Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
Med. Chem. Commun., 2017, Advance Article DOI: 10.1039/C6MD00707D, Research Article
E. Lattmann, J. Sattayasai, R. Narayanan, N. Ngoc, D. Burrell, P. N. Balaram, T. Palizdar, P. Lattmann
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using a range of assays.
Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
aSchool of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK E-mail: e.lattmann@aston.ac.uk
bDepartment of Pharmacology, Faculty of Medicine, Khon Kaen University, 40002 Khon Kaen, Thailand
cDepartment of Medicine, University of Tennessee Health Science Center, Memphis, USA
dPNB Vesper Life Science PVT, Cochin, India
Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C6MD00707D
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC50 of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg−1 PNB-001 was equivalent to 40 mg kg−1 tramadol. The CCK2-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg−1 dose of prednisolone, which served as a standard.
General Method: The relevant amine (2.5 times excess) was added to a solution of lactone A – E (0.7 mol) in ether (10 ml) and stirred on ice for 30 minutes, allowing to warm up to RT over the time. The resultant mixture was poured into 5 ml water and separated by separating funnel. The mixture was washed with water three times. The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. All compounds gave an oily solid which were passed through a column (80% ether, 20% petrol ether). The resulting fractions were dried from excess solvent under vacuum to yield crystals. 4-Chloro-1-cyclopropyl-5-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one 1 Yield = 83 %; mp: 177-179 oC;
Abstract: The present paper demonstrate a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.
Scheme: Literature methods for synthesis of parvaquone
Scheme: IBX mediated oxidative arylation towards synthesis of 1 (Parvaquone)
Scheme : Cyclohexyl radical mediated postulated mechanism for formation of Parvaquone, 1
Synthesis of 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone (parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one lot and stirred for 5 min at room temperature. To this was added dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL of acetonitrile over the course of 20 min. During the addition of 8 exotherm (up to 35 °C) was observed with evolution of nitrogen gas in the form of bubbles. Reaction progress was monitored by TLC (using mobile phase, hexane: ethyl acetate/5:95). After satisfactory TLC, water (20 mL) was added to the reaction mixture and acetonitrile was evaporated using rotary evaporator. To the residue obtained was added dichloromethane (30 mL). Oganic layer was separated and washed with saturated sodium bicarbonate solution followed by saturated solution of sodium sulphite. Separated organic layer was dried over anhydrous sodium sulphate and evaporated to obtain crude 1 which was further purified by column chromatography (mobile phase – hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g, 60% yield); mp 136-138 °C (lit.18 135-136°C); FT-IR (KBr): 3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm-1;
Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.
After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.
During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.
Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings suggest that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.
Scheme 1. Synthetic scheme
Table 1.
Table 2.
Highlights
Designed and synthesized a novel series of diarylheptanoids.
Compounds 4i, 5b, 5d, and 5g significantly inhibit in vitro TNF-α production from human cells.
Oral administration of these compounds significantly inhibits TNF-α production in mice.
These compounds may have potential therapeutic implications for TNF- α -mediated auto-immune/inflammatory diseases.
ABOUT GUEST BLOGGER
Dr. Dnyaneshwar B. Gophane, Ph. D.
Post doc fellow at Purdue university and university of Iceland
Email, gophane@gmail.com
Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry. These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.
Keminntek Laboratories is a Hyderabad (India) based Contract Research Organization in Pharmaceutical sector in specific Pharmaceutical Intermediates, Speciality Chemicals, Impurities and Active Pharmaceutical Ingredients. Promoters of Keminntek Laboratories are Young and Dynamic Technocrats and established with a vision to provide a best-in class pharmaceutical services. Keminntek Laboratories would be a value-added and innovative-in –approach business partner. It has a strong talent pool of qualified and experienced scientists drawn from the national and international institutes and industry. It has a capability to synthesize in mg to multi-kg scale.
About Us
Vision
Our vision is to build Keminntek Laboratories into a world class leading pharmaceutical service provider based on innovation while keeping health and prosperity in mind. Imperatively, we will continue our business with high standards of ethics in the interest of society and environment.Mission
We are committed towards improving people’s health through science and innovation. Our mission is to provide better access of the affordable medicines to the patients and positively impact prosperity.
Team
Promoters of this company are very well qualified and experienced personalities in Pharmaceutical sector
We have a team consisting
Ph.Ds from premier Indian Institutes and postdocs from abroad
M. Sc (Chemistry) with 2-12 years pharmaceutical industry experience
Our team expertise lies in process R&D of pharmaceutical intermediates, NCEs (Medicinal Chemistry) development, pharmaceutical impurities, and custom synthesis of specialty chemicals
It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).[2]
Adverse effects
The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.[2] Central neurotoxicity is more common with tegafur than with fluorouracil.[2]
tegafur is a derivative of 5-fluorouracil, and in 1967, Hiller of the former Soviet Union synthesized tegafur (SA Hiller, RA Zhuk, M. Yu. Lidak, et al. Substituted Uracil [ P, British Patent, 1168391 (1969)). In 1974, it was listed in Japan. China was successfully developed by Shandong Jinan Pharmaceutical Factory in 1979. Its present origin is Shanghai and Shandong provinces and cities. The anti-cancer effect of tegafur is similar to that of 5-fluorouracil and is activated in vivo by 5-fluorouracil through liver activation. Unlike 5-fluorouracil, tegafur is fat-soluble, has good oral absorption, maintains high concentrations in the blood for a long time and easily passes through the blood-brain barrier. Clinical and animal experiments show that tegafur on gastrointestinal cancer, breast cancer is better, the role of rectal cancer than 5-fluorouracil good, less toxic than 5-fluorouracil. Teflon has a chemotherapy index of 2-fold for 5-fluorouracil and only 1 / 4-1 / 7 of toxicity. So the addition of fluoride is widely used in cancer patients with chemotherapy.
[0003] The first synthesis of tegafur is Hiller ([SA Hiller, RA Zhuk, Μ. Yu. Lidak, et al. Substituted Uracil [P], British Patent, 1168391 (1969)]. 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-Fu, 1) and 2-chlorotetrahydrofuran (Thf-Cl), and it is reported that this synthesis must be carried out at low temperature (- 20 to -40 ° C), because Thf-Cl is unstable, and excess Thf-Cl results in a decomposition reaction, thereby reducing the yield of Thf-Fu.
[0004] Earl and Townsend also prepared 1_ (tetrahydro-2-furyl) uracil using Thf-Cl and 2,4-bis (trimethylsilyl) uracil, and then using trifluoromethyl fluorite to product Fluorination. Mitsugi Yasurnoto reacts with the Friedel-Crafts catalyst in the presence of 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-U, 1) 2-acetoxytetrahydrofuran (Thf-OAc, 2) (Kazu Kigasawa et al., 2-tert-Butoxy), & lt; RTI ID = 0.0 & gt;, & lt; / RTI & gt; (K. Kigasawa, M. Hiiragi, K. ffakisaka, et al. J. Heterocyclic Chem. 1977, 14: 473-475) was reacted with 5-Fu at 155-160 ° C. Reported in the literature for the fluoride production route there are the following questions: 1, high energy consumption. In the traditional synthesis method, in order to obtain the product, the second step of the reaction needs to continue heating at 160 ° C for 5-6 hours, high energy consumption; 2, difficult to produce, low yield: 5-fluorouracil as a solid powder The reaction needs to be carried out at a high temperature (160 ° C), which requires the use of a high boiling solvent N, N-dimethylformamide (DMF). But it is difficult to completely remove the fluoride from the addition of fluoride, because DMF can form hydrogen bonds with the fluoride molecules, difficult to separate from each other; 3, in order to unreacted 5-fluorouracil and tegafur separation and recycling , The use of carcinogenic solvent chloroform as a extractant in the conventional method to separate 5-fluorouracil and tegafur. However, the main role of chloroform on the central nervous system, with anesthesia, the heart, liver, kidney damage; the environment is also harmful to the water can cause pollution. Therefore, the use of volatile solvent chloroform, even if the necessary measures to reduce its volatilization, will still cause harm to human health and the environment; 4, low yield. Since both NI and N-3 in the 5-fluorouracil molecule react with 2-tert-butoxytetrahydrofuran, the addition of tegafur is also the addition of 1,3-bis (tetrahydro-2-furyl) -5 – Fluorouracil. Therefore, the improvement of the traditional production process of tegafur is a significant and imminent task.
Example 1 (for example, the best reaction conditions):
Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 10. 0 mg CuCl2, microwave irradiation 250W at 25 ° C reaction 0. 6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), and microwave irradiation at 400 ° C for 100 ° C. After distilling off the low boiling solvent, the oil was obtained. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give 1.34349 g of product. Melting point: 160-165 ° C. The yield was 75%.
[0011] Example 2
Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 3.8 g (100 mmol) of ethanol were added to a single-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 5mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), microwave irradiation 400W, reaction temperature 60 ° C under the reaction pool. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give the product 0. 46 g. Melting point: 160-165 ° C. The yield was 15%.
