Review, Continuous Processing

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Jun 272016

Continuous Processing

Continuous production is a flow production method used to manufacture, produce, or process materials without interruption. Continuous production is called a continuous process or a continuous flow process because the materials, either dry bulk or fluids that are being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.

Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Some chemical plants can operate for more than one or two years without a shutdown. Blast furnaces can run four to ten years without stopping.^[1]

Production workers in continuous production commonly work in rotating shifts.

Processes are operated continuously for practical as well as economic reasons. Most of these industries are very capital intensive and the management is therefore very concerned about lost operating time.

Shutting down and starting up many continuous processes typically results in off quality product that must be reprocessed or disposed of. Many tanks, vessels and pipes cannot be left full of materials because of unwanted chemical reactions, settling of suspended materials or crystallization or hardening of materials. Also, cycling temperatures and pressures from starting up and shutting down certain processes (line kilns, boilers, blast furnaces, pressure vessels, etc.) may cause metal fatigue or other wear from pressure or thermal cycling.

In the more complex operations there are sequential shut down and start up procedures that must be carefully followed in order to protect personnel and equipment. Typically a start up or shut down will take several hours.

Continuous processes use process control to automate and control operational variables such as flow rates, tank levels, pressures, temperatures and machine speeds.^[2]

Semi-continuous processes

Many processes such as assembly lines and light manufacturing that can be easily shut down and restarted are today considered semi-continuous. These can be operated for one or two shifts if necessary.

History

The oldest continuous flow processes is the blast furnace for producing pig iron. The blast furnace is intermittently charged with ore, fuel and flux and intermittently tapped for molten pig iron and slag; however, the chemical reaction of reducing the iron and silicon and later oxidizing the silicon is continuous.

Semi-continuous processes, such as machine manufacturing of cigarettes, were called “continuous” when they appeared.

Many truly continuous processes of today were originally batch operations.

The Fourdrinier paper machine, patented in 1799, was one of the earliest of the industrial revolution era continuous manufacturing processes. It produced a continuous web of paper that was formed, pressed, dried and reeled up in a roll. Previously paper had been made in individual sheets.

Another early continuous processes was Oliver Evans‘es flour mill (ca. 1785), which was fully automated.

Early chemical production and oil refining was done in batches until process control was sufficiently developed to allow remote control and automation for continuous processing. Processes began to operate continuously during the 19th century. By the early 20th century continuous processes were common.

Shut-downs

In addition to performing maintenance, shut downs are also when process modifications are performed. These include installing new equipment in the main process flow or tying-in or making provisions to tie-in sub-processes or equipment that can be installed while the process is operating.

Shut-downs of complicated processes may take weeks or months of planning. Typically a series of meetings takes place for co-ordination and planning. These typically involve the various departments such as maintenance, power, engineering, safety and operating units.

All work is done according to a carefully sequenced schedule that incorporates the various trades involved, such as pipe-fitters, millwrights, mechanics, laborers, etc., and the necessary equipment (cranes, mobile equipment, air compressors, welding machines, scaffolding, etc.) and all supplies (spare parts, steel, pipe, wiring, nuts and bolts) and provisions for power in case power will also be off as part of the outage. Often one or more outside contractors perform some of the work, especially if new equipment is installed.

Safety

Safety meetings are typically held before and during shutdowns. Other safety measures include providing adequate ventilation to hot areas or areas where oxygen may become depleted or toxic gases may be present and checking vessels and other enclosed areas for adequate levels of oxygen and insure absence of toxic or explosive gases. Any machines that are going to be worked on must be electrically disconnected, usually through the motor starter, so that it cannot operate. It is common practice to put a padlock on the motor starter, which can only be unlocked by the person or persons who is or are endangered by performing the work. Other disconnect means include removing couplings between the motor and the equipment or by using mechanical means to keep the equipment from moving. Valves on pipes connected to vessels that workers will enter are chained and locked closed, unless some other means is taken to insure that nothing will come through the pipes.

