was not significant. The results show that the variance in the CSF flow pulsation amplitudes can be explained by concurrent evaluation of the CSF and vascular flows. Improvement in the techniques, and controlled experiments, may allow use of CSF flow pulsation amplitudes for clinical applications in the non-invasive assessment of intracranial dynamics by MRI.

Synthesis of 5-Iodo-1,2,3-triazole-Containing Macrocycles Using Copper Flow Reactor Technology

A new macrocyclization strategy to synthesize 12- to 31-membered 5-iodo-1,2,3-triazole-containing macrocycles is described. The macrocycles have been generated using a simple and efficient copper-catalyzed cycloaddition in flow under environmentally friendly conditions. This methodology also permits the facile, regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazole-containing macrocyles using palladium-catalyzed cross-coupling reactions.

Efficient Access to New Chemical Space Through Flow—Construction of Druglike Macrocycles Through Copper‐Surface‐Catalyzed Azide–Alkyne Cycloaddition Reactions

A series of 12- to 22-membered macrocycles, with druglike functionality and properties, have been generated by using a simple and efficient copper-catalyzed azide-acetylene cycloaddition reaction, conducted in flow in high-temperature copper tubing, under environmentally friendly conditions. The triazole-containing macrocycles have been generated in up to 90 % yield in a 5 min reaction, without resorting to the high-dilution conditions typical of macrocyclization reactions. This approach represents a very efficient method for constructing this important class of molecules, in terms of yield, concentration, and environmental considerations.

A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor.

Summary We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained active in excess of 100 trials without showing any loss of catalytic activity.

Strained Cyclophane Macrocycles: Impact of Progressive Ring Size Reduction on Synthesis and Structure

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide-alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries. These strained cyclophane macrocyclic systems provide access to spatial orientations of functionality that would not be readily available in unstrained or acyclic analogs. The most strained system prepared represents the first report of an 11-membered cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring and establishes a limit to the ring strain that can be generated using this macrocycle synthesis methodology.

Use of Bifunctional Ureas to Increase the Rate of Proline-Catalyzed α-Aminoxylations

The rate of the proline-catalyzed alpha-aminoxylation of aldehydes is significantly increased in the presence of a bifunctional urea. Structure-activity relationship data indicate that both an amine and a urea are crucial for rate enhancement. The evidence presented herein suggests that this rate enhancement originates from the hydrogen bonding interaction between the bifunctional urea and an oxazolidinone intermediate to increase the rate of enamine formation. Proline derivatives that are incapable of forming oxazolidinones exhibit no rate enhancement in the presence of the bifunctional urea. The rate enhancement is general for a variety of aldehydes, and the faster reactions do not reduce yields or selectivities.

Overt naming in aphasia studied with a functional MRI hemodynamic delay design.

The purpose of this study was to develop a functional MRI method to examine overt speech in stroke patients with aphasia. An fMRI block design for overt picture naming was utilized which took advantage of the hemodynamic response delay where increased blood flow remains for 4-8 s after the task [(Friston, K.J., Jezzard, P., Turner, R., 1994. Analysis of functional MRI time-series. Hum. Brain Mapp. 1, 153-171)]. This allowed task-related information to be obtained after the task, minimizing motion artifact from overt speech (Eden, G.F., Joseph, J., Brown, H.E., Brown, C.P., Zeffiro, T.A., 1999. Utilizing hemodynamic delay and dispersion to detect fMRI signal change without auditory interference: the behavior interleaved gradients technique. Magn. Reson. Med. 41, 13-20; Birn, RM., Bandettini, P.A., Cox, R.W., Shaker, R., 1999. Event-related fMRI of tasks involving brief motion. Hum. Brain Mapp. 7, 106-114; Birn, R.M., Cox, R.W., Bandettini, P.A., 2004. Experimental designs and processing strategies for fMRI studies involving overt verbal responses. NeuroImage 23, 1046-1058). Five chronic aphasia patients participated (4 mild-moderate and 1 severe nonfluent/global). The four mild-moderate patients who correctly named 88-100% of the pictures during fMRI, had a greater number of suprathreshold voxels in L supplementary motor area (SMA) than R SMA (P < 0.07). Three of these four mild-moderate patients showed activation in R BA 45 and/or 44; along with L temporal and/or parietal regions. The severe patient, who named no pictures, activated almost twice as many voxels in R SMA than L SMA. He also showed activation in R BA 44, but had remarkably extensive L and R temporal activation. His poor naming and widespread temporal activation may reflect poor modulation of the bi-hemispheric neural network for naming. Results indicate that this fMRI block design utilizing hemodynamic response delay can be used to study overt naming in aphasia patients, including those with mild-moderate or severe aphasia. This method permitted verification that the patients were cooperating with the task during fMRI. It has application for future fMRI studies of overt speech in aphasia.

Cerebrospinal fluid flow waveforms: effect of altered cranial venous outflow

Abstract Our purpose was to assess the effect of alterations in the cranial venous outflow on cerebrospinal fluid (CSF) flow waveforms using phase-contrast MRI. Thirteen healthy subjects were assessed for CSF flow and cerebral vascular flow at the C2–3 level, both before and after jugular venous compression (JVC). The flow waveforms were assessed both as an aggregate, and after dividing subjects in two groups based on percent jugular venous flow (PJVF) i. e. jugular outflow expressed as percent of cerebral arterial inflow. Group 1: 7 subjects with PJVF more than and including median (predominantly jugular outflow); Group 2: 6 subjects with PJVF less than median (predominantly extra-jugular outflow). CSF waveforms: JVC produced rounding of contours and flattening of dicrotic waves, with the effect being greater in group 1 than group 2. In group 1, systolic upslopes of the waveforms increased. No significant aggregate amplitude changes were noted; amplidutes increased in group 1 (P = 0.001), and decreased in group 2 (P = 0.03). Temporal interval to the maximum CSF systolic flow significantly increased in group 1. Vascular flow: Arterial flow significantly decreased in group 1. Jugular flow significantly decreased in both groups. The results suggest that CSF flow waveforms are sensitive to alterations in the cranial venous outflow. Changes in group 1 are most likely because of an elevation in intracranial pressure. Analysis of CSF flow waveforms appears a promising noninvasive tool for assessment of cranial compartment.

High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences.

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.