Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

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Jan 052016

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

1 Diphenhydramine Hydrochloride

Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride

Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.

In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.

The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Scheme 2. Continuous Flow Synthesis of Olanzapine

Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.

In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd₂dba₃ as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H₂O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et₃SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.

The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)₄ as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Riccardo Porta, Maurizio Benaglia^*, and Alessandra Puglisi^*

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00325

Publication Date (Web): November 26, 2015

*E-mail: maurizio.benaglia@unimi.it., *E-mail: alessandra.puglisi@unimi.it.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00325

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

University of Milan

Department of Chemistry

Milano, Italy

Maurizio Benaglia

University of Milan, Milano · Department of Chemistry

Riccardo Porta

PhD Student

University of Milan, Milano · Department of Chemistry

Alessandra Puglisi

University of Milan, Milano · Department of Chemistry

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Map of milan italy

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Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

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Nov 112015

The safe use of diazo reagents for the preparation of a key structure in the synthesis of milnacipran analogues is described herein. Using continuous flow technology, the diazo reagent is synthesized, purified, dried, and subsequently used in semi-batch mode for an intramolecular cyclopropanation. Side products formed in the reaction are isolated and rationalized to optimize the process. Different separation techniques in flow are compared with regard to their ability to produce pure and dry diazo reagents. The studies yield a scalable process to a key intermediate in the syntheses of milnacipran and its possible substituted analogues.

Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

Simon T. R. Müller^†, Aurélien Murat^‡, Paul Hellier^§, and Thomas Wirth^*^†

^† School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, U.K.

^‡ Institut de Recherche Pierre Fabre, 81603 Gaillac, France

^§ Pierre Fabre Médicament, Parc Industriel de la Chartreuse, 81106 Castres, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00308

Publication Date (Web): October 29, 2015

*E-mail: wirth@cf.ac.uk.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00308

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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NEW PATENT…..DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE”

polymorph, PROCESS Comments Off

Sep 012015

WO2015124764

ERREGIERRE S.P.A. [IT/IT]; Via Francesco Baracca, 19 I-24060 San Paolo D’argon (IT)

Erregierre SpA

DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE”

Abstract

A novel process is described for the production of Dabigatran etexilate mesylate, a 5 compound having the following structural formula: and two novel intermediates of said process.

(WO2015124764) SYNTHESIS PROCESS OF DABIGATRAN ETEXILATE MESYLATE, INTERMEDIATES OF THE PROCESS AND NOVEL POLYMORPH OF DABIGATRAN ETEXILATE click herefor patent

Dabigatran etexilate mesylate is an active substance developed by Boehringer

Ingelheim and marketed under the name Pradaxa^® in the form of tablets for oral administration; Dabigatran etexilate mesylate acts as direct inhibitor of thrombin (Factor I la) and is used as an anticoagulant, for example, for preventing strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that could form following surgery.

Dabigatran etexilate mesylate is the INN name of the compound 3-({2-[(4-{Amino-[(E)-hexyloxycarbonylimino]-methyl}-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate methanesulphonate, having the following structural formula:

The family of compounds to which Dabigatran etexilate belongs was described for the first time in patent US 6,087,380, which also reports possible synthesis pathways.

The preparation of polymorphs of Dabigatran etexilate or Dabigatran etexilate mesylate is described in patent applications US 2006/0276513 A1 , WO 2012/027543 A1 , WO 2008/059029 A2, WO 2013/124385 A2, WO 2013/124749 A1 , WO 2013/1 1 1 163 A2 and WO 2013/144903 A1 , while patent applications WO 2012/044595 A1 , US 2006/0247278 A1 , US 2009/0042948 A2, US 2010/0087488 A1 and WO 2012/077136 A2 describe salts of these compounds.

One of the objects of the invention is to provide an alternative process for the preparation of Dabigatran etexilate mesylate and two novel intermediates of the process.