Continuous processor (equipment)

Continuous Production can be supplemented using a Continuous Processor. Continuous Processors are designed to mix viscous products on a continuous basis by utilizing a combination of mixing and conveying action. The Paddles within the mixing chamber (barrel) are mounted on two co-rotating shafts that are responsible for mixing the material. The barrels and paddles are contoured in such a way that the paddles create a self-wiping action between themselves minimizing buildup of product except for the normal operating clearances of the moving parts. Barrels may also be heated or cooled to optimize the mixing cycle. Unlike an extruder, the Continuous Processor void volume mixing area is consistent the entire length of the barrel ensuring better mixing and little to no pressure build up. The Continuous Processor works by metering powders, granules, liquids, etc. into the mixing chamber of the machine. Several variables allow the Continuous Processor to be versatile for a wide variety of mixing operations:^[3]

Barrel Temperature
Agitator speed
Fed rate, accuracy of feed
Retention time (function of feed rate and volume of product within mixing chamber)

Continuous Processors are used in the following processes:

Compounding
Mixing
Kneading
Shearing
Crystallizing
Encapsulating

The Continuous Processor has an unlimited material mixing capabilities but, it has proven its ability to mix:

Plastics
Adhesives
Pigments
Composites
Candy
Gum
Paste
Toners
Peanut Butter
Waste Products

EXAMPLE…………….

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2014, 18 (11), pp 1427–1433

DOI: 10.1021/op400179f, http://pubs.acs.org/doi/full/10.1021/op400179f

EXAMPLE…………….

Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO₃)₂ and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO₃)₂, Cu(OTf)₂ was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date

1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);

13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;

19F NMR (376 MHz, CDCl3, ppm) δ -80.98.

1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.

2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.

A Concise Flow Synthesis of Efavirenz^†

DOI: 10.1002/anie.201411728

http://onlinelibrary.wiley.com/doi/10.1002/anie.201411728/abstract

SUPP INFO

http://onlinelibrary.wiley.com/store/10.1002/anie.201411728/asset/supinfo/anie_201411728_sm_miscellaneous_information.pdf?v=1&s=e1b253efab4a6f4cd5bd245694623e2459700ff5

NEXT EXAMPLE…………….

Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al₂O₃ support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H₂-TPR, and N₂ adsorption–desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al₂O₃, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance

( ACS Sustainable Chem. Eng. 2015, 3,1890−1896)

The synthesis of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole from 2-nitro-2′-hydroxy-5′-methylazobenzene over Pd/γ-Al₂O₃ in a fixed-bed reactor was investigated. Pd/γ-Al₂O₃ catalysts were prepared by two methods and characterized by XRD, TEM, H₂-TPR, and N₂ adsorption–desorption. Employed in the above reaction, the palladium catalyst impregnated in hydrochloric acid exhibited much better catalytic performance than that impregnated in ammonia–water, which was possibly attributed to the better dispersion of palladium crystals on γ-Al₂O₃. This result demonstrated that the preparation process of the catalyst was very important. Furthermore, the reaction parameters were optimized. Under the optimized conditions (toluene, NAB/triethylamine molar ratio 1:2, 60 °C, 2.5 MPa hydrogen pressure, 0.23 h^–1 liquid hourly space velocity), about 90% yield of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole was obtained. Finally, the time on stream performance of the catalyst was evaluated, and the reaction could proceed effectively over 200 h without deactivation of the catalyst.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al₂O₃ by a Continuous Process

ACS Sustainable Chem. Eng., 2015, 3 (8), pp 1890–1896

DOI: 10.1021/acssuschemeng.5b00507

Publication Date (Web): July 06, 2015

http://pubs.acs.org/doi/abs/10.1021/acssuschemeng.5b00507

NEXT EXAMPLE…………….

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

continuous flow processing of organometallic reagents

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

https://www.vapourtec.com/flow-chemistry-resource-centre/publications-citing-vapourtec/continuous-flow-processing-of-organometallic-reagents-using-an-advanced-peristaltic-pumping-system-and-the-telescoped-flow-synthesis-of-ez-tamoxifen/

NEXT EXAMPLE…………….

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

A versatile multi-step continuous flow synthesis for the preparation of substituted pyrazoles is presented.

The automated synthesis utilises a metal-free ascorbic acid mediated reduction of diazonium salts prepared from aniline starting materials followed by hydrolysis of the intermediate hydazide and cyclo-condensation with various 1,3-dicarbonyl equivalents to afford good yields of isolated functionalised pyrazole products.

The synthesis of the COX-2 selective NSAID was demonstrated using this approach.

J.-S. Poh, D. L. Browne, S. V. Ley, React. Chem. Eng., 2016, DOI: 10.1039/C5RE00082C

NEXT EXAMPLE…………….

