| 1. |
- Adeyemi, Ahmed, et al.
(författare)
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Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
- 2017
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Ingår i: Organic Process Research & Development. - : AMER CHEMICAL SOC. - 1083-6160 .- 1520-586X. ; 21:7, s. 947-955
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Tidskriftsartikel (refereegranskat)abstract
- A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.
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| 2. |
- Andersen, Sören M., et al.
(författare)
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A scalable route to 5-substituted 3-isoxazolol fibrinolysis inhibitor AZD6564
- 2014
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 18:8, s. 952-959
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Tidskriftsartikel (refereegranskat)abstract
- A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester.
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| 3. |
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| 4. |
- Börner, Tim, et al.
(författare)
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A Process Concept for High-Purity Production of Amines by Transaminase-Catalyzed Asymmetric Synthesis: Combining Enzyme Cascade and Membrane-Assisted ISPR
- 2015
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 19:7, s. 793-799
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Tidskriftsartikel (refereegranskat)abstract
- For the amine transaminase (ATA)-catalyzed synthesis of chiral amines, the choice of donor substrate is of high importance for reaction and process design. Alanine was investigated as an amine donor for the reductive amination of a poorly water-soluble ketone (4-phenyl-2-butanone) in a combined in situ product removal (ISPR) approach using liquid-membrane extraction together with an enzyme cascade. This ISPR strategy facilitates very high (>98%) product purity with an integrated enrichment step and eliminates product as well as coproduct inhibition. In the presented proof-of-concept alanine shows the following advantages over the other frequently employed amine donor isopropyl amine: (i) nonextractability of alanine affords high product purity without any additional downstream step and no losses via coextraction, (ii) higher maximum reaction rates, and (iii) broader acceptance among ATAs.
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| 5. |
- Carlson, Rolf, et al.
(författare)
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Canonical analysis of response surfaces : a valuable tool for process development
- 2005
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 9:3, s. 321-330
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Tidskriftsartikel (refereegranskat)abstract
- The principles of response surface modelling are briefly described. The computations involved in the canonical analysis of response surface models are given in detail. Three examples of canonical analysis in the context of organic synthesis development are discussed. These examples treat enamine synthesis by a modified titanium tetrachloride procedure, kinetic modelling, and the synthesis of the trimethylsilyl enol ether from methyl vinyl ketone.
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| 6. |
- Carlson, Rolf, et al.
(författare)
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Identification of important experimental variables in organic synthetic procedures by near-orthogonal experiments
- 2012
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 16:8, s. 1371-1377
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Tidskriftsartikel (refereegranskat)abstract
- A new strategy is presented for the design of screening experiments in synthetic chemistry when the objective is to identify the important experimental variables from a limited number of experimental runs. The methodology is based on Taylor expansion (response surface) models The experimental design is constructed in such a way that the vector of the variables in the Taylor model in each run are near-orthogonal to each other. This is achieved by laying out a grid of possible experiments in the experimental space, expanding this candidate experimental design matrix to the corresponding model matrix, i.e. the matrix containing columns for all variables in the Taylor expansion. This model matrix is then factorised by singular value decomposition, SVD. The row in the model matrix that is most parallel to the first singular vectors is selected as the first experiment. .The variation displaced by this first experiment is removed from the elements of the model matrix by projections. The resulting matrix is the orthogonal complement to the first selected row. The procedure is repeated until all dimensions of the model space have been spanned by the selected experiments The singular vectors are mutually orthogonal, and selected experiments will be nearly orthogonal and span the dimensions of the model space. The experiments can be run in sequence and thus allow for a systematic search, one experiment at a time. It is shown that subset selections from such designs in combination with PLS modelling can be used to identify the important variables. The principles are illustrated with two examples: (a) a dibromination of an acetyl with four experimental variables and (b) a synthesis of an enamine by condensing a ketone and morpholine in the presence of molecular sieves in which seven experimental variables are involved. In the acetal bromination, it was found that 5 experiments out of 12 were sufficient for identifying the most important variables. In the enamine example, 8 experiments out of 30 were sufficient.
