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Monday 10 July 2017

NaBH4, twin screw technology (i.e., granulator, melt extruder, etc.) to yield the desired product in a continuous manner


Abstract Image
In this work the application of green chemistry principles such as process intensification and the replacement of reagents and solvents to more benign alternatives were coupled with the advantages of continuous manufacturing. The reduction of lipophilic aromatic aldehydes using an aqueous alkaline solution of NaBH4 was achieved by means of mechanical shearing and kneading provided by a custom-made batch reactor at the lab scale and a twin screw extruder at the kilo scale. The process was run continuously for 17 min to yield 1.41 kg of product (89% purity). The benefits of running the process in a continuous manner instead a conventional fed-batch mode were discussed in terms of both environmental and economic factors.

Screwing NaBH4 through a Barrel without a Bang: A Kneaded Alternative to Fed-Batch Carbonyl Reductions

Institute of Chemical and Engineering Sciences, 1 Pesek Road, 627833, Jurong Island, Singapore
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00107
 
 
 
Image result for Valerio Isoni
Institute of Chemical & Engineering Sciences (ICES)
Institute of Chemical and Engineering Sciences, 1 Pesek Road, 627833, Jurong Island, Singapore
The chemical industry has been a major part of the Singapore economy for many years, based on a strong foundation as a major oil refining centre with a long history, and strategically placed at the heart of the Asia - Pacific region. In recent years the pharmaceuticals industry has also seen major growth, so that chemistry and chemical engineering science now make a very significant contribution to Singapore's economy.
In order to strengthen this position and to foster future development to grow from dependence solely on manufacturing to secure a more knowledge dependant, high tech research and development based business environment, Agency for Science, Technology and Research (A*STAR) and Economic Development Board (EDB) looked at how to bolster the local science and technology base. As a result, the Institute of Chemical and Engineering Sciences (ICES) came into being, to provide highly trained R&D manpower, to establish a strong science base and to develop technology and infrastructure to support future growth.
Starting from a small centre in the National University of Singapore (NUS), ICES was established as an autonomous national research institute under A*STAR on October 1st 2002. Since that time, we have grown rapidly. We have established world leading laboratories, pilot facilities, and the necessary infrastructure to carry out a world class research programme in chemistry and chemical engineering sciences. We have the capability to cover the range of activities from exploratory research to process development, optimisation and problem solving. We can go from very small lab scale right to kg and pilot scale in one organisation, with all of the necessary skills directly at hand and integrated into a project oriented environment.
 
 
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Thursday 6 July 2017

Increasing global access to the high-volume HIV drug nevirapine through process intensification




 


Increasing global access to the high-volume HIV drug nevirapine through process intensification
Green Chem., 2017, 19,2986-2991
DOI: 10.1039/C7GC00937B, Paper
Jenson Verghese, Caleb J. Kong, Daniel Rivalti, Eric C. Yu, Rudy Krack, Jesus Alcazar, Julie B. Manley, D. Tyler McQuade, Saeed Ahmad, Katherine Belecki, B. Frank Gupton
Fundamental elements of process intensification were applied to generate efficient batch and continuous syntheses of the high-volume HIV drug nevirapine.

Green Chemistry

Increasing global access to the high-volume HIV drug nevirapine through process intensification

 

Abstract

Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.
Preparation of Nevirapine (1).