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

NEXT EXAMPLE…………….

RAFT RAFT (Reversible Addition Fragmentation chain Transfer), a type of controlled radical polymerization, was invented by CSIRO in 1998 but developed in partnership with DuPont over a long term collaboration. Conventional polymerisation is fast but gives a wide distribution of polymer chain lengths. (known as a high polydispersity index ). RAFT is more versatile than other living polymerization techniques, such as atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP), it not only leads to polymers with a low polydispersity index and a predetermined molecular weight, but it permits the creation of complex architectures, such as linear block copolymers, comblike, star, brush polymers and dendrimers. Monomers capable of polymerizing by RAFT include styrenes, acrylates, acrylamides, and many vinyl monomers. CSIRO is the owner of the RAFT patents and is actively commercialising the technology. There are 12 licences in force and CSIRO is pursuing interest in a number of fields including human health, agriculture, animal health and personal care. RAFT is the dominant polymerization technique for the creation of polymer-protein or polymer-drug conjugates, permitting (for example) the combination of a polymer exhibiting high solubility with a drug molecule with poor solubility.. Though RAFT can be carried out in batch, it also lends itself to continuous flow processing, as this processing method offers an easy and reproducible scale-up route of the oxygen sensitive RAFT process. The possibility to effectively exclude oxygen using continuous flow reactors in combination with inline degassing methods offers advantages over batch processing at scales beyond the laboratory environment. Challenges associated with the high viscosity of the polymer product solution can be controlled using pressuriseable continuous flow reactor systems. http://www.csiro.au/products/RAFT.html

Examples………..

Cyclohexaneperoxycarboxylic acid (6, has been developed as a safe, inexpensive oxidant, with demonstrated utility in a Baeyer−Villiger rearrangement.³⁴ Solutions of cyclohexanecarboxylic acid in hexane and 50% aqueous H₂O₂ were continuously added to 45% H₂SO₄ at 50−70 °C and slightly reduced pressure. The byproduct H₂O was removed azeotropically, and the residence time in the reactor was 3 h. Processing was adjusted to maintain a concentration of 6 at 17−19%, below the detonable level, and the product was kept as a stable solution in hexane. These operations enhanced the safety margin in preparing 6.

Scheme . Generation of cyclohexaneperoxycarboxylic acid

Examples………..

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuousprocessing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Org. Process Res. Dev., 2012, 16 (5), pp 1003–1012

DOI: 10.1021/op200352k, http://pubs.acs.org/doi/full/10.1021/op200352k

Examples………..

Abstract Image

Continuous Biocatalytic Processes

Org. Process Res. Dev., 2009, 13 (3), pp 607–616

DOI: 10.1021/op800314f, http://pubs.acs.org/doi/full/10.1021/op800314f

Scheme . Biotransformation of sodium l-glutamate to γ-aminobutyric acid (GABA) by single-step α-decarboxylation with glutamate decarboxylase

PICS…………..

References

American Iron and Steel Institute
Benett, Stuart (1986). A History of Control Engineering 1800-1930. Institution of Engineering and Technology. ISBN 978-0-86341-047-5.
Ziegler, Gregory R.; Aguilar, Carlos A. (2003). “Residence Time Distribution in a Co-rotating, Twin-screw Continuous Mixer by the Step Change Method”. Journal of Food Engineering(Elsevier) 59 (2-3): 1–7.

Sources and further reading

R H Perry, C H Chilton, C W Green (Ed), Perry’s Chemical Engineers’ Handbook (7th Ed), McGraw-Hill (1997), ISBN 978-0-07-049841-9
Major industries typically each have one or more trade magazines that constantly feature articles about plant operations, new equipment and processes and operating and maintenance tips. Trade magazines are one of the best ways to keep informed of state of the art developments.

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PIERRE FABRE CDMO Supercritical Fluids – A supercritical CO2 GMP Unit for Pharmaceutical Applications.

companies, PROCESS Comments Off

Jun 132016

Pierre Fabre's Supercritical CO2 GMP unit.

read all by clicking

http://www.pharmaceutical-technology.com/contractors/contract/supercritical-fluids/?WT.mc_id=WN_Comp

The article gives contact details of below person

…….//////PIERRE FABRE CDMO, Supercritical Fluids, supercritical CO2 GMP Unit, Pharmaceutical Applications.