[0012] Example 3
Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 20mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1301: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give the product 1.81 g. Melting point: 160-165 ° C. The yield was 61%.
[0013] Example 4
Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran and 19 g (500 mmol) of ethanol were added to a single-necked flask. To this was added 20 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give product U6g. Melting point: 160-165 ° C. The yield was 43%.
[0014] Example 5
Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 9.5 g (250 mmol) of ethanol were added to a single-necked flask. To this was added 30 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 6001, reaction temperature 1001: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give 1.15 g of product. Melting point: 160-165 ° C. The yield was 38%.
[0015] Example 6
Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 25 ml of tetrahydrofuran (THF). And then weighed 15mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 5001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give product 2.10 g. Melting point: 160-165 ° C. The yield was 70%.
Paper
A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.
Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions
Tegafur, a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967. The compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.
The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, a rapid breakdown of the released 5-FUra in the gastrointestinal tract is avoided.(6) In injectable form, tegafur provoked serious side effects, such as nausea, vomiting, or central nervous system disturbances.
The first generation of oral formulation of tegafur , UFT) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding the USA.
S-1 is the next generation of oral formulation of tegafur.(7) It is a combination of tegafur, gimeracil, and oteracil in a fixed molar ratio of 1:0.4:1, respectively.
Gimeracil inhibits the enzyme responsible for the degradation of 5-FUra. Oteracil prevents the activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well-tolerated, but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent. Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea, and Singapore for the treatment of patients with gastric cancer.
In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin. Currently, S-1 has not been approved by the FDA in the United States.
There is a great interest in further examination of S-1 as an anticancer chemotherapeutic. Currently, 23 clinical trials with S-1 has been registered in National Institutes of Health (NIH). Combinations of S-1 and other anticancer agents have been employed in a majority of these trials.
El Sayed, YM; Sadée, W (1983). “Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes”. Cancer Research. 43 (9): 4039–44. PMID6409396.
Amstutz, U; Froehlich, TK; Largiadèr, CR (September 2011). “Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.”. Pharmacogenomics. 12 (9): 1321–36. doi:10.2217/pgs.11.72. PMID21919607.
AIST: Integrated Spectral Database System of Organic Compounds. (Data were obtained from the National Institute of Advanced Industrial Science and Technology (Japan))
ACD-A: Sigma-Aldrich (Spectral data were obtained from Advanced Chemistry Development, Inc.)
Professor, Organic Chemistry: Organic and Medicinal Chemistry
Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq. 1) and 18 (Table 2). To a solution of the alkylated 2-(sulfonylethyl)-4,5-diphenyloxazole 5 (0.12 mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15 mL), was added an excess of food-grade aluminum foil (2.32 mmol, 20 equiv) with vigorous stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux until the metal disappeared. The reaction mixture was then allowed to cool to room temperature and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate was concentrated to a crude residue which was submitted to gravity-column chromatography on silica gel to provide 2-methyl-4,5-diphenyloxazole 4 (96%) or 2-ethyl-4,5-diphenyloxazole 18 (97%).
General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones 5-17. To a stirred solution of an alkylated 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole (0.12 mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol, 15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant crude residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate) to afford the pure products 18–27 listed in Table 2.
Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq. 1) and 18 (Table 2). To a solution of the alkylated 2-(sulfonylethyl)-4,5-diphenyloxazole 5 (0.12 mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15 mL), was added an excess of food-grade aluminum foil (2.32 mmol, 20 equiv) with vigorous stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux until the metal disappeared. The reaction mixture was then allowed to cool to room temperature and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate was concentrated to a crude residue which was submitted to gravity-column chromatography on silica gel to provide 2-methyl-4,5-diphenyloxazole 4 (96%) or 2-ethyl-4,5-diphenyloxazole 18 (97%).
General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones 5-17. To a stirred solution of an alkylated 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole (0.12 mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol, 15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant crude residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate) to afford the pure products 18–27 listed in Table 2.
Typical procedure: Synthesis of Oxaprozin
Ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate(28). To a prechilled solution of 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole 3 (100 mg, 0.27 mmol) in dry THF (15 mL) was added potassium tert-butoxide (33 mg, 0.29 mmol) under a nitrogen atmosphere. The resulting yellow solution was stirred (5°C) for 30 min. To the reaction mixture was slowly added ethyl bromoacetate (49 mg, 32.4 μL, 0.29 mmol) and stirring was continued (16 h) at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was quenched with cold water (20 mL) and extracted with dichloromethane (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude oily residue. The residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate, 4:1) afford pure ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate 28 as off-white solid ( 88 mg, 72%).
Ethyl 3-(4,5-diphenyloxazol-2-yl)acrylate (29). To a cooled (5°C) solution of sulfonyloxazole ester 28 (225 mg, 0.49 mmol) in dry THF was added potassium tert-butoxide (60.2 mg, 0.54 mmol) under nitrogen and the reaction mixture was then stirred at 5-10°C (2 h) while monitoring by TLC. After completion of the reaction, the reaction mixture was extracted with dichloromethane (2 x 25 mL) followed by washing the extracts with water and brine then drying over anhydrous Na2SO4. Removal of the drying agent and concentration of the filtrate gave a crude residue which was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide unsaturated oxazole ester 29 as a colorless oil (100 mg, 65%).
Ethyl 3-(4,5-diphenyloxazol-2-yl)propanoate (30).17 The unsaturated oxazole ester 30 (160 mg, 0.50 mmol) was dissolved in methanol (25 mL) then 10% Pd/C (16 mg, 10% wt/wt) was added at room temperature. The reaction mixture was purged with nitrogen while stirring followed by the addition of hydrogen gas (balloon) and then stirring was continued (16 h) under an atmosphere of hydrogen. Upon completion of reaction, the reaction mixture was filtered through a bed of Celite while washing with methanol (2 x 30 mL). The combined filtrates were concentrated and the crude residue was submitted to gravity-column chromatography (hexane/ethyl acetate, 4:1) to afford 30 as an off-white solid (129 mg, 80%).
Methyl 3-(4,5-diphenyloxazol-2-yl)propanoate (31).13To a clear solution of sulfonyloxazole ester 28 (80 mg, 0.173 mmol) in methanol (10 mL) was added magnesium turnings (63 mg, 2.60 mmol) followed by solid mercuric chloride (4.7 mg, 0.017 mmol) at room temperature. The resulting reaction mixture was stirred (2 h) while monitoring the reaction progress by TLC. After completion of the reaction, the heterogeneous mixture was then filtered through a Celite bed followed by washing with methanol (2 x 15 mL). The methanolic filtrates were combined and concentrated to afford a crude residue. The residue was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide ester 31 as an off-white solid (52 mg, 97%).
3-(4,5-Diphenyloxazol-2-yl)propanoic acid(Oxaprozin)(32).13 Ethyl ester 30 (128 mg, 0.39 mmol) or methyl ester 31 (65 mg, 0.21 mmol) and 20% aquous NaOH solution (3 mL) was stirred overnight at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was slowly acidified to pH 3-4 using conc. HCl (3 mL) at room temperature and stirring was continued (3 h). After the neutralization was complete the reaction mixture was diluted with cold water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to give a white solid residue. The residue was submitted to gravity-column chromatography (chloroform/methanol, 9:1) to afford pure Oxaprozin 32 as white solid (80 mg, 68%, from the ethyl ester 30) or (60 mg, 97%, from the methyl ester 31).
ABOUT GUEST BLOGGER
Dr. Pravin C. Patil
Postdoctoral Research Associate at University of Louisville
Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.
After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.
During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.
Prof K. G. Akamanchi
Prof. K. G. Akamanchi
Professor, Pharmaceutical Sciences and Technology
Email ID : kg.akamanchi@ictmumbai.edu.in
Reseach Area : Development of Novel Methodologies, Hypervalent Iodine Chemistry, Synthesis of drug and drug intermediates, Design and Synthesis of Potential bioactive molecules, Protein Isolation and Bioassay
SEE…………
Frederick A. Luzzio
Professor, Organic Chemistry: Organic and Medicinal Chemistry
502-852-7323
502-852-6066
faluzz01@louisville.edu
About
The long term goals of our research are focused at the interface of chemistry and biology. We are interested in solving problems in biomedicine using the techniques and application of synthetic organic, medicinal and natural products chemistry. Toward our goals in biomedicine we concentrate our efforts in the following three areas of organic chemistry: (1) the development of new methods and strategy which are applicable to the synthesis of biologically active compounds; (2) the total synthesis of a wide range of complex molecules including natural products, pharmaceutical leads and their analogues; and (3) the isolation and discovery of biologically active compounds from natural sources. Within our objectives in item 1 (above), we have had a long-term collaboration with the Clinical Pharmacology Section of the National Cancer Institute in which we have synthesized metabolites and analogues of thalidomide, a small-molecule immunomodulator and angiogenesis inhibitor. The derivatives and analogues of thalidomide were stereospecifically synthesized in order to ascertain the mode of action and the molecular target of this small molecule. Ultimately, the synthetic studies are leading to analogues of thalidomide which are more potent, but which have less undesirable side effects than the parent compound. In the neurosciences area we have completed an enantioselective synthesis of both optical isomers of a key intermediate in preparing the histrionicotoxins, a group of compounds which are isolated for the neurotoxic Amazon “poison dart” frogs. One of our present natural products projects (under item 3,above) entails the isolation, neurotoxicity assays and synthesis of a series of naturally-occurring compounds called acetogenins from the North American paw paw tree Asimina triloba. The isolation, purification and structural confirmation of the natural products has been conducted in collaboration with the Neurosciences Department within the University of Louisville School of Medicine. In the area of anti-infectives (under 1), we are designing and synthesizing an array of nitrogen and nitrogen/oxygen heterocyclic scaffolds bearing acetylenic and azido groups for use in the so-called “click reaction.” The multiply-connected scaffolds have proven to be effective for inhibiting micro-organisms working in tandem to produce biofilms necessary for their establishment and survival.