These objects are achieved with the present invention, which, in a first aspect thereof, relates to a process for the production of Dabigatran etexilate mesylate, comprising the following steps:

a) reacting 4-methylamino-3-nitrobenzoic acid (I) with thionyl chloride to give 4- methylamino-3-nitrobenzoyl chloride hydrochloride (II):

(I) (ID

b) reacting compound (II) with 3-(2-pyridylamino) ethyl propanoate (III) to give the compound 3-[(4-methylamino-3-nitro-benzoyl)-pyridyn-2-yl-amino]-ethyl propanoate (IV):

(II) (IV)

reducing compound (IV) with hydrogen to 3-[(3-amino-4-methyl benzoyl)-pyridin-2-yl-amino]ethyl propanoate (V):

(IV) (V)

d) reacting N-(4-cyanophenyl)glycine (VI) with 1 ,1 -carbonyldiimidazole (CDI) to give 4-(2-imidazol-1 -yl-2-oxo-ethylamino)-benzonitrile (VII):

(VI) (VII)

e) reacting compound (VII) with compound (V) obtained in step c) to give one of compounds 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino- benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (VIII) and 3-[(3-amino-4-{[(2- (4-cyano-phenylamino)-acetyl]-methylamino}-benzoyl)-pyridin-2-yl- amino]ethyl propanoate (IX), or a mixture of the two compounds (VIII) and (IX):

f) transforming, through treatment with acetic acid, compounds (VIII) or (IX) or the mixture thereof into the compound 3-({2-[(4-cyano-phenylamino)-methyl]- 1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate (X), and then treating compound (X) with hydrochloric or nitric acid to form the corresponding salt (XI):

CHsCOOH

[(VIII) ; (IX)]

wherein A is a chlorine or nitrate anion;

liberating in solution compound (X) from salt (XI), and reacting compound (X) in solution with ethyl alcohol in the presence of hydrochloric acid and 2,2,2-trifluoroethanol to give the compound 3-({2-[(4-ethoxycarbonimidoyl-phenylamino)-methyl]-1 -methyl-1 H-benzimidazol-5-carbonyl}-pyridin-2-yl-amino)-ethyl propanoate hydrochloride (XII):

reacting compound (XII) with ammonium carbonate to form compound Dabigatran ethyl ester (XIII):

reacting compound (XIII) with maleic acid to produce the maleate salt thereof (XI 11 ‘) and isolating the latter:

j) reacting maleate salt (XI 11 ‘) with hexyl chloroformate to give compound Dabigatran etexilate (XIV :

hexyl chloroformate

k) reacting compound (XIV) with methanesulfonic acid to give the salt Dabigatran etexilate mesylate:

a gatran etex ate mesy ate

EXAMPLE 12

Preparation of Dabigatran etexilate mesylate (step k).

All the Dabigatran etexilate obtained in Example 1 1 (4.7 kg; 7.49 moles) is loaded into a reactor along with 28.2 kg of acetone and the mass is heated at 50-60 °C until a complete solution is obtained; it is then filtered to remove suspended impurities. The filtered solution is brought to 28-32 °C. Separately, a second solution is prepared by dissolving 0.705 kg (7.34 moles) of methanesulfonic acid in 4.7 kg of acetone; the second solution is cooled down to 0-10 °C. The second solution is poured into the Dabigatran etexilate solution during 30 minutes, while maintaining the temperature of the resulting solution at 28-32 °C with cooling. The salt of the title is formed. The mass is maintained at 28-32 °C for 2 hours, then cooled to 18-23 °C to complete precipitation and the system is maintained at this temperature for 2 hours; lastly, centrifugation takes place, washing the precipitate with 5 kg of acetone. The precipitate is dried at 60 °C.

4.88 kg of Dabigatran etexilate mesylate, equal to 6.74 moles of compound, are obtained, with a yield in this step of 90%.

EXAMPLE 13

0.5 g of the crystalline compound (XIV) obtained in Example 1 1 are ground thoroughly and loaded into the sample holder of a Rigaku Miniflex diffractometer with copper anode.

The diffractogram shown in Figure 1 is obtained; a comparison with the XRPD data of the known Dabigatran etexilate polymorphs allows to verify that the polymorph of Example 1 1 is novel.

EXAMPLE 14

0.7 g of the crystalline compound (XIV) obtained in Example 1 1 are loaded into

the sample holder of a Perkin-Elmer DSC 6 calorimeter, performing a scan from ambient T to 350 °C at a rate of 10 °C/min in nitrogen atmosphere. The graph of the test is shown in Figure 2, and shows three endothermic phenomena with peaks at 83.0-85.0 °C, 104.0-104.2 °C and 129.9 °C; events linked to the thermal decomposition of the compound are evident at about 200 °C.