A Process Monitoring Solution that is Flexible and Scalable

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Jun 072016

A Process Monitoring Solution that is Flexible and Scalable
The Unscrambler® X Process Pulse II can be utilised in all levels of an organisation, providing solutions to a variety of challenges using real-time process…

A Process Monitoring Solution that is Flexible and Scalable

02 June 2016 by CAMO Software

The Unscrambler® X Process Pulse II can be utilised in all levels of an organisation, providing solutions to a variety of challenges using real-time process monitoring.

The device can be applied across many different industries and research fields to improve product development, manufacturing, and quality control, with powerful multivariate models.

Data analysts often face challenges with the data they want to analyse, which can be in different formats, coming from different systems, or it can be a mix of historical and live data and contain a large number of variables.

Unscrambler® X Process Pulse II handles all of these challenges, and translates the data into what is actually happening in the production process.

Download available at ………

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/////////// Process Monitoring, Solution, Flexible, Scalable

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

PROCESS Comments Off

Jun 062016

Fig. 1. Schematic Representation of a Complex Fluidized-Bed Granulator

1: Exhaust air, 2: bag filter, 3: partition tube, 4: impeller, 5: rotor disc, 6: inlet air, 7: screen, 8: spray nozzle.

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

Shouichi Hosaka¹⁾, Yasufumi Okamura¹⁾, Yuji Tokunaga¹⁾

1) Research and Development Division, Sawai Pharmaceutical Co., Ltd.

Released on J-STAGE 20160601

Chemical and Pharmaceutical Bulletin
Vol. 64 (2016) No. 6 p. 644-649

http://doi.org/10.1248/cpb.c15-00640

https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/_html

Abstract

A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.

Conclusion

Three types of treated particles were prepared using a complex fluidized-bed granulator equipped with a particle-sizing mechanism under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable.

By processing CEF with HPC-L using this device, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed one. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile.

The present method is applicable to the design of fine particles of approximately 100 µm in size with a narrow distribution, which improved the solubility of drug substance.

////////fine particle, particle size distribution, dissolution, complex fluidized-bed granulator

Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jun 032016

A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho-bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C–O coupling on the ortho-bromide. The scope of this methodology was demonstrated on several similar substrates.

Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process

Zhiguo J. Song^*, et al

Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway New Jersey 07065, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00141

Publication Date (Web): May 25, 2016

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00141

*E-mail: zhiguo_song@merck.com., *E-mail: lushi_tan@merck.com.

Benzofurans are important building blocks for the synthesis of biologically active compounds in the pharmaceutical industry and compound 3 has been an important intermediate in Merck’s hepatitis C program.(1, 2)

1 as a pale yellow solid (3.1 kg, 86% yield, 98.8% LACP). Mp: > 240 °C.

¹H NMR (400 MHz, DMSO-d₆)δ 8.54 (d, J = 4.5 Hz, 1H), 8.07 (s, 1H), 8.07–7.94 (m, 3H), 7.42 (t, J = 8.9 Hz, 2H), 3.34 (s, 3H), 3.22 (d, J = 4.1 Hz, 3H), 2.85 (d, J = 4.6 Hz, 3H);¹³C NMR (100 MHz, DMSO-d₆) δ 26.2, 38.2, 112.8, 113.4, 115.9 (d, J = 22 Hz), 119.7, 124.2, 125.2, 128.7, 129.6 (d, J = 8.8 Hz), 136.9, 151.8, 154.4, 162.4, 162.9 (d, J = 247.1 Hz).

¹⁹F NMR (376 MHz DMSO-d₆) δ 109.9

AHR-FAB-MS calcd for C₁₈H₁₆BrFN₂O₄S: MH⁺, 455.2980. Found: 455.0055 (MH⁺).

(a) Burns, C. J., Del Vecchio, A. M., Bailey, T. R., Kulkarni, B. A., Faitg, T. H., Sherk, S. R., Black-Ledge,C. W., Rys, D. J., Lessen, T. A., Swestock, J., Deng, Y., Nitz, Theodore, J., Reinardt, J. A., Feng, H., andSaha, A. K. Patent WO 2004041201.

(b) McComas, C. C., Liverton, N. J., Habermann, J., Koch, U.,Narjes, F., Li, P., Peng, X., Soll, R., and Wu, H. WO 2011106929.

(c) McComas, C. C., Liverton, N. J., Soll,R., Li, P., Peng, X., and Wu, H. WO 2011106986.