Education
1976 B.S. Vanderbilt University
1979 M.S. Tufts University
1982 Ph.D. Tufts University
1982-1985 Postdoctoral Fellow, Harvard University
Current Service
Executive Committee/Treasurer, International Society of Heterocyclic Chemistry HETCHEM@louisville.edu
Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules
Catal. Sci. Technol., 2017, Advance Article DOI: 10.1039/C7CY01130J, Paper
Kazuto Suzuki, Joshua Kyle Stanfield, Osami Shoji, Sota Yanagisawa, Hiroshi Sugimoto, Yoshitsugu Shiro, Yoshihito Watanabe
The benzylic hydroxylation of non-native substrates was catalysed by cytochrome P450BM3, wherein “decoy molecules” controlled the stereoselectivity of the reactions.
The hydroxylation of non-native substrates catalysed by wild-type P450BM3 is reported, wherein “decoy molecules”, i.e., native substrate mimics, controlled the stereoselectivity of hydroxylation reactions. We employed decoy molecules with diverse structures, resulting in either a significant improvement in enantioselectivity or clear inversion of stereoselectivity in the benzylic hydroxylation of alkylbenzenes and cycloalkylbenzenes. For example, supplementation of wild-type P450BM3 with 5-cyclohexylvaleric acid-L-phenylalanine (5CHVA-Phe) and Z-proline-L-phenylalanine yielded 53% (R) ee and 56% (S) ee for indane hydroxylation, respectively, although 16% (S) ee was still observed in the absence of any additives. Moreover, we performed a successful crystal structure analysis of 5CHVA-L-tryptophan-bound P450BM3 at 2.00 Å, which suggests that the changes in selectivity observed were caused by conformational changes in the enzyme induced by binding of the decoy molecules.
Professor and Head of the Department E-mail:helen.p@rmp.srmuniv.ac.in Area: Chemistry Affiliation: Department of Chemistry, Ramapuram Campus, SRM University
Education
Ph.D.
Organic Synthesis
Bharathidasan University, Tiruchirapalli, 2000
M.Sc.
General Chemistry
Bharathidasan University, Tiruchirapalli, 1994
B.Sc.
General Chemistry
Bharathidasan University, 1992
Other Details:
Course
Chemistry
Principles of Environmental Science
Research Interests
Organic Synthesis
Medicinal Chemistry
Crystal Growth
Molecular Docking
Nano Synthesis
Selected PublicationS
A. Santhoshkumar, Helen P. Kavitha*, R. Suresh, Hydrothermal Synthesis, Characterization and Antibacterial Activity of NiO Nanoparticles, Journal of Advanced Chemical Sciences-Article in press
R. Kavipriya, Helen P. Kavitha, B. Karthikeyan, and A. Nataraj,” Molecular structure, spectroscopic (FT-IR, FT-Raman), NBO analysis of N,N0-diphenyl-6-piperidin-1-yl-[1,3,5]-triazine-2,4-diamine, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 150 (2015) 476–487.
S. Sathishkumar, Helen P. Kavitha and S. Arulmurugan, In-silico anti-inflammatory evaluation of some novel tetrazolo and triazolodiazepine derivatives against COX-2 protien, International Journal of Advanced Chemical Science and Applications, 3(1), 2015
S. Arulmurugan and Helen P Kavitha, S. Sathishkumar and R. Arulmozhi. Review on biologically active benzimidazole, Miniriveviews in organic chemistry, 12(1), 178-195, 2015.
S. Sathishkumar and Helen P. Kavitha, Synthesis, Characterization and Anti-inflammatory Activity of Novel Triazolodiazepine Derivatives, IOSR Journal of Applied Chemistry, 8(1),47-52, 2015.
A. Silambarasan, Helen P. Kavitha, S. Ponnusamy, M. Navaneethan, Y. Hayakawa, Investigation of photocatalytic behavior of l-aspartic acid stabilized Zn(1−x)MnxS solid solutions on methylene blue Applied Catalysis A: General, 476, 22,1-8, 2014.
S. Sathish Kumar and Helen P. Kavitha, Synthesis and Biological Applications of Triazole Derivatives-A Review Mini-Reviews in Organic Chemistry, 10(1), 2013.
Helen P. Kavitha and S. Arulmurugan Synthesis, characterization and cytotoxic activity of benzoxazole, benzimidazole, imidazole and tetrazole Acta pharmaceutica 63(2), 253-264, 2013
Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, N-[2-(3,4-Dimeth-oxy¬phenyl)eth¬yl]-N-methyl-naphthalene-1-sulfonamide, Acta Crystallogr Sect E, 68(Pt 3): o890, 2012.
Jasmine P. Vennila, D. Jhon Thiruvadigal, and Helen P. Kavitha Antibacterial evaluation of some organic compounds as potential inhibitors for glucosamine-6-phospate synthase Journal of Pharmacy Research, 5(4), 1963-1966, 2012.
Helen P. Kavitha and R. Arulmozhi , Synthesis, Characterization and Anti inflammatory Activity of Some New Tetrazoles Derived from Quinazoline-4-one , International Journal of Chemistry, 1-6, 2012.
S. Arulmurugan, Helen P. Kavitha and S. Sathish Kumar. Synthesis, characterization and molecular docking studies of some new benzoxazole, benzimidazole, imidazole and tetrazole compounds as potential inhibitors for thymidylate synthase, International Journal of Science and Technology, 1, 1-11 2012.
Jasmine P. Vennila, Jhon Thiruvadigal, G. E. Theboral Sugi Kamala, Helen P Kavitha, Chakkaravarthi and V. Manivannan N-[2-(3,4-Dimeth-oxy¬phen¬yl)eth¬yl]-N-methyl¬benzene-sulfonamide” Acta Crystallogr Sect E Struct Rep Online. 68(Pt 3), o882, 2012.
Helen P Kavitha, A. Silambarasan, S. Ponnusamy, M. Navaneethan and Y, Hayakawa, Monodispersed synthesis of hierarchical wurtzite ZnS nanostructures and its functional properties” Materials Letters 81, 209-211, 2012.
Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-(4-Bromophenyl)-3-(4-hydroxyphenyl)-1,3-thiazolidin-4-one” Acta Cryst., E67, o1902, 2011.
Jasmine P. Vennila, D Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan 2,4-Bis(morpholin-4-yl)-6-phenoxy-1,3,5-triazine” Acta Cryst. E67, o2451, 2011.
Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-Chloro-4,6-bis(piperidin-1-yl)-1,3,5-triazine” Acta Cryst. E67, o312, 2011.
Helen P. Kavitha, Samiappan Sathish kumar and Ramachandran Balajee Antimicrobial Activity and Molecular Docking Studies of Some Novel Tetrazolo Diazepine Derivatives, Journal of Pharmacy Research,4(9), 2946-2949, 2011
Helen P. Kavitha and R. Arulmozhi Study of Antimicrobial and Analgesic Activities of Novel Tetrazoles Derived from Quinazolin-4-one, Journal of Pharmacy Research , 4(12), 4696-4698, 2011.
R.Thilagavathy, Helen.P.Kavitha, R.Amrutha and Bathey.R.Venkatraman Structural parameters, charge distribution and vibrational frequency analysis using theoretical SCF methods, Elixir Comp. Chem. 40, 5514-5516, 2011.
S. Sathish Kumar, Helen P. Kavitha, S. Arulmurugan and B. R. Venkatraman, Review on Synthesis of Biologically Active Diazepam Derivatives Mini-Reviews in Organic Chemistry, 8, 1-17, 2011.
Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, B. Gunasekaran and V. Manivannan, (E)-4-{(4-Bromopenzylidene) amino} phenol, Acta Cryst, E66, O316, 2010.
Subramaniyan Arulmurugan and Helen P. Kavitha, 2-Methyl-3-{4-[-(1H-tetrazol-5-yl)ethylamino]phenyl}-3H-quinazolin-4-one”, Molbank, M695,1-5, 2010.