Preparation of CYCLOR (7), Step 1A: To a solution of CAPIC (2, 15 g, 105 mmole, 1.0 equiv) in diglyme (75 mL) in a 500 mL 3-neck round-bottom flask fitted with overhead stirrer, thermocouple, and addition funnel was added NaH (7.56g, 189 mmole, 1.8 equiv). The reaction mixture was stirred at room temperature for 30 minutes and gradual evolution of H2 gas was observed. The temperature of the reaction mixture was slowly increased to 60 °C (10 °C/hr increments). A preheated (55 °C) solution of MeCAN (5, 21.19 g, 192.2 mmol, 1.05 equiv) in diglyme (22.5 mL) was added over a period of an hour to the reaction mixture kept at 60 °C. The reaction mixture was allowed to stir at 60 °C for 2 hours. If desired, 7 may be isolated at this stage. The reaction mixture is cooled to 0 – 10 °C and the pH is adjusted to pH 7-8 using glacial acetic acid and stirred for an hour. The precipitate is collected by vacuum filtration and dried under vacuum to a constant weight to afford CYCLOR (7) (29.89g, 94%).
1H NMR (300MHz, CHLOROFORM-d)  = 8.44 (dd, J = 1.8, 5.3 Hz, 1 H), 8.21 (d, J = 4.7 Hz, 1 H), 8.15 (br. s., 1 H), 7.87 (dd, J = 2.1, 7.9 Hz, 1 H), 7.54 (s, 1 H), 7.20 (d, J = 5.3 Hz, 1 H), 6.66 (dd, J = 4.7, 7.6 Hz, 1 H), 2.95 - 2.84 (m, 1 H), 2.35 (s, 3 H), 0.91 - 0.77 (m, 2 H), 0.62 - 0.47 (m, 2 H).
13C NMR (75MHz, CHLOROFORM-d)  = 166.8, 159.2, 153.2, 148.3, 146.9, 136.0, 129.9, 125.1, 111.1, 108.4, 77.4, 76.6, 23.8, 18.8, 7.0.
HRMS (ESI) C15H15ClN4O m/z [M+H] + found 303.0998, expected 303.1012.
Preparation of nevirapine (1), Step 1B: In a 150 mL, 3 neck flask, fitted with overhead stirrer, thermocouple and addition funnel, a suspension of NaH (7.14 g, 178.5 mmol, and 1.7 equiv) in diglyme (22.5 ml) was heated to 105 °C and crude CYCLOR (7) reaction mixture from Step 1 (preheated to 80 °C) was added over a period of 30 minutes while maintaining the reaction mixture at 115 °C. The reaction mixture was stirred for 2 hours at 117 °C for ~2 hours then cooled to room temperature. Water (30 mL) was added to quench the excess sodium hydride and the reaction was concentrated in vacuo to remove 60 mL of diglyme. To the resulting suspension was added water (125 mL), cyclohexane (50 mL) and ethanol (15 mL). The pH of the mixture was adjusted to pH 7 using glacial acetic acid (19.5 g, 3.09 mmol) at which precipitate formed. After stirring for 1 hour at 0 °C, the precipitate was collected via vacuum filtration and the filter cake was washed with ethanol: water (1:1 v/v) (2 x 20 mL). The solid was dried between 90-110°C under vacuum to provide nevirapine (25.4 g, 91% over two steps).
1H NMR (400MHz, CDCl3)  = 8.55 (dd, J = 2.0, 4.8 Hz, 1 H), 8.17 (d, J = 5.0 Hz, 1 H), 8.13 (dd, J = 2.0, 7.8 Hz, 1 H), 7.61 (s, 1 H), 7.08 (dd, J = 4.8, 7.8 Hz, 1 H), 6.95 (dd, J = 0.6, 4.9 Hz, 1 H), 3.79 (tt, J = 3.6, 6.8 Hz, 1 H), 2.37 (s, 3 H), 1.07-0.93 (m, 2 H), 0.59-0.50 (m, 1 H), 0.50-0.41 (m, 1 H).
13C NMR (101MHz, CDCl3)  = 168.4, 160.5, 153.9, 152.1, 144.3, 140.3, 138.8, 124.8, 121.9, 120.1, 118.9, 29.6, 17.6, 9.1, 8.8.
HRMS (ESI) C15H14N4O m/z [M+H] + found 267.1239, expected 267.1245.
Purification of nevirapine. To a cooled (0 °C) suspension of nevirapine (10g, 375.5 mmole) in water (43 ml) was added a 10 M solution of HCl (11.6 ml, 117.5 mmole) dropwise. The solution was allowed to stir for 30 minutes and activated carbon (0.3g) was added. After stirring for 30 minutes, the solution was filtered over Celite. The filtrate was transferred to flask and cooled to 0 °C. A 50% solution of NaOH was added dropwise until a pH of 7 is reached. A white precipitate appeared and the solution was stirred for 30 minutes and filtered. The solid was washed with water (3 x 10ml). The wet cake was dried between 90-110°C under vacuum to a constant weight to provide nevirapine (9.6 g, 96%).