(d) McComas, C. C., Liverton, N. J., Soll, R., Li, P.,Peng, X., Wu, H., Narjes, F., Habermann, J., Koch, U., and Liu, S. WO 2011106992.

(e) McComas, C. C.,Liverton, N. J., Habermann, J., Koch, U., Narjes, F., Li, P., Peng, X., Soll, R., Wu, H., Palani, A., He, S.,Dai, X., Liu, H., Lai, Z., London, C., Xiao, D., zorn, N., and Nargund, R. WO 2013033971.
He, S.; Li, P.; Dai, X.; McComas, C. C.; Du, C.; Wang, P.; Lai, Z.; Liu, H.; Yin, J.; Bulger, P. G.; Dang, Q.;Xiao, D.; Zorn, N.; Peng, X.; Nargund, R. P.; Palani, A. Tetrahedron Lett. 2014, 55, 2212– 2216, DOI: 10.1016/j.tetlet.2014.02.051

//////Concise Cu (I), Catalyzed, Synthesis, Substituted Benzofurans, Tandem SNAr/C–O Coupling Process

Supporting Info

Activated nanostructured bimetallic catalysts for C-C coupling reactions: recent progress

PROCESS, SYNTHESIS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, 6,3341-3361
DOI: 10.1039/C5CY02225H, Minireview

Rohit Kumar Rai, Deepika Tyagi, Kavita Gupta, Sanjay Kumar Singh
This minireview highlights the recent progress made in the last decade towards the development of activated bimetallic alloy nanoparticle catalysts for C-C coupling reactions, including asymmetric C-C bond coupling reactions.

Minireview

Activated nanostructured bimetallic catalysts for C–C coupling reactions: recent progress

Rohit Kumar Rai,^a Deepika Tyagi,^a Kavita Gupta^a and Sanjay Kumar Singh*^a^b

*Corresponding authors

^aDiscipline of Chemistry, Indian Institute of Technology (IIT) Indore, Simrol, Indore, 452 020 India

^bCentre for Material Science and Engineering, Indian Institute of Technology (IIT) Indore, Simrol, Indore, 452 020 India
E-mail: sksingh@iiti.ac.in
Fax: +91 731 2438 933

Catal. Sci. Technol., 2016,6, 3341-3361

DOI: 10.1039/C5CY02225H

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C5CY02225H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

Catalysts based on bimetallic nanoparticles have received tremendous scientific and industrial attention and are established as an important class of active catalysts. These catalysts displayed improved catalytic activities compared to their monometallic counterparts for several reactions, which is attributed to their highly modified surface structures (electronic and geometrical) due to the synergic cooperation between the two metals of the bimetallic nanoparticle catalyst. Moreover, such synergic interactions are more prominent in alloy nanoparticle catalysts, where the probability of metal-to-metal interactions is higher in comparison with other systems (such as core–shell nanoparticles). This minireview highlights the recent progress made in the last decade towards the development of activated bimetallic alloy nanoparticle catalysts for C–C coupling reactions, including asymmetric C–C bond coupling reactions. Herein, the influence of the modified electronic structures of the newly formed bimetallic alloy nanoparticle catalysts on their activated catalytic performance is also discussed extensively.

भारतीय प्रौद्योगिकी संस्थान इंदौर
INDIAN INSTITUTE OF TECHNOLOGY INDORE

School of Basic Sciences

Discipline of Chemistry

Dr. Sanjay Kumar Singh

Assistant Professor

Chemistry

Organometallics and Nanotech Catalysis Group

Discipline of Chemistry, School of Basic Sciences

Indian Institute of Technology Indore, Simrol, Indore 452 020

Dr. Sanjay Kumar Singh

Assistant Professor

Chemistry

sksingh[at]iiti.ac.in

Mr. Rohit Rai

Ph.D. Student (CSIR-SRF), Since Jan. 2013

He obtained his Masters degree in Organic Chemistry from BHU Varanasi in the year 2012. He is presently engaged in the development of nanoparticle based heterogeneous catalysts for important organic reactions.

rohitrai47[at]gmail.com; phd12123108[at]iiti.ac.in

Rohit Kumar Rai
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd12123108[at]iiti.ac.in

Research Topic: Development of nanoparticle based heterogeneous catalysts for important organic reactions