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| 7. |
- Carlson, Rolf, et al.
(författare)
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Orthogonal experiments in the development of organic synthetic processes
- 2009
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 13:4, s. 798-803
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Tidskriftsartikel (refereegranskat)abstract
- A new strategy is presented for the design of explorative experiments in synthetic chemistry when the objective is to identify the important experimental variables. The methodology is based on Taylor expansion (response surface) models, and the principles are: A grid of possible settings of the experimental variables is laid out in the experimental domain. These experiments define a candidate design matrix, DC. From DC, a candidate model matrix, XC is defined by appending columns for each variable in the Taylor model XC is then factored by singular value decomposition (SVD), and XC = USVT. The rows in XC that are most parallel to the singular column vectors in V are selected, and the corresponding experiments in DC are identified. This gives the experimental design. The selected experiments are nearly orthogonal, and they span the dimensions of the model space. The experiments can be run in sequence, and thus, they allow for a systematic search, one experiment at a time. The design principles are illustrated by an example of the dibromination of an acetal. Four variables were studied, and from 12 experiments, all the main effects and all two-factor interaction effects were estimated. From the response surface model, conditions for quantitative yield were predicted, and a mol-scale synthesis carried out under these conditions afforded 98% yield of the isolated pure, >97% product.
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| 8. |
- Carlson, Rolf, et al.
(författare)
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Principal properties and designs for discrete variations
- 2005
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 9:5, s. 680-689
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Tidskriftsartikel (refereegranskat)abstract
- A problem that is often encountered when a new synthetic reaction is developed is to determine suitable combinations of reagents, co-reagents, catalysts, solvents, etc. This contribution presents general strategies for designing experiments when the objective is to explore the discrete variations defined by different reagents, different catalysts, different solvents, etc. The concept of principal properties is introduced, and it is shown how the principal properties of the constituents of the reaction system can be used for the selection of suitable test systems. Chemical examples are provided by the following: the selection of test solvents in the reduction of an enamine; the selection of combinations of Lewis acids and amines in the synthesis of benzamides; the selection of ketone substrates, amines, and solvents in the Willgerodt-Kindler reaction; and the selection of ketone substrates, Lewis acid catalysts, and solvents for analysing the regioselectivity in the Fischer indole synthesis with dissymmetric ketones.
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| 9. |
- Codan, Lorenzo, et al.
(författare)
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Design of Crystallization Processes for the Resolution of Conglomerate-Forming Chiral Compounds Exhibiting Oiling Out
- 2012
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 16:2, s. 294-310
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Tidskriftsartikel (refereegranskat)abstract
- A methodology for the design of cooling crystallization processes for chiral resolution from nonracemic initial solutions is presented. Such processes are encountered when chiral resolution is attained by hybrid processes, where the crystallization step is preceded by a pre-enrichment step accomplished by either asymmetric synthesis or another separation technique. The work focuses on substances that crystallize as conglomerates and accounts for the occurrence of oiling out, i.e., an undesired liquid liquid phase separation during crystallization. The generic ternary phase diagrams for conglomerate-forming systems with and without oiling out are derived. This knowledge is then applied to identify suitable operating conditions for chiral resolution. As crystallization is started from saturated solutions, the crystallization process is characterized by three parameters: the initial enantiomeric excess and the initial temperature, which together implicitly define the position of the operating point in the phase diagram, and the final operating temperature, which defines the composition and the amount of the phases present at the end of crystallization. For any initial enantiomeric excess, the methodology yields distinct areas in the initial versus final temperature plane containing pairs of operating temperatures that are suitable for chiral resolution. Such operating map bears great potential in improving the design and optimization of chiral resolution processes by crystallization.
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| 10. |
- Croker, D. M., et al.
(författare)
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Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution
- 2015
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Ingår i: Organic Process Research & Development. - Washinhton, USA : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 19:12, s. 1826-1836
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Tidskriftsartikel (refereegranskat)abstract
- Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10-70 degrees C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered: Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals.
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