Figure 1 is an XRPD spectrum of the novel polymorph of Dabigatran etexilate of the invention;

Figure 2 is the graph of a DSC test on the novel polymorph of Dabigatran etexilate of the invention.

ERREGIERRE S.p.A

Pietro Carlo Gargani, CEO and president of ERREGIERRE S.p.A., oversees a company with a firm commitment to serving its customers innovative products

ERREGIERRE was founded by two entrepreneurs in 1974 in San Paolo d’Argon, in the northern Italian region of Bergamo. It lodged one of its first major …

San Paolo d'Argon

///////////ERREGIERRE S.p.A, DABIGATRAN, WO 2015124764

Investigating Scale-Up and Further Applications of DABAL-Me3 Promoted Amide Synthesis

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Aug 112015

Amides, amidines and amidrazones have been prepared on up to 100g scale from the corresponding esters using DABAL-Me₃.A derivative of Imatinib (Gleevec) was prepared on a 26g scale.

Continuous flow methodology was shown to provide a useful method for larger scales (productivities of >50 g h–1) and could be performed successfully on a smaller laboratory scale using a FlowSyn flow synthesiser.

D. S. Lee, Z. Amara, M. Poliakoff, T. Harman, G. Reid, B. Rhodes, S. Brough, T. McInally, S. Woodward, Org. Process Res. Dev., 2015: DOI: 10.1021/acs.oprd.5b00101

Indian Generics 2016

PROCESS, regulatory Comments Off

Aug 032015

The generic APIs market is expected to continue to rise faster than the branded/innovative APIs, by 7.7%/year to reach $30.3 billion in 2016. Asia-Pacific is expected to show the fastest growth rates (10.8%/year). The 24 fastest growing markets will include 11 in Asia-Pacific, seven in Eastern Europe and CIS, four in Africa-Middle East and two in Latin America (Figure ).

Figure – Top growth markets for generic APIs to 2016

By 2016, China will account for 27.7% of the global generic API merchant market, while the US will have fallen to 23.8%; the mature markets as a whole will see their share fall from 41.8% in 2012 to 36.9%. India will be the third largest, with a 7.2% share.

Telescoping multistep reactions

PROCESS, SYNTHESIS Comments Off

Jul 292015

Telescoping multistep reactions

The synthesis of fine chemicals sometimes requires multiple reactions and tedious work-up between each step is often necessary. Purification may involve the addition of a quenching reagent, multiple aqueous and organic extractions, the addition of a drying agent, filtration, evaporation, and further purification by chromatography, distillation, or recrystallization. These operations all require significant input of energy and materials that ultimately end up as large amounts of waste. Methods and technologies that eliminate or simplify one or many of these steps can make a significant influence on the environmental impact of a multistep chemical synthesis. Continuous processing is particularly suitable for ‘telescoping’ reaction sequences, and many methods have been developed to facilitate this.¹

One strategy utilizes solid supported reagents packed into columns which allow starting materials to flow in and product to be collected at the outlet without requiring separation of the spent reagent. Different columns may be linked in series, allowing multistep processes to take place. Extra operations may also be necessary, such as solvent changes or the removal of unwanted side products. Methods for automating these processes have also been developed. An example from the Ley group illustrates many of these technologies in the design of a single apparatus to continuously prepareImatinib (Gleevec) from simple starting materials (Scheme 1).2Acid chloride 5 and aniline 6 in DCM were flowed through a cartridge containing immobilized DMAP as a nucleophilic catalyst, followed by a basic cartridge to scavenge any remaining 5. The formation of the amide 7 was monitored by an in-line UV spectrometer and subsequently added to a vial containing piperazine 8 in DMF at 50 °C, which facilitated evaporation of the DCM. Once a particular amount of 7 was obtained, as indicated by the UV spectrometer, a connected autosampler would collect this solution and pump it through an immobilized base to induce a substitution reaction, followed by an immobilized isonitrile to scavenge any remaining 8. An immobilized acid was used to ‘catch’ amine 9 through protonation, allowing unreacted 7 to go to waste. ‘Release’ of 9 through deprotonation followed by the addition of aniline 10 and a palladium catalyst facilitated a cross-coupling reaction, furnishing the crude Imatinib, which was then evaporated onto a silica gel column for automated chromatography. Pure product was isolated in 32% overall yield and >95% purity. While not explicitly demonstrated, the possibility of using this apparatus to form analogs by using modified starting materials is proposed. The ability to perform multi-step synthesis of pharmaceuticals without handling of the intermediates is particularly interesting, as exposure to these species can be hazardous.