Ms. Deepika Tyagi

Ph.D. Student (UGC-SRF), Since Jan. 2013

She obtained her Masters degree in Organic Chemistry from C.C.S. Meerut University in the year 2011. She is presently engaged in the development of homogeneous catalysts based on organometallic and coordination complexes for important organic reactions.

tyagi.deepika30[at]gmail.com; phd12123112[at]iiti.ac.in

Deepika Tyagi
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd12123112[at]iiti.ac.in

Research Topic: Development of homogeneous catalysts based on metal complexes for important organic reactions

Ms. Kavita Gupta

Ph.D. Student (CSIR-SRF), Since Jul., 2013

She obtained her Masters degree in Organic Chemistry from Dr. B.R.A. University, Agra in the year 2010. She is presently engaged in the development of catalytic systems for the conversion of bioderived molecules to bio-fuel components and other important products.

phd1301131005[at]iiti.ac.in

Kavita Gupta
Ph.D. Scholar
Dr. Sanjay Research Group

M-Block, IIT Indore
Email: phd1301131005[at]iiti.ac.in

Research Topic: Development of catalysts for important catalytic reactions

ALL AUTHORS

//////Activated nanostructured, bimetallic catalysts, C-C coupling reactions, recent progress

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

PROCESS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, 6,3378-3385
DOI: 10.1039/C6CY00033A, Paper

Gang Yang, Lijun Zhou
Several key issues regarding the mechanisms of proline catalysis are unravelled by first-principles calculations that can guide future catalyst design.

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

Gang Yang*^a and Lijun Zhou^a

*Corresponding authors

^aCollege of Resource and Environment & Chongqing Key Laboratory of Soil Multi-scale Interfacial Process, Southwest University, Chongqing, PR China
E-mail: theobiochem@gmail.com
Fax: +86 023 68250444
Tel: +86 023 68251545

Catal. Sci. Technol., 2016,6, 3378-3385

DOI: 10.1039/C6CY00033A

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C6CY00033A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

Proline is an efficient and versatile catalyst for organic reactions while a number of issues remain controversial. Here, ab initio and density functional calculations were used to unravel a few key issues of catalytic mechanisms in water and organic solvents. Zwitterionic proline that predominates in water and DMSO is assumed to be the active conformation for catalysis, and reactivity differences in two solvents are revealed. Meanwhile, an abundance of experimental observations can be finely interpreted by the present computational results, including those seemingly contradictory. Although bearing lower activation barriers than that in DMSO, the production of enamines and further aldol products in water will be blocked at an early stage (J. Am. Chem. Soc., 2006, 128, 734) because the reaction in water is significantly driven towards acetyl formation that is kinetically and thermodynamically preferred. Due to significant promotion of the rate-determining proton transfer step, aldol reactions in organic solvents can be obviously initiated by the addition of some water (Angew. Chem., Int. Ed., 2004, 43, 1983). In order to show catalytic effects in water (an obviously environmentally benign solvent), proline has to be structurally modified so that canonical structures can be the principal (or sole) conformations, which is in line with the analyses of all proline-based catalysts available in water (e.g., J. Am. Chem. Soc., 2006, 128, 734, Catal. Commun., 2012, 26, 6). Thus, the present results provide insightful clues to mechanisms of proline-mediated catalysis as well as future design of more efficient catalysts.

IF YOU HAVE ENJOYED IT ………EMAIL ME amcrasto@gmail.com, +919323115463, India

INDIA FLAG

DR ANTHONY CRASTO , WORLDDRUGTRACKER, HELPING MILLIONS, MAKING INDIA AND INDIANS PROUD

//////Mechanisms, reactivity, differences, proline-mediated catalysis, water , organic solvents

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jun 012016

Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C6CY00855K, Communication

Nicholas J. Weise, Syed T. Ahmed, Fabio Parmeggiani, Elina Siirola, Ahir Pushpanath, Ursula Schell, Nicholas J. Turner
An industrial-scale method employing a phenylalanine ammonia lyase enzyme

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

Nicholas J. Weise,^a Syed T. Ahmed,^a Fabio Parmeggiani,^a Elina Siirola,^b Ahir Pushpanath,^b Ursula Schell^b and Nicholas J. Turner*^a

*Corresponding authors

^aManchester Institute of Biotechnology & School of Chemistry, University of Manchester, 131 Princess Street, Manchester, UK
E-mail: nicholas.turner@manchester.ac.uk

^bJohnson Matthey Catalysts and Chiral Technologies, 28 Cambridge Science Park, Milton Road, Cambridge, UK

Catal. Sci. Technol., 2016, Advance Article

DOI: 10.1039/C6CY00855K

SEE

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C6CY00855K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

An intensified, industrially-relevant strategy for the production of enantiopure halophenylalanines has been developed using the novel combination of a cyanobacterial phenylalanine ammonia lyase (PAL) and ammonium carbamate reaction buffer. The process boasts STYs up to >200 g L⁻¹ d⁻¹, ees ≥ 98% and simplified catalyst/reaction buffer preparation and work up.