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Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C-C coupling reactions


Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C-C coupling reactions
Green Chem., 2017, 19,2931-2935
DOI: 10.1039/C7GC00789B, Communication
O. N. Chupakhin, A. V. Shchepochkin, V. N. Charushin
A simple and efficient electrochemical method for the synthesis of asymmetrical bi(het)aryls through direct functionalization of the C(sp2)-H bond in azaaromatics with fragments of (hetero)aromatic nucleophiles has been developed

Green Chemistry

Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C–C coupling reactions

 

Abstract

The synthesis of asymmetrical bi(het)aryls through direct functionalization of the C(sp2)–H bond in azaaromatics with fragments of (hetero)aromatic nucleophiles has first been carried out under electrochemical oxidative conditions. This versatile method for C–C bond formation between two aryl fragments can be realized under very mild potential-controlled oxidative conditions, and it does require neither incorporation of any halogen atoms or other leaving groups, nor the use of metal catalysts. The use of the electrochemical SHN methodology for modification of azaaromatic compounds has first been demonstrated.
str5
Synthesis of compounds 3a-d
The potassium tert-butoxide (0.55 mmol), corresponding phenols 2a-d (0.55 mmol) and acetonitrile (10mL) were added to electrochemical cell under argon atmosphere. The reaction mixture was stirred at room temperature for 15 min. Then 10-methylacridinium tetrafluoroborate 1 (0.5 mmol, 140 mg) was added to the reaction mixture, and stirred at room temperature for 1 h. The supporting electrolyte (40 mL) was placed in the anode and in the cathode cell compartment (10 mL). Finally, the acetic acid (1 mmol, 57 μL) was placed in the anode cell compartment. Electrolysis was carried out at a controlled potential (reference electrode Ag/AgNO3). Upon passing 2.1F of electricity (for a two-electron process), the electrolysis was stopped, the solvent was distilled off in vacuum from the anolyte, the residue was washed with 30 ml of ether and 10 ml of water. The residue was recrystallized from water and dried on air. 9-(4-Hydroxy-3,5-dimethyl-phenyl)-10-methyl-acridinium tetrafluoroborate (3a) Orange needles. 195 mg (98%). The product was identified as a compound 3a by comparing its 1H NMR spectra with its given in the literature. Satisfactory elemental analysis for C, H and N were obtained for compound 3a; none of the experimentally found percentages deviated from the theoretical values by more than 0.3%.2
1H NMR (500 MHz, [D6]DMSO): δ 9.09 (s, 1H), 8.82 (d, 2H, J=9.2 Hz), 8.45-8.42 (m, 2H), 8.12-8.10 (m, 2H), 7.94-7.91 (m, 2H), 7.16 (s, 2H), 4.90 (s, 3H), 2.33 (s, 6H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ 161.5, 155.2, 141.1, 138.2, 130.3, 130.1, 127.6, 125.7, 124.8, 123.5, 119.0, 38.8, 16.6 ppm.
str5
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Monday 3 July 2017

One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone


One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone
Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC00578D, Communication
Lei Song, Mingyuan Zheng, Jifeng Pang, Joby Sebastian, Wentao Wang, Minjie Qu, Jian Zhao, Xinhong Wang, Tao Zhang
An efficient and environmentally benign method for the synthesis of 2-hydroxymethyl-5-methylpyrazine (HMMP) from biomass derived 1,3-dihydroxyacetone was developed.

Green Chemistry

One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone

*Corresponding authors

Abstract

An efficient and green method for the synthesis of 2-hydroxymethyl-5-methylpyrazine was achieved from biomass derived 1,3-dihydroxyacetone and diammonium phosphate via a one-pot reaction. The product yield was as high as 72% under optimized conditions of pH = 8.0–9.1 at 90 °C for 1 hour in a dioxane and water mixture as a solvent. A possible reaction mechanism was proposed according to the reaction kinetics, NMR and in situ ATR-IR characterization studies.
1HNMR (500 MHz, D2O) δ 8.51 – 8.32 (m, 1H), 4.71 (dd, J = 31.0, 6.2 Hz, 1H), 2.49 (d, J = 24.6 Hz, 2H). 13CNMR (126 MHz, D2O) δ 152.99, 151.49, 143.62, 141.27, 61.87, 19.82.

