Lomustine, an important agent for treatment of brain tumors and Hodgkin’s lymphoma, has been synthesized using continuous flow methodology. Desorption electrospray ionization mass spectrometry (DESI-MS) was used to quickly explore a large number of reaction conditions for one of the reaction steps and guide the efficient translation of optimized conditions to continuous lomustine production. Using only four inexpensive commercially available starting materials and a total residence time of 9 min, lomustine was prepared via a linear sequence of two chemical reactions performed separately in two telescoped flow reactors. Sequential offline extraction and filtration resulted in a 63% overall yield of pure lomustine at a production rate of 110 mg/h. The primary advantages of this approach are the rapid manufacture of lomustine with two telescoped steps to avoid isolation and purification of a labile intermediate and the mild conditions used in the nitrosylation step, thereby significantly increasing the purity and yield of this active pharmaceutical ingredient.
Traditional methods to discover optimal reaction conditions for small molecule synthesis is a time-consuming effort that requires large quantities of material and a significant expenditure of labor. High-throughput techniques are a potentially transformative approach for reaction condition screening, however, rapid validation of the reaction hotspots under continuous flow conditions remains necessary to build confidence in high throughput screening hits. Continuous flow technology offers the opportunity to upscale the screening hotspots and optimize their output of the target compounds due to the exceptional heat and mass transfer ability of flow reactions that are conducted in a smaller and safer reaction volume. We report a robotic high throughput technique to execute reactions in multi-well plates that were coupled with fast mass spectrometric analysis using an autosampler to accelerate the reaction screening process. Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions were screened in this system and a heat map was generated to identify the best reaction conditions for downstream scale-up under continuous flow. Here, high throughput experimentation reactions in 96-well plates were performed for 1 h at 50 °C, 100 °C, 150 °C, and 200 °C before diluting them into 384-well plates for mass analysis. With the aid of high throughput tools, 648 unique experiments were conducted in duplicate. The cross-coupling reactions were evaluated as a function of stoichiometry, temperature, concentration, order of addition, and substrate type. The hotspots from high throughput experimentation were examined using a microfluidic Chemtrix system that confirmed the positive reaction leads as true positives. Negative outcomes identified by these experiments were found to be true negatives by microfluidic reaction evaluation. Quantitation of product yields was performed using high-performance liquid chromatography-mass spectrometry (HPLC/MS-MS).
Tributyl-, dibutyl-, and triphenyl-tin isocyanates have been prepared ; the isolation of diphenyltin di-isocyanate was accompanied by hydrolysis. The di-isocyanates are sensitive to moisture and hydrolysis products of the type R,Sn,(NCO),O, and R,Sn,(NCO),(OH),O, were isolated. An additional hydrolysis product of diphenyltin di-isocyanate, Ph,Sn,(NCO) 2(OH),, was obtained. The 2,2'-bipyridyl derivative of diphenyltin di-isocyanate was found to be a 1 : 2 adduct and it is concluded that this compound cmtains a bridging bipyridyl group.LITTLE is known about organotin isocyanates.claimed to have isolated triethyltin isocyanate but the first detailed account of its preparation was reported by Anderson and Vasta.2 An attempt to prepare dimethyltin di-isocyanate under aqueous conditions gave what was described as a 1 : 1 mixture of the latter compound and dimethyltin oxide. For reasons which will become apparent it seems likely that this product was di-tl-(isocyanatodimethylstannyloxo)bis(isocyanatodimethyltin) (IT ; R = Me, X = NCO).The heterogeneous reaction between the appropriate organotin chloride in ether or light petroleum and silver isocyanate gave triphenyltin isocyanate, tributyltin isocyanate, and dibutyltin di-isocyanate. Since this work was completed the preparation of triphenyltin isocyanate by a similar method has been briefly r e p ~r t e d . ~ Treatment of Early workers 1 (a) P. Kulmiz,
The ability of organotin maleates to undergo Diels-Alder reactions with a range of dienes has been examined. Crystalline adducts have been obtained from 2,3-dimethylbuta-l,3-diene with triphenyltin methyl maleate and from cyclopentadiene with triphenyltin methyl maleate, tributyltin methyl maleate, dibutyltin bis(rnethy1 maleate). and dibutyltin maleate. The products expected from the Diels-Alder reactions of 2.3-dimethylbuta-I ,3-diene with triphenyltin methyl maleate, tributyltin methyl maleate and dibutyltin bis(methy1 maleate) have been synthesised by an alternative methpd.
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