S. Arulmurugan, Helen P. Kavitha and B. R. Venkatraman Biological Activities of Schiff Base and its Complexes”: A Review, Rasayan Journal of Chemistry, 3(3), 385-410, 2010.
R. Thilagavathy, Helen P Kavitha and B. R. venkatraman Isolation, Characterization and Anti-Inflammatory Property of Thevetia Peruviana E-journal of Chemistry,7(4), 1584-1590, 2010.
Subramaniyan Arulmurugan, Helen P. Kavitha, B. R. Venkatraman, Synthesis, Characterization and Study of antibacterial activity of some novel tetrazole derivatives” , Orbital Elec. J. Chem, 2(3), 271-276, 2010.
With R. Thilagavathi “Synthesis of 3-{4-[4-(benzylideneamino) benzene sulfonyl]-phenyl}-2-phenylquinazoline-4(3H)-one” Molbank, M589, 2009.
With S.Sathish Kumar “Synthesis of 3-Methyl-1-Morpholin-4-ylmethyl-2,6-Diphenylpiperidin-4-One”, Molbank, M617, 2009.
With S. Sathish Kumar “6-Methyl-2,7-Diphenyl-1,4-Diazepan-5-One”, Acta Cryst., E65, (o3211), 2009.
With R. Thilagavathi “2-phenyl-4H-3,1-benzoxazian-4-one”, Acta., Cryst. (E), E65, (o127), 2009.
With Jasmine P. Vennila “4-nitrophenyl napthalene-1-sulfonate”, Acta Cryst. (E), (o1848), E64, 2008.
With R. Arulmozhi,”1- Naphthyl-9-HCarbazole-4-Sulphonate”, Acta Cryst., E66, 010208, 2008.
With T. Nithya “Antibacterial activity of Solanum Trilobatum”, Journal of Ecotoxicol.Environ. Monit., 14, (237-239), 2004.
“Synthesis and Antimicrobial activity of1-(9’Acridinyl)-5-substituted phenyl Tetrazoles”, Asian Journal of chemistry, 16, (1191-1192), 2004.
With S. V. Selva bala “Study of Hypoglysemic Activity of Solanum Xanthocarpum L. on Alloxanised Diabetic Rats”, Adv. Pharmacol Toxicol., 4, (19-24), 2003.
Helen P. Kavitha “Study of anajesic activity some novel 1-(9’Acridinyl)-5-substituted phenyl tetrazoles”, Indian Journal of Chemical Technology, 9, (361-362), 2002.
With S.Malliga, “Effect of Soaking the Wood of Emblica officinalis,on Some Water Parameters”, Journal of Swamy Bot. 15, (89-90), 1998.
Working Papers
With S. Arulmurugan, “Review on Biologically Active Benzimidazole derivatives”: Mini reviews in organic Chemistry.
Academic Experiences
Assistant Professor(S. G), SRM University, Ramapuram from Sep 2007 to Jun 2012
Lecturer, SRM University, Ramapuram from Aug 2004 to Aug 2007
Senior Lecturer, VRS College, Villupuram from Aug 2002 to May 2004
Lecturer, VRS College, Villupuram, from Aug 2000 to May 2002
Lecturer, ADM College for Women, Nagapattinam from July 94 to April 95
Other Professional Experiences
4 Scholars have been awarded Ph.D Degree
Guiding 3 Ph.D candidates
Guided 8 M. Phil and 20 M. Sc projects
Principal Investigator for a pilot project funded by SRM University (completed)
Co-investigator for a UGC major project (completed)
Reviewer for International Journals
Convenor for the National Conference on New Renaissance in Chemical Research, 2011 and 2015.
Member Board of Studies –Chemistry,SRM University.
Doctoral Committee member in Karunya University
Undertaking consultancy work in the department
Question paper setter for various universities
Convenor for many programmes conducted in the campus
Chief Superintendent for SRM University-Ramapuram campus
Member in various professional bodies such as MISTE, FICCE and CTA
Author of five books in chemistry
Executive council member in Association of Chemistry Teachers, Mumbai
Achievement and Award
Received Award and cash prize for Research from SRM University from the year 2006-15
Alice Coletti, Francesco Antonio Greco, Daniela Dolciami, Emidio Camaioni, Roccaldo Sardella, Maria Teresa Pallotta, Claudia Volpi, Ciriana Orabona, Ursula Grohmann, Antonio Macchiarulo
Structure-function relationships of IDO1 and structure-activity relationships of inhibitors are discussed with an outlook on next generation IDO1 ligand.
aDepartment of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, 06123 Perugia, Italy E-mail:antonio.macchiarulo@unipg.it Fax: +39 075 585 5161 Tel: +39 075 585 5160
bDepartment of Experimental Medicine, University of Perugia, P.le Gambuli, 06132 Perugia, Italy
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) mediates multiple immunoregulatory processes including the induction of regulatory T cell differentiation and activation, suppression of T cell immune responses and inhibition of dendritic cell function, which impair immune recognition of cancer cells and promote tumor growth. On this basis, this enzyme is widely recognized as a valuable drug target for the development of immunotherapeutic small molecules in oncology. Although medicinal chemistry has made a substantial contribution to the discovery of numerous chemical classes of potent IDO1 inhibitors in the past 20 years, only very few compounds have progressed in clinical trials. In this review, we provide an overview of the current understanding of structure–function relationships of the enzyme, and discuss structure–activity relationships of selected classes of inhibitors that have shaped the hitherto few successes of IDO1 medicinal chemistry. An outlook opinion is also given on trends in the design of next generation inhibitors of the enzyme.
Introduction Indoleamine 2,3-dioxygenases (IDOs) are heme-containing proteins that catalyze the oxidative cleavage of the indole ring of tryptophan (L-Trp, 1) to produce N-formyl kynurenine (2) in the first rate limiting step of the kynurenine pathway (Figure 1).1,2 The family includes two related enzymatic isoforms, namely IDO1 and IDO2, sharing ∼60% of sequence similarity and featuring distinct biochemical features.3,4 A third enzyme of the family is the tryptophan-2,3-dioxygenase (TDO2) which is structurally unrelated to IDO1 and IDO2 and is endowed with a more stringent substrate specificity for L-Trp.5 Although TDO2 is expressed almost exclusively in hepatocytes where it regulates L-Trp catabolism in response to the diet, IDO1 and IDO2 are widely expressed in macrophages and dendritic cells exerting immunoregulatory functions.6 These are accomplished through two major mechanisms including depletion of tryptophan and production of bioactive metabolites along the kynurenine pathway. Specifically, the first mechanism postulates that raising levels of Interferon-γ (IFN-γ) induce IDO1 expression in macrophages and dendritic cells during pathogen infection, leading to consumption of L-Trp and growth arrest of pathogens, whose diet is sensitive to this essential nutrient.7 The second mechanism grounds on production of kynurenine metabolites that bind to the aryl hydrocarbon receptor (AhR), activating signaling pathways that enhance immune tolerance.8-10 Among the three proteins, IDO1 is the most characterized enzyme and in recent years a second signal-transducing function was revealed for this protein.11,12 In particular, this signalling function relies on the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the non-catalytic domain of IDO1.13 The immunosuppressive cytokine transforming growth factor-β (TGF-β) stimulates phosphorylation of ITIMs by Sarcoma-family (Src-family) kinases and consequent interaction of the phosphorylated enzyme with Src Homology 2 domain Phosphatase-1 (SHP-1) and Src Homology 2 domain Phosphatase-2 (SHP-2), eventually leading to long-term expression of IDO1 and immune tolerance. Conversely, in pro-inflammatory environmental conditions, increasing levels of interleukin-6 (IL-6) trigger the interaction of
phosphorylated IDO1 with suppressor of cytokine signalling 3 (SOCS3) that tags the enzyme for proteasome degradation, shortening IDO1’s half-life and promoting inflammatory response.14 The breakthrough discovery that IDO1 plays a crucial role in the maintenance of maternal immune tolerance ushered in a great deal of interest on the enzyme, by then considered a master regulatory hub of immunosuppressive pathways in pregnancy, autoimmune diseases, chronic inflammation, and cancer.15 In this framework, elevated levels of IDO1 expression found in several tumour cells were associated to the participation of the enzyme in the tumor immuno-editing process which sets up immune tolerance to tumor antigens.16,17 On this basis, academic groups and pharmaceutical companies have been engaged in the development of IDO1 inhibitors.18 Although part of these efforts has proved successful, with a large array of potent and selective inhibitors being disclosed in literature and patent applications, only few compounds have hitherto entered clinical trials (3-7, Figure 1).2,19-22 At this regard, some studies have highlighted challenges in the development of enzyme inhibitors mostly due to redox properties of the enzyme that may account for unspecific mechanism of inhibition of many compounds discovered in preclinical studies.23,24 Starting with an overview on the architecture of IDO1 and its structure-function relationships, in this article we discuss selected classes of inhibitors that have shaped advances in the medicinal chemistry of IDO1, providing outlooks on future trends in the design of next generation compounds.