	Scheme 1 Multistep synthesis of Imatinib (Gleevec).

The above example utilizes packed cartridges of scavengers to effect purification. An alternative method is to more closely emulate typical batch purification operations such as distillation andextraction, but on a small, continuous scale. Several different ‘chip’ purification devices have been developed for this purpose.^3-12 Some of these technologies were used together in a combined triflation/Heck reaction of phenols (Scheme2). After the initial triflation step in dichloromethane, the product is combined with a stream of aqueous HCl and passed on to a chip containing a membrane that allows the organic phase to pass through while the aqueous stream is passed to waste. The purified triflate then combines with a stream of DMF and the material enters a distillation device heated to 70 °C which allows the volatile dichloromethane to be carried out of the reactor with a stream of nitrogen gas. The product then enters a final reactor where it combines with a stream ofalkene and catalyst to form the Heck product. The whole reactor was operated continuously for 5.5 hours, generating approximately 32 mg of product per hour.


	Scheme 2 Triflation/Heck coupling facilitated by automated extraction and distillation.

Integration of multiple reaction steps, separations, and purifications into one continuous process has great potential for avoiding energy intensive and wasteful intermediate purification. While great progress has been made, the development of a truly general set of reagents, methods, and devices still requires more research. Immobilized reagents can be wasteful to scale up, and there are significant limitations to current microreactor extraction and distillation technologies. Crystallization is another very important technique in pharmaceutical synthesis, and while there are an increasing number of methods for continuous crystallization,14 15 , it is yet to be used as an intermediate purification step in an automated multi-step synthesis. Lastly, large scale applications of such complex, streamlined processes are required before a thorough assessment of their environmental impact in comparison with traditional batch routes can be made.

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How flow chemistry can make processes greener…………Supercritical fluids

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Jul 232015

Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,¹ chromatography,² and as a reaction medium³ have all been commercialized, particularly for supercritical carbon dioxide (scCO₂).⁴ Academic examples using scMeOH, scH₂O, and scCO₂ for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.⁵

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).⁶ They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO₂ under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.


	Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH₂O) can be an interesting green solvent only obtainable at very high temperature (T_c = 374 °C) and pressure (P_c = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO₂; however, it has also been shown to be an effective solvent for selective oxidations.⁷ Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH₂O, a reaction carried out on industrial scale in acetic acid (Scheme 2).⁸ By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H₂O₂.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.⁹


	Scheme 2 Selective oxidation in supercritical water.

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)
Solvent	Molecular weight	Critical temperature	Critical pressure	Critical density
Solvent	g/mol	K	MPa (atm)	g/cm³
Carbon dioxide (CO₂)	44.01	304.1	7.38 (72.8)	0.469
Water (H₂O) (acc. IAPWS)	18.015	647.096	22.064 (217.755)	0.322
Methane (CH₄)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C₂H₆)	30.07	305.3	4.87 (48.1)	0.203
Propane (C₃H₈)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C₂H₄)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C₃H₆)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH₃OH)	32.04	512.6	8.09 (79.8)	0.272
Ethanol (C₂H₅OH)	46.07	513.9	6.14 (60.6)	0.276
Acetone (C₃H₆O)	58.08	508.1	4.70 (46.4)	0.278
Nitrous oxide (N₂O)	44.013	306.57	7.35 (72.5)	0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids
	Density (kg/m³)	Viscosity (µPa∙s)	Diffusivity (mm²/s)
Gases	1	10	1–10
Supercritical Fluids	100–1000	50–100	0.01–0.1
Liquids	1000	500–1000	0.001

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P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407

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Cyclopentene-1,3-dione derivative

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jul 202015

the isolated cyclopentenedione derivative may have structure 1a or 1b or even exist as an equilibrium mixture between these two enol forms showing average ¹H and ¹³C NMR spectra due to a proposed rapid interconversion between 1a and 1b.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Synthetic results

Our approach to cyclopentenedione derivative (1) started with the preparation of furylmethylcarbinol (3) by the reduction of commercially available 2-acetylfuran (2) with NaBH₄ (Scheme 2).⁵ Compound 3 was isolated in 98% yield and transformed into 4-hydroxy-5-methylcyclopenten-2-one (4) in 90% yield after treatment with ZnCl₂-HCl (pH 6.0) under reflux in dioxane-H₂O for 48 h.⁶ Upon treatment of 4-hydroxy-5-methylcyclopenten-2-one (4) with phosphate buffer (pH 8.0) in refluxing dioxane for 24 h, 4-hydroxy-2-methylcyclopenten-2-one (5) was obtained in 65% yield.⁷By using this strategy we were able to prepare up to gram quantities of hydroxyketone 5.