///////Intensified, biocatalytic production, enantiomerically pure, halophenylalanines, acrylic acids, ammonium carbamate, ammonia source

Flow approach towards AZD 6906

flow synthesis, PROCESS Comments Off

May 272016

Scheme 1: Flow approach towards AZD6906 (65).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry, Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

In 2012 researchers from AstraZeneca (Sweden) reported upon a scale-up campaign for their gastroesophageal reflux inhibitor programme. Specifically, flow chemical synthesis was used to efficiently and reliably provide sufficient quantities of the target compound AZD6906 (65), which had been prepared previously in batch. From these earlier batch studies concerns had been raised regarding exothermic reaction profiles as well as product instability which needed to be addressed when moving to larger scale synthesis. Flow was identified as a potential way of circumventing these specific problems and so was extensively investigated. The developed flow route [1 ] started with the reaction of methyl dichlorophosphine (66) and triethyl orthoacetate (67), which in batch could only be performed under careful addition of the reagent and external cooling using dry ice/acetone. Pleasingly, a simple flow setup in which the two streams of neat reagents were mixed in a PTFE T-piece maintained at 25 °C was found effective in order to prepare the desired adduct 68 in high yield and quality showcasing the benefits of superior heat dissipation whilst also safely handling the toxic and pyrophoric methyl dichlorophosphine reagent (Scheme 1).

As the subsequent Claisen condensation step was also known to generate a considerable exotherm, a similar flow setup was used in order to allow the reaction heat to dissipate. The superiority of the heat transfer process even allowed this step to be performed on kilogram quantities of both starting materials (68, 69) at a reactor temperature of 35 °C giving the desired product 72 within a residence time of only 90 seconds. Vital to the successful outcome was the efficient in situ generation of LDA from n-BuLi and diisopropylamine as well as the rapid quenching of the reaction mixture prior to collection of the crude product. Furthermore, flow processing allowed for the reaction of both substrates in a 1:1 ratio (rather than 2:1 as was required in batch) as the immediate quenching step prevented side reactions taking place under the strongly basic conditions. Having succeeded in safely preparing compound 72 on kilogram scale, the target compound 65 was then generated by global deprotection and subsequent recrystallisation where batch was reverted to as the conditions had been previously devised and worked well.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry

Telephone: +44 (0) 191 33 42185

Member in the Centre for Sustainable Chemical Processes

(email at i.r.baxendale@durham.ac.uk)

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.

Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Process Res. Dev. 2012, 16, 925–929. doi:10.1021/op200340c

Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906

Tomas Gustafsson, Henrik Sörensen, and Fritiof Pontén*

Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

Org. Process Res. Dev., 2012, 16 (5), pp 925–929

DOI: 10.1021/op200340c

Publication Date (Web): February 21, 2012

*Telephone: +46 31 776 16 65. Email: fritiof.ponten@astrazeneca.com.

This article is part of the Continuous Processes 2012 special issue.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture. This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale. One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative. The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

////Flow synthesis, AZD 6906

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

PROCESS, SYNTHESIS Comments Off

Mar 232016

Herein, the first continuous cross-dehydrogenative homocoupling of an unactivated arene using oxygen as sole oxidant is reported. Employing microreactor technology which enables the use of elevated temperatures and pressures leads to a boost of the catalytic reaction. Hence, a major reduction in reaction time is achieved. Due to the significance as precursor for MOFs as well as high-tech and high-value polymers, the study focused on the production of 3,4,3′,4′-tetramethyl-biphenyl.

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

Nico Erdmann, Yuanhai Su, Benjamin Bosmans, Volker Hessel, and Timothy Noël^*

Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00044

Publication Date (Web): March 10, 2016

*E-mail: t.noel@tue.nl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00044