Green Chem., 2017, Advance Article DOI: 10.1039/C7GC01566F, Tutorial Review
Lian Yang, Tao Dong, Hrishikesh M. Revankar, Cheng-Pan Zhang
Advances of fluorination in aqueous media during the last few decades are summarized in this review
Advances in aqueous fluorination during the last few decades are summarized in this review. Fluorinated compounds have dominated a large percentage of agrochemicals and pharmaceuticals and a mass of functional materials. The incorporation of fluorine atoms into organic molecules has become one of the mainstream technologies for their functional modification. Water is very environmentally friendly and has advantageous physicochemical properties. Fluorination reactions in aqueous media are highly sought-after, and have attracted great attention in research areas ranging from medicinal chemistry to materials science. In early times and for a long time, fluorination was thought to be diametrically opposed to water or moisture. However, recent examples have conflicted with this viewpoint. The successful merger of “untamed” fluorine and “mild” water in chemical reactions has set up a new prospect for green chemistry. A considerable amount of remarkable research works have been carried out using water as a (co)solvent and/or a reactant for transformations including electrophilic, radical, or nucleophilic fluorination. We hope that this review will serve as a guide to better understand and to further broaden the field of fluorine chemistry in aqueous conditions.
Conclusion
The installation of fluorine atoms into organic and organometallic frameworks can dramatically change their physical, chemical, and biological properties. Organofluorides have entered many fields of science and technology with a tremendous impact on these domains. The development of efficient, selective, and mild methods to build C-F bonds is of great importance, which is highly desirable to keep up with the rapidly growing demand of novel fluorine-containing scaffolds. In early times, most fluorination reactions required harsh conditions and moisture-sensitive, highly toxic, and explosive atomic fluorine transfer agents like fluorine gas, xenon difluoride, hypofluorite, antimonytrifluoride, and diethylaminosulfurtrifluoride. The discovery of stable electrophilic fluorination reagents such as Selectflour and NFSI has remarkably changed the dilemma, which realized a large number of safe, mild, and easily controllable electrophilic and radical fluorination reactions in aqueous media. Although the exact mechanisms are still unclear at present, it does never hamper the green fluorination method development with these reagents. A mass of successful examples have confirmed that the aqueous reaction medias have positive impacts on electrophilic and radical fluorination reactions with using the N-F reagents and in many cases water can also be a nucleophile for the entire conversions.
In addition, water was generally thought to be an unsuitable medium for nucleophilic fluorination because the fluoride ions can be “trapped” in aqueous medias by hydrogen bonding and become unreactive. Thus, their use in organic synthesis has been quite limited to polar aprotic solvents. Although the strong hydrogen bond formed between fluoride and water diminished the nucleophilicity of fluoride ions, the recent examples of nucleophilic fluorination in aqueous media have implied that this “negative” effect does not always harm the reaction. Besides, the radioisotope 18F has been considered to be a good choice for PET imaging owing to its desirable radiochemical properties. With a half-life of 110 minutes, the introduction of [ 18F]fluorine atoms into biomolecules has to be completed in a swift manner to minimize the loss of radioactivity. Nucleophilic incorporation of [18F]F‒ in aqueous conditions could rapidly produce [18F]fluorinesubstituted biomolecules, which avoided azeotropic drying process, shortened the production time, and minimized the loss of activity. We summarized the recent aqueous fluorination reactions in three sections according to their possible mechanisms. The successful amalgamation of “ill-tempered” fluorine and “benign” water has boded well for green fluorine chemistry. Water behaves as a cosolvent to dissolve fluorination reagents and/or as a reactant for bifunctionalization. Since the aspects of green chemistry has drawn much attention from the society, the pursuit of more efficient and milder reaction conditions for greener fluorination in aqueous medias will never end. Although a large number of research works have been published in this area, it’s only the tip of the iceberg with a wide scope for improvement. We hope that this review will serve as a guide to understand and to further broaden the field of aqueous fluorine chemistry. To meet the principle of green chemistry in modern synthesis, the development of new fluorination reagents as well as valid catalytic systems is crucial for mild and selective C-F bond formation. It’s undoubted that a growing number of green fluorination methodologies in aqueous media will be witnessed in the near future.
ABSTRACT In the present study an attempt was made to increase the therapeutic effectiveness of losartan potassium,by increasing the solubility and dissolution rate via solid dispersion using β-cyclodextrin as carrier. Losartan potassium is an Antihypertensive agent but failed to show good therapeutic effect. Eight solid dispersion formulations of losartan potassium were prepared by using different drug:polymer ratios viz.1:2,1:2,1:3,1:4 by novel methods like Hot melt extrusion,Lyophilization.prepared solid dispersions were evaluated. The blend of all the formulations showed good flow properties such as angle of repose, bulk density, tapped density. All the solid dispersion formulations were compressed into orodispersible tablets with weight equivalent to losartan potassium of 25mg by direct compression method using 6mm punch on 8 station rotary tablet punching machine. The prepared tablets were evaluated for its hardness, disintegration, weight variation, friability and invitro dissolution studies.The Infra Red spectra revealed that there is no incompatability between the drug and excipients. The prepared tablets were shown good post compression parameters and they passed all the quality control evaluation parameters as per I.P limits. Among all the formulations F4 and F8 formulations showed maximum % drug release i.e.93.83%(Lyophilization), 97.10%(Hot melt extrusion method) within 45min.these are compared with pure drug which shows %drug release58.67%. The optimized formulations were subjected to different kinetic models.the formulations were found to follow zero order release. optimized formulations Were subjected to Accelerated stability study for 3 months according to ICH guidelines.The results found to satisfactory.
Considering all evaluation parameters and % drug release F8 formulation shown better % drug release compared with F4 formulation. hence F8 formulation considered as optimised formulation.
CONCLUSION Losartan potassium is belongs to class II drugs, that is, characterized by low solubility and low permeability therefore, the enhancement of its solubility and dissolution profile is expected to significantly improve its bioavailability and reduce its side effects. The precompression blends of Losartan were characterized with respect to angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. The precompression blend of all the batches indicates well to fair flowability and compressibility. Among all the formulations F8 formulation, showed good result that is 97.10 % in 45 minutes. As the concentration of polymer increases the drug release was decreased.
Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India
Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India
Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue
ACS AuthorChoice – 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.
INTRODUCTION
Benzimidazol-2-ones 1 are an important class of heterocycles and a privileged scaffold in medicinal chemistry. They consist of cyclic urea fused with the aromatic backbone, which can potentially interact in a biological system by various noncovalent interactions such as hydrogen bonding and π stacking. Benzimidazolone derivatives exhibit a wide range of biological activities, and they are useful in treating various diseases including cancer, type II diabetes, central nervous system disorders, pain management, and infectious disease.1 Selected compounds embedded with a benzimidazol-2-one moiety along with their use are captured in Figure 1. It is worth mentioning that oxatomide drug with a benzimidazol-2-one core was approved for marketing a few years ago.2a Very recently, US Food and Drug Administration approved a new drug called flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in females, which contains benzimidazol-2- one motif.2b
CONCLUSIONS
We have developed a mild and new protocol for the synthesis of benzimidazol-2-ones from quinoxalinediones through decarbonylation. The present methodology can be an addition to the toolbox to prepare benzimidazolones, and it will be useful in medicinal chemistry, particularly, late-stage functionalization of natural products, drug scaffolds, or an intermediate containing quinoxaline-2,3-diones. As direct application of this method, we have successfully developed a new route for the synthesis of recently approved drug flibanserin and a urea analogue of antibiotic natural product hunanamycin A. Later application demonstrates the utility of the present method in late-stage functionalization
Synthesis of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1,3-dihydro-2Hbenzo[d]imidazol-2-one (Flibanserin)
HRMS (ESI): m/z calculated for C20H22ON4F3[M+H]+ 391.1740 found 391.1743;
Scheme 4. Synthesis of Flibanserin through Ring Contraction
The same methodology was applied for the synthesis of flibanserin, also known as “female viagra”, which is the first approved medication for treating HSDD in women and is classified as a multifunctional serotonin agonist antagonist.(14, 15) Our synthesis of flibanserin commenced with 1-benzyl-1,4-dihydroquinoxaline-2,3-dione 36,(16) which was reacted with known chloride 37(17) under the basic condition in DMF to give the desired product 38 in good yield. Compound 38 was subjected for the decarbonylative cyclization under the optimized condition to afford the product 39 in 59% yield. Finally, the benzyl group was deprotected using trifluoromethanesulfonic acid in toluene under microwave irradiation,(8b, 18) which gave flibanserin in excellent yield (Scheme 4). The final product was isolated as HCl salt, and all of the spectral data are in agreement with the published data.(15c)
Rahul D. Shingare completed his M.Sc (Chemistry) from Fergusson College, Pune in 2008. He worked as a research associate in Ranbaxy and Lupin New drug discovery center, Gurgaon and Pune respectively until 2012 and currently pursuing his doctoral research in NCL – Pune from 2012.