Diketone 6 was obtained in almost quantitative yield by the smooth oxidation of hydroxyketone 5 with MnO₂(Scheme 3).^8,9 At this point, all that remained was to carry out the necessary acylation coupling. It was with some gratification that we observed that the reaction between lithium enolate of diketone 6 and cinnamic anhydride 7 gave a 57:43 mixture of cyclopentenediones 1a/1b in 22% yield, after purification by flash column chromatography, together with starting material and by-products arising from O-acylation (Scheme 3).

In order to try to improve the yields for formation of 1a/1b, we tested a new synthetic route (Scheme 4). Protection of the OH-functionality in 5 with TESCl and imidazole at room temperature gave ketone 8 in 85% yield. Treatment of 8 with LDA in THF at –78 ºC, followed by slow addition of cinnamaldehyde, gave aldol adduct 9 as a mixture of diastereoisomers. Oxidation of the OH-function at C9 in allylic alcohol 9 under standard Swern¹¹ conditions followed by removal of the TES protecting group with TBAF in THF led to diol 10 in 60% overall yield. The last step involved treatment of diol 10 under standard Swern oxidation conditions, to give a 59:41 mixture of 1a/1b in 79% yield.¹¹

The correct structure for the natural product was confirmed as being 1a by the heteronuclear long-range coupling (ⁿJ_CH; n = 2,3,4) obtained by HMBC experiments in CDCl₃ as solvent. Heteronuclear long-range coupling of C11 (d_C 201.3) with H13 (d_H6.70,³J_CH) and H15 (d_H2.12, ³J_CH), as well as between C14 (d_C 191.8) with H13 (d_H6.70,²J_CH) and H15 (d_H2.12, ⁴J_CH) for 1a, together with the long-range coupling of C11 (d_C 200.7) with H12 (d_H6.61,²J_CH) and H15 (d_H2.11, ⁴J_CH), as well as between C14 (d_C 192.3) with H12 (d_H6.61,³J_CH) and H15 (d_H2.11 ppm, ³J_CH) for 1b, unambiguously established the correct structure as being 1a (Figure 10).

cyclopentenedione derivative (1) as a yellow solid. Rf 0.37 (30% EtOAc/Hexane); IR (film) n_max/cm^-1: 3428, 2965, 1632, 1589, 1266, 1103, 1023, 803, 742, 699; (HRMS) Exact mass calc. for C₁₅H₁₂O₃: 240.0786. Found: 240.0787.

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.16 no.3a São Paulo May/June 2005

http://dx.doi.org/10.1590/S0103-50532005000300024

Short synthesis of a new cyclopentene-1,3-dione derivative isolated from Piper carniconnectivum

Luiz C. Dias^*; Simone B. Shimokomaki; Robson T. Shiota

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532005000300024

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas – SP, Brazil

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Flow chemistry can make processes greener….Swern oxidation

MANUFACTURING, PROCESS, SYNTHESIS Comments Off

Jul 202015

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride,dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine.The reaction is known for its mild character and wide tolerance of functional groups.

The by-products are dimethyl sulfide (Me₂S), carbon monoxide (CO), carbon dioxide (CO₂) and — when triethylamine is used as base — triethylammonium chloride (Et₃NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood.Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO₂ and CO and producing chloro(dimethyl)sulfonium chloride, 4.

After addition of the alcohol 5, the chloro(dimethyl)sulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million. A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock’s synthesis of the sesquiterpene isovelleral,the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.

Rapid, exothermic reactions are challenging to do in batch reactors. Reagents such as organometallics, strong bases, and highly active electrophiles are often added slowly to a reaction mixture under energy-intensive cryogenic conditions to prevent an uncontrollable exotherm. Quenching of these high-energy reagents may again require low temperature. This issue is scale dependent,1 and without proper precautions, both the likelihood and hazard of a runaway reaction increase with the size of a reactor.