Image result for Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Image result for Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Image result for State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
Image result for State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
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Dr. Shengmei Lu
Associate Professor
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road Dalian 116023
Tel: 86-411-84379771
Fax: 86-411-84694447
Sheng-Mei Lu, was born in 1977 in Henan Province. She received her B.S. in 1999 and M. S. degrees in 2002 in chemistry at Central China Normal University in Wuhan. In September 2002, she came to Dalian Institute of Chemical Physics, Chinese Academy of Sciences and received her Ph.D. degree in January 2006. From November, 2006 to December, 2008, she worked as post-doctor in Prof. Carsten Bolm’s group in RWTH-Aachen University with the Alexander Humboldt-Foundation Fellowship. From October 2009, she joined in Prof. Can Li’s group, State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.

Dr. R. Rajesh
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian, 116023, China
Email: rajesh@dicp.ac.cn
Tel: +86-15542638326
Fax : +86-411-84694447
Education
2015, Doctoral Degree, Pondicherry Central University;
2008, Master Degree, Madurai Kamaraj University (Madurai);
2006, Bachelor Degree, Periyar Arts and Science college (Cuddalore);
Working Experience2015.8-present, Post Doctor Fellow, Dalian Institute of Chemical Physics.

One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone


One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone
Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC00578D, Communication
Lei Song, Mingyuan Zheng, Jifeng Pang, Joby Sebastian, Wentao Wang, Minjie Qu, Jian Zhao, Xinhong Wang, Tao Zhang
An efficient and environmentally benign method for the synthesis of 2-hydroxymethyl-5-methylpyrazine (HMMP) from biomass derived 1,3-dihydroxyacetone was developed.

Green Chemistry

One-pot synthesis of 2-hydroxymethyl-5-methylpyrazine from renewable 1,3-dihydroxyacetone

*Corresponding authors

Abstract

An efficient and green method for the synthesis of 2-hydroxymethyl-5-methylpyrazine was achieved from biomass derived 1,3-dihydroxyacetone and diammonium phosphate via a one-pot reaction. The product yield was as high as 72% under optimized conditions of pH = 8.0–9.1 at 90 °C for 1 hour in a dioxane and water mixture as a solvent. A possible reaction mechanism was proposed according to the reaction kinetics, NMR and in situ ATR-IR characterization studies.
1HNMR (500 MHz, D2O) δ 8.51 – 8.32 (m, 1H), 4.71 (dd, J = 31.0, 6.2 Hz, 1H), 2.49 (d, J = 24.6 Hz, 2H). 13CNMR (126 MHz, D2O) δ 152.99, 151.49, 143.62, 141.27, 61.87, 19.82.

Image result for Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Image result for Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Materials Science and Engineering, Dalian Polytechnic University, Dalian, China
Image result for State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
Image result for State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
//////////
Dr. Shengmei Lu
Associate Professor
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road Dalian 116023
Tel: 86-411-84379771
Fax: 86-411-84694447
Sheng-Mei Lu, was born in 1977 in Henan Province. She received her B.S. in 1999 and M. S. degrees in 2002 in chemistry at Central China Normal University in Wuhan. In September 2002, she came to Dalian Institute of Chemical Physics, Chinese Academy of Sciences and received her Ph.D. degree in January 2006. From November, 2006 to December, 2008, she worked as post-doctor in Prof. Carsten Bolm’s group in RWTH-Aachen University with the Alexander Humboldt-Foundation Fellowship. From October 2009, she joined in Prof. Can Li’s group, State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.

Dr. R. Rajesh
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian, 116023, China
Email: rajesh@dicp.ac.cn
Tel: +86-15542638326
Fax : +86-411-84694447
Education
2015, Doctoral Degree, Pondicherry Central University;
2008, Master Degree, Madurai Kamaraj University (Madurai);
2006, Bachelor Degree, Periyar Arts and Science college (Cuddalore);
Working Experience2015.8-present, Post Doctor Fellow, Dalian Institute of Chemical Physics.