Current Research Interests:Antibacterial Natural Product Hunanamycin A: Total Synthesis, SAR and Related Chemistry.
Akshay Kulkarni completed his M.Sc. from Ferguson College, Pune University in the year 2015 and joined our group as a Project Assistant in the month of October, 2015.
Current research interest: Synthesis of silicon incorporated biologically active antimalerial compounds.
e-mail : as.kulkarni@ncl.res.in
Dr.D. Srinivasa Reddy
Organic Chemistry Division
CSIR-National Chemical Laboratory
Stahl, S. M.Mechanism of action of Flibanserin, A multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorderCNS Spectrums2015, 20, 1 DOI: 10.1017/s1092852914000832
Sustainable chemistry: how to produce better and more from less?
Green Chem., 2017, Advance Article DOI: 10.1039/C7GC02006F, Perspective
P. Marion, B. Bernela, A. Piccirilli, B. Estrine, N. Patouillard, J. Guilbot, F. Jerome
This review describes the rapid evolution of chemistry in the context of a sustainable development of our society. Written in collaboration between scientists from different horizons, either from public organizations or chemical companies, we aim here at providing recommendations to accelerate the emergence of eco-designed products on the market.
Sustainable chemistry: how to produce better and more from less?
aSOLVAY, 85 rue des frères Perret, BP 62, F-69192 Saint Fons Cedex, France
bINCREASE FR CNRS 3707/Centre de Recherche sur l’Intégration Economique et Financière, Université de Poitiers, 2 rue Jean Carbonnier, Bât A1, 86073 Poitiers Cedex 9, France
cBIOSYNTHIS, 6 Chemin de la Pierre Percée, 91410 Saint-Cyr-sous-Dourdan, France
dARD-Agro-industrie Recherches et Développements, Green Chemistry Department, Route de Bazancourt, F-51110 Pomacle, France
ePENNAKEM LLC, 3324 Chelsea avenue, Memphis, USA
fSEPPIC-AIR LIQUIDE, 127 chemin Poudrerie, 81105 Castres, France
gINCREASE FR CNRS 3707/Institut de Chimie des Milieux et Matériaux de Poitiers, Université de Poitiers, ENSIP, 1 rue Marcel Doré, 86073 Poitiers, France E-mail:francois.jerome@univ-poitiers.fr
Abstract
The International Symposium on Green Chemistry (ISGC) organized in 2013, 2015 and 2017 has gathered many senior and young talented scientists from all around the world (2200 attendees in three editions), either from academia or industry. Through outstanding conferences, communications, debates, and round tables, ISGC has been the witness of the rapid evolution of chemistry in the context of a sustainable development of our societies, not only at the scientific and industrial levels but also on education, networking and societal aspects. This critical review synthesizes the different points of view and the discussions having taken place at ISGC and gives a general picture of chemistry, including few scientific disciplines such as catalysis, processes, resource management, and environmental impact, among others, within the framework of sustainable development. This critical review, co-authored by researchers from public organizations and chemical companies (small, medium and large industrial groups) provides criteria and recommendations which, in our view, should be considered from the outset of research to accelerate the emergence of eco-designed products on the market.
Conclusions
Sustainable chemistry is the only mean to generate performant products and long lasting solutions able to generate business and profit for chemical industry. Performance is the best systemic answer for customer needs and our societies. Defining sustainable chemistry is, however, far to be an easy task because chemistry is a highly dynamic system. The sustainability of a value chain is for instance directly depending on the access to energy (and above all to its origin – coal, gas, biomass…) and on the supply of raw materials. In the current economic context, it could be not so easy to predict what will be the best source of energy or raw materials for a desired product in the future. The development of predictive tools is now essential and will represent probably one of the next scientific challenges in the coming years. During the last 20 years, utilization of renewable feedstocks in chemical processes has become a strategy of growing interest but it definitely does not guarantee the establishment of a sustainable chemistry. Indeed, in some cases, it is more sustainable to produce a chemical from a fossil carbon source using decarbonized energy than the reverse. It is very important to distinguish the carbon found in the final product from the carbon content corresponding to the energy which is required the product production (going from raw materials to manufacturing, end of life, etc.). In this area, the concept of biorefinery can help to secure developments and to minimize investments in production plant by mutualizing facilities and R&D initiatives. Cooperation with local producers can also be a valuable way to implement new bio‐based products while favouring sustainable agricultural practices. Whatever the raw materials (renewable or fossil), a complete and systemic life cycle analysis of the whole chain value (from resources to manufacturing, use and end of life) must be performed because it gives us an accurate picture of the overall economic, environmental and societal performances of a product in an application for a defined market. In general, one should never forget that sustainable chemistry should help the society to produce more and better (products). Emergence of sustainable innovations on the market takes a lot of time because chemists have to reinvent chemistry. To achieve our transition to a sustainable society, we must think differently and bring together the worlds of finance, manufacturers, researchers and public authorities. The current method of funding of research and innovation is not satisfying yet because too often based on short‐term projects and with high Technology Readiness Level. Governments have to realize that this funding method slows down, and sometime also hampers, the emergence of future sustainable innovations. Evolution of regulations with the aim of banning toxic, eco‐toxic or poor biodegradable products is an important driver for sustainable innovation. It is now seen and shared as a positive sign providing opportunities to develop systemically better solutions and allowing chemical companies advocating sustainable development and products as a must to stay in the competition. As examples, ban of CFC, replacement of chlorinated or other toxic solvents, substitution of endocrine disruptors lead to better solutions for the global benefit of our societies. Improving public perception and awareness on sustainable chemistry is on the way but more efforts will be needed in the future to definitely contribute to the emergence of eco‐ designed chemicals on the market.
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Below we provide a bulleted list to summarize the main recommendations that are, in our views, essential for designing sustainable products. (1) Products design & Manufacture: For the intended application, sustainable chemicals must imperatively bring a global benefit, created by a scientific or technological breakthrough, while minimizing risks. They should also generate profit to emerge on the market. Products should be produced according to the 12 principles of green chemistry. In addition, their end of life should be integrated at the outset of research, (2) Resources: They should be available for future generations and should have low environmental impact (protecting endangered species, deforestation, erosion of biodiversity, contamination of natural resources, global warming, etc.), it should make progress the societal development of concerned area (sharing any benefits with local producer, no child labour, help developing countries, etc.) and their utilization should not destabilise other supply chains. Non edible raw material, a return to the idea of ‘localness’ and the need for closeness should be preferred, (3) Process: The ideal process would be a low Capex or a progressive Capex process and should be energy‐efficient, not use solvents, be without effluents, should limit the number of reactional and purification steps and should be developed rapidly to limit the associated risks and costs. Efforts are still needed for miniaturisation of equipment, intensification and development of continuous reactors, (4) Energy: The chemical industry is also energy intensive. Although less than 10% of fossil carbon is used for the manufacture of chemicals, finding decarbonized sources of energy is mandatory to avoid the depletion of carbon reserves and price increase and to ensure that future generations will have access to the same resource in the same amount, (5) Life cycle assessment: it should be assessed in all cases, the earlier the better, by preferring a ‘cradle to grave’ approach. It should give an accurate picture of the overall economic, environmental and societal performances of a product in an application for a defined market, (6) Education: we should improve public awareness and perception on sustainable chemistry to facilitate the acceptation of sustainable products by the consumer. More education programs should be launched in the future not only to reassure the consumer but also to create a pool of students better armed to tackle the future challenges of (sustainable) chemistry. The rapid development of digital tools should be helpful to address this issue, (7) Network: we should prefer working in an open innovation mode by bringing together the worlds of finance, manufacturers, researchers and public authorities to accelerate the emergence of eco‐designed chemicals on the market. Networks should enable local players to adapt to changes in their environment while optimising their economic and environmental efficiency, (8) Funding: A good balance between funding to applied research and basic research must be addressed in order to continuously generate scientific innovation. However, public authorities must realise that societal challenges are more important than the short term financial challenges faced by businesses. The current model of our economy based on rapid profitability is unfortunately not well adapted for these advances since long‐term investments will be needed for a more sustainable development of our society, (9) Legislation & Regulation: it should facilitate the emergence of sustainable chemicals by banning harmful chemicals for the human health and the environment, even those nowadays generating substantial profits. The registration process of improved sustainable chemicals by the concerned agencies should be quicker than now to speed up their integrations on the market, (10) Predictive methods: the development of tools to accurately predict the technical and application performances, the economic efficiency, the environmental and societal performance of a targeted product should be developed to limit the risks and costs associated with potential failure and to reassure the investors. It is also urgent to develop these tools for chemicals that are intended to be dispersed in nature.
Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, FLAME-Lab – Flow Chemistry and Microreactor Technology Laboratory, Via E. Orabona 4, 70125, Bari. Italy
Guest Editor: L. Vaccaro Beilstein J. Org. Chem.2017,13, 520–542. doi:10.3762/bjoc.13.51 Received 14 Nov 2016, Accepted 20 Feb 2017, Published 14 Mar 2017
Abstract
Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.