The high surface area to volume ratio found in flow reactors makes heat transfer more efficient than in batch, allowing rapid removal of thermal energy given off. These features serve to give the chemist or engineer more control over reaction temperature and reduces the risk of thermal runaway.

Many instances have been reported of reactions being performed safely at 0 °C or room temperature in flow that would require cryogenic conditions in batch.^2,3,4 This has a further benefit on the overall processing time, as the reaction will occur faster at the elevated temperature and inefficient cooling and warming steps are avoided. A remarkable example demonstrating these principles is the room temperature Swern oxidation reaction by Yoshida and co-workers .⁵

The Swern reaction is a reliable procedure for converting alcohols to ketones and aldehydes using DMSOactivated by an electrophile (typically COCl₂ or TFAA) as the oxidant. In batch, the reaction takes place over three exothermic steps, each of which requires dropwise addition of reagents at cryogenic temperatures.^{6, 7}

PROCESS TO FLOW

When converting the process to flow, the Yoshida group found that the Swern oxidation could be done at room temperature with good yields and purity. Moreover, instead of having reaction times on the order of minutes or hours, the whole process was completed in seconds. They attributed the success of their process to the precise temperature control that can be obtained in flow systems, as well as the ability to quickly transfer unstable intermediates to subsequent steps. Using only a series of syringe pumps, stainless steel tubing, and commercial micromixers, they could prepare over 10 grams of material per hour. Being able to perform reactions on species with very short lifetimes is another general advantage of performing reactions in flow.⁸


	Scheme Room temperature Swern oxidation.

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MORE……..

http://thalesnano.com/products/IceCube

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The Swern oxidation. The center column (green background) shows the desired chemical path, with added reagents shown in black boxes. The outer columns (red background) show the potential chemical pathways for side-product formation (8 and 9).

http://www.mdpi.com/2227-9717/2/1/24/htm

REF

R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem., Int. Ed., 2011, 50, 7502–7519
V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld and B. Werner, Org. Process Res. Dev., 2004, 8, 511–523 Search PubMed.
A. Nagaki, Y. Tomida, H. Usutani, H. Kim, N. Takabayashi, T. Nokami, H. Okamoto and J.-i. Yoshida, Chem.–Asian J., 2007, 2, 1513–1523
T. Gustafsson, H. Sörensen and F. Pontén, Org. Process Res. Dev., 2012, 16, 925–929 Search PubMed.
T. Kawaguchi, H. Miyata, K. Ataka, K. Mae and J.-I. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416
A. K. Sharma and D. Swern, Tetrahedron Lett., 1974, 15, 1503–1506 Search PubMed.
A. K. Sharma, T. Ku, A. D. Dawson and D. Swern, J. Org. Chem., 1975, 40, 2758–2764
J.-i. Yoshida, Chem. Rec., 2010, 10, 332–341

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Application in Febuxostat synthesis

PROCESS, SYNTHESIS, Uncategorized Comments Off

Jul 172015

………..

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Abstract

Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr₂, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions.

The nitrile moiety is an important group that is found in pharmaceuticals and agrochemicals. In addition the nitrile can serve as a stable intermediate for amides, carboxylic acids, ketones, aldehydes, etc. As a result, many methods to make nitriles have been reported. In a new publication Togo et al. report their development of a one-pot metal-cyanide-free protocol to make electron-rich aromatic nitriles ( Eur. J. Org. Chem. 2015, 2023). The reaction first reacts arenes with zinc bromide (ZnBr₂) and dichloromethyl methyl ether to make in situ the (dichloromethyl)arene, that then reacts with aq. ammonia and iodine to make the nitrile. The electron-rich aromatic nitriles are formed in moderate-to-high yields (59–94%). They demonstrate usefulness of this reaction by synthesizing febuxostat.

Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions

Toshiyuki Tamura,
Katsuhiko Moriyama and
Hideo Togo^*

Article first published online: 9 FEB 2015

Tamura, T., Moriyama, K. and Togo, H. (2015), Facile One-Pot Transformation of Arenes into Aromatic Nitriles under Metal-Cyanide-Free Conditions. Eur. J. Org. Chem., 2015: 2023–2029. doi: 10.1002/ejoc.201403672