Green chemistry’s birth was driven by the necessity to consider and face the urgent question of sustainability. Chemical production concerns an extended range of fields such as textiles, construction, food, cosmetic components, pharmaceuticals and so forth. An innovative approach to the chemistry world requires new strategies and criteria for an intelligent chemistry. It is understood that all this matter has big implications in economy and politics. Recent studies predicted a growth of green chemical processing up to $100 billion in 2020 (Pike Research study) [1]. All this offers important and arduous challenges expressed in terms of new synthetic strategies using sustainable, safe, and less toxic materials. On green chemistry we can read Paul Anastas and John Warne’s 12 principles, set up in 1998, which illustrate the characteristics of a greener chemical process or product [2]. Microreactor technology and flow chemistry could play a pivotal role in the context of sustainable development. In fact, flow chemistry is becoming a new technique for fulfilling several of the twelve green chemistry principles. The microreactor approach, could provide protection, preserves atom economy, guarantees less hazardous chemical synthesis and allows the use of safer solvents and auxiliaries. Furthermore, it pushes towards designing of chemistry with a lower environmental and economic impact, enhance the importance of catalysis, allows real-time analysis for pollution prevention and provides inherently safer chemistry (Figure 1) [3]. Without claiming to be exhaustive, in this review we report recently published representative synthetic applications that demonstrate the growing contribution of flow chemistry and microreactor technology in green and sustainable synthesis [4-7].
Figure 1: Microreactor technologies and flow chemistry for a sustainable chemistry.
Review
Flow microreactors: main features
The peculiar properties of microreactors [8] derive from their small size and can be ascribed mainly to the following characteristics: a) fast mixing: in a flow microreactor, in striking contrast to batch conditions, mixing takes place by molecular diffusion so that a concentration gradient can be avoided; b) high surface-to-volume ratio: the microstructure of microreactors allows for a very rapid heat transfer enabling fast cooling, heating and, hence, precise temperature control; c) residence time: it is the period of time the solution of reactants spend inside the reactor, and it gives a measure of the reaction time. The residence time is strictly dependent on the characteristics of the reactor (i.e., length of the channels, volume), and on the flow rate. The residence time is one of the crucial factors to be considered in optimizing flow reactions, especially when unstable or short-lived reactive intermediates are concerned. Microreactor technology provides also several benefits. Safety benefits, because of the high efficiency in heat exchange, and avoided accumulation of unstable intermediates. Economy benefits, due to lower manufacturing and operating costs, reduced work-up procedures, use of less raw materials and solvents and reduced waste. Chemistry benefits associated to the use of microreactor technology are the improved yields and selectivities, the possibility to conduct reactions difficult or even impossible to perform in batch, and the use of reaction conditions that allow exploring new chemical windows [9].
Contribution of flash chemistry to green and sustainable synthesis
The concept of flash chemistry as a “field of chemical synthesis using flow microreactors where extremely fast reactions are conducted in a highly controlled manner to produce desired compounds with high selectivity” was firstly introduced by Yoshida [10]. Flash chemistry can be considered a new concept in both organic and sustainable synthesis involving chemical transformations that are very difficult or practically impossible to conduct using conventional batch conditions. With the aim to show how flow microreactor technology and flash chemistry could contribute to the development of a sustainable organic synthesis, very recent examples have been selected and will be discussed here. In the context of green chemistry [11], protecting-group free organic synthesis has received particular attention in the last years, because of atom economy [12-15] and reduction of synthetic steps [16]. It has been demonstrated by Yoshida that protecting-group-free synthesis could be feasible using flash chemistry and microreactor technology [17,18]. Recently, Yoshida and co-workers developed flash methods for the generation of highly unstable carbamoyl anions, such as carbamoyllithium, using a flow microreactor system [19]. In particular, they reported that starting from different substituted carbamoyl chloride 1 and lithium naphthalenide (LiNp) it was possible to generate the corresponding carbamoyllithium 2, that upon trapping with different electrophiles provided several amides and ketoamide 3(Scheme 1).
Scheme 1: A flow microreactor system for the generation and trapping of highly unstable carbamoyllithium species.
The use of an integrated microflow system allowed the preparation of functionalized α-ketoamides by a three-component reaction between carbamoyllithium, methyl chloroformate and organolithium compounds bearing sensitive functional groups (i.e., NO2, COOR, epoxide, carbonyl) (Scheme 2).
Scheme 2: Flow synthesis of functionalized α-ketoamides.
It should be stressed that this kind of sequential transformations are practically impossible to perform using conventional batch chemistry because of the incompatibility of sensitive functional groups with organolithiums, and because of the high chemical and thermal instability of the intermediates.
In 2015 Yoshida reported another remarkable finding on the use of protecting-group-free organolithium chemistry. In particular, the flash chemistry approach was exploited for generating benzyllithiums bearing aldehyde or ketone carbonyl groups [20]. This reaction could be problematic for two reasons: a) the competing Wurtz-type coupling, (i.e., the coupling of benzyllithiums with the starting benzyl halides); b) the nucleophilic attack of organolithium species to aldehyde or ketone carbonyl groups (Scheme 3).
Scheme 3: Reactions of benzyllithiums.
The authors reported that the extremely fast micromixing avoided undesired Wurtz-type coupling [21,22]. It is well known, that competitive reactions can be controlled or even avoided under fast micromixing [23-27]. Moreover, high-resolution residence time control was essential for survival of carbonyl groups. In fact, this transformation can be achieved only with a residence time of 1.3 ms at −78 °C. Under these flow conditions, the aldehyde or ketone carbonyl moiety can survive the nucleophilic organolithium attack. Remarkably, the flow microreactor system allowed also the generation of benzyllithiums at 20 °C, rather than under cryogenic (−95 °C) conditions adopted with a conventional batch protocol. In addition, THF could be used in place of mixed solvents (Et2O/THF/light petroleum). Under the optimized conditions, the reactions of benzyllithiums with different electrophiles, gave adduct products in good yields (Scheme 4).
Scheme 4: Trapping of benzyllithiums bearing carbonyl groups enabled by a flow microreactor. (Adapted with permission from [18], copyright 2015 The Royal Society of Chemistry).
Another useful aspect of the flash chemistry relies on the possibility to generate highly reactive intermediates, such as halomethyllithium carbenoids, that need to be used under internal-quenching technique in batch mode. In 2014, the first example of effective external trapping of a reactive chloromethyllithium (CML) has been reported [28]. α-Haloalkyllithiums are a useful class of organometallic reagents widely employed in synthetic chemistry. In fact, they allow the direct homologation of carbonyl compounds and imines leading to β-halo-alcohols and amines that are useful building blocks [29-31]. This work represents a remarkable example of flash chemistry, and has elements of sustainability considering that in batch macroreactors, in order to avoid metal-assisted α-elimination, in situ quenching, an excess of reagents, and very low temperature are required [32,33].
Running the reaction in a flow system at −40 °C, by using residence times between 0.18–0.31 s high yields of homologated products have been obtained under external quenching conditions (Scheme 5).
Scheme 5: External trapping of chloromethyllithium in a flow microreactor system.
The results described above nicely show the potential, as green technology, of flow microreactor systems for synthetic processes involving highly unstable intermediates. Another nice example on the use of microreactor technology for the development of sustainable chemical processes, is represented by the direct introduction of the tert-butoxycarbonyl group into organometallic reagents [34]. The reaction between organolithium reagents and di-tert-butyl dicarbonate run under flow conditions, allowed a straightforward preparation of several tert-butyl esters. The use of a flow process resulted more efficient, versatile and sustainable compared to batch. Moreover, this operationally simple procedure complements well with the already available strategies for the preparation of tert-butyl esters, avoiding the use of inflammable and explosive gaseous isobutylene [35], the use of harsh conditions [36], the use of peroxides [37], the use of toxic gas such as CO or transition metals [38-42]. The flow process, for the direct C-tert-butoxycarbonylation of organolithiums, has been optimized in a green solvent such as 2-MeTHF by a precise control of the residence time, and without using cryogenic conditions (Scheme 6). In addition, many organolithiums were generated from the corresponding halo compounds by a halogen/lithium exchange reaction using hexyllithium as a more sustainable base [43,44].
Scheme 6: Scope for the direct tert-butoxycarbonylation using a flow microreactor system.
The concept of flash chemistry has been successfully employed for outpacing fast isomerization reactions. The accurate control of the residence time, realized in a microreactor, could suppress or avoid isomerization of unstable intermediates. This is often unavoidable when the same reactions are run in batch mode [45-47].
Yoshida and Kim recently provided an astonishing example on the potential of flash chemistry in controlling fast isomerization of organolithiums [48]. The authors designed a chip microreactor (CMR), able to deliver a reaction time in the range of submilliseconds (0.33 ms) under cryogenic conditions. By using such an incredible short residence time, it was possible to overtake the very rapid anionic Fries rearrangement, and chemoselectively functionalize ortho-lithiated aryl carbamates (Scheme 7).
Scheme 7: Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science).
This CMR has been developed choosing a fluoroethylene propylene–polymide film hybrid for fabrication because this material offers exceptional physical toughness at low temperature and high pressure as well as chemical inertness. The most relevant aspect of this microreactor, concerns the 3D design of the mixing zone (Figure 2). The mixing efficiency was evaluated on the basis of computational fluids dynamics (CFD). The simulation results showed that serpentine 3D-structured channels (Figure 2), possessing five turns after each mixing point in a total length of 1 mm, was able to deliver the highest mixing efficiency. The inner volume for the reactor was of 25 μL. This CMR provides mixing efficiency levels of 95% with a total flow rates of 7.5 mL/min corresponding to a residence time of about 0.3 milliseconds.
Figure 2: Chip microreactor (CMR) fabricated with six layers of polyimide films. (Reproduced with permission from [43], copyright 2016 American Association for the Advancement of Science).
To show the potential use of this microdevice in organic synthesis, the synthesis of Afesal [49], a biologically active compound having anthelmintic activity was reported as application.
This outstanding result by Yoshida and Kim, demonstrates how microdevices and flash chemistry could contribute to the development of new sustainable synthetic strategies, and how microreactor technology could help in taming the reactivity of unstable species [50].
Contribution of continuous-flow metal-, organo-, and photocatalysis in green chemistry
The development of continuous-flow catalysis is appealing because it combines the advantages of a catalytic reaction with the benefits of flow microreactors. Under homogeneous conditions a soluble catalyst, which flows through the reactor together with the reactants, is employed. At the end of the process, a separation step would be required in order to remove the catalyst and byproducts. On the other hand, heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a continuous-flow process, the catalyst can be fixed on a suitable hardware, and the reaction mixture allowed to flow through the system. The use of recyclable catalysts in continuous-flow conditions represents an innovative strategy for the development of more environmentally friendly synthesis. In the last decade, organic photochemistry got a sort of renaissance, emerging as useful approach in modern sustainable and green synthesis.
Concerning the heterogeneous catalysis with palladium, practical procedures for recovering and reusing of the catalysts have been recently reported [51-53]. A versatile Pd-catalysed synthesis of polyfunctionalized biaryls, using a flow microreactor, has been recently reported by Yoshida [54]. Using the integrated microflow system reported in Scheme 8, arylboronic esters were prepared by a lithiation/borylation sequence, and used in a Suzuki–Miyaura coupling in a monolithic reactor. A remarkable aspect of the process was the use of an integrated supported monolithic Pd(0) catalyst that allowed to perform cross-coupling reactions in continuous flow mode (Scheme 8).
Scheme 8: Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of products.
This integrated microflow system allow to handle the borylation of aryl halides (Ar1X), and the subsequent Suzuki–Miyaura coupling using different aryl halide (Ar2X). Without requiring the protection of sensitive functionalities, running the flow system using a residence time (tR) of about 4.7 min at a temperature above 100 °C, high yields of coupling products were obtained. Noteworthy, the Suzuki–Miyaura coupling did not require the use of a base. The authors applied the presented method to the synthesis of adapalene, used in the treatment of acne, psoriasis, and photoaging.
Fluorinated aromatic compounds are extremely important in agrochemical, pharmaceutical and medicinal fields [55-58]. Buchwald and co-workers suggested a telescoped homocatalysis procedure consisting of a three-step sequence (metalation, zincation and Negishi cross-coupling) which furnishes an easy access to a variety of functionalized 2-fluorobiaryl and heteroaryl products (Scheme 9) [59]. This strategy is rightfully considered green because it guarantees the employment of readily available and cheap starting materials, the safe handling of highly thermally unstable or dangerous intermediates, and the use of higher temperature with respect to the batch mode in which the proposed reactions have to be carried out at −78 °C.
Scheme 9: Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).
The use of 2-MeTHF as greener solvent, contributes to further validate the green procedure. The 2-MeTHF solutions of fluoroarenes 4 together with the hexane solution of n-BuLi were pumped into the flow system at −40 °C. The generated organozinc intermediate meets the solution of haloarenes and the catalyst, leading to the formation of the desired products 5a–j (Scheme 9). Noteworthy, the homogeneous catalysis requires only 1% of the XPhos-based palladium catalyst. A sonication bath was employed to prevent clogging and the reaction required a residence time of 15 min.
Next, they turned their attention to the arylation of fluoro-substituted pyridines. The regioselective lithiation of halopyridines with lithium diisopropylamide (LDA) was conducted under mild conditions on substrate 6(Scheme 10). The addition of a little amount of THF was necessary in order to avoid clogging and the tendency of the lithiated intermediate to eliminate.
Scheme 10: Experimental setup for the coupling of fluoro-substituted pyridines. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).
The optimized conditions were suitable for the functionalization of 2-fluoropyridine, 2,6- difluoropyridine and 4-(trifluoromethyl)pyridine leading to products 7a–g reported in Scheme 10. Another promising field is the sustainable flow organocatalysis, and recently Pericàs reported an interesting synthesis and application of a recyclable immobilized analogue of benzotetramisole (BMT) used in a catalytic enantioselective Michael addition/cyclization reactions under continuous-flow conditions (Scheme 11) [60].
Scheme 11: Continuous flow process setup for the preparation of 11 (Reproduced with permission from [54], copyright 2015 American Chemical Society).
Resin-bound catalyst 10 was swollen with dichloromethane in a medium-pressure chromatography column used as a reactor. Dichloromethane solutions of substrate 9 reacted with the mixed phenylacetic pivalic anhydride (deriving from phenylacetic acetic (8) and pivaloyl chloride) inside the catalytic reactor producing the expected products 11. This ingenious system was equipped with an in-line FTIR probe, for monitoring the transformation, and an in line liquid–liquid separator to avoid tedious work-up procedures, thus saving solvents, resources and optimizing work times. This system was demonstrated to work for 11 h with higher conversion and enantioselectivity (er >99.9%) in comparison to the batch mode [61]. Pericàs and co-workers taking advantage of the high catalytic activity, robustness and recyclability of the supported catalyst, performed also straightforward gram synthesis of target compounds.
In the context of photocatalysis and oxidations using flow microreactors [62,63], Noël reported a metal-free photocatalytic aerobic oxidation of thiols to disulfides under continuous-flow conditions [64]. Disulfides are useful molecules employed as drugs, anti-oxidants or pesticides as well as rubber vulcanizating agents [65]. Symmetric disulfides are generally obtained by oxidative coupling of thiols [66]. Noël and co-workers set up a microflow system equipped with a mass flow controller (MFC) able to introduce pure oxygen as the oxidant to oxidize a solution of thiol containing 1% of Eosin Y. The flow stream was exposed to white LED light in order to activate the reaction, and a dilution with pure EtOH was needed at the output to avoid clogging (Scheme 12). The residence time of 20 min guaranteed a limited irradiation time and high purity of the products.
Scheme 12: Continuous-flow photocatalytic oxidation of thiols to disulfides.
The disulfides were obtained with excellent yields, and the process was executed on challenging thiols as in the case of disulfide 12 (Scheme 12), used as food flavour additive [67]. To demonstrate the usefulness of the flow methodology, and its applicability, the photocatalytic aerobic oxidation of a peptide to obtain oxytocin in continuous flow was reported (Scheme 12). Full conversion was achieved in water with 200 s of residence time.
Noël optimized, for the first time, a trifluoromethylation of aromatic heterocycles by continuous-flow photoredox catalysis. The process benefited from the use of microreactor technology and readily available photocatalysts. The process was also employable for perfluoroalkylation. The developed process occurred in less time with respect to batch mode, and under milder conditions. The set-up of the reactor allowed for the use of gaseous CF3I by means of a mass flow controller. Selected examples of trifluoroalkylated products are reported in Scheme 13[68].
Scheme 13: Trifluoromethylation by continuous-flow photoredox catalysis.
Tranmer reported a “traceless reagents” chemistry with the continuous-flow photosynthesis of 6(5H)-phenanthridinones, poly(ADP-ribose) polymerase (PARP) inhibitors [69]. The relevance of the work resides in the use of green solvents, the absence of heavy metals, the use of convenient temperatures, and the increased safety by eliminating UV-exposure locating the UV lamp within the microreactor. Hazard of fires caused by the hot UV lamps approaching the auto-ignition temperature of flammable solvents, very often underestimated, is totally prevented thanks to a specific cooling system. 2-Halo-N-arylbenzamides were converted into 6(5H)-phenanthridinones by a photocyclization reaction. In order to run this step, a flow system with a photochemical reactor equipped with a medium pressure Hg lamp and 10 mL reactor coil, was employed. Good yields were obtained from different 2-chlorobenzamides disclosing that either electron-donating or electron withdrawing ortho-substituents were tolerated (Scheme 14).
Scheme 14: Flow photochemical synthesis of 6(5H)-phenanthridiones from 2-chlorobenzamides.
A metal- and catalyst-free arylation procedure carried out under continuous-flow conditions was recently reported by Fagnoni [70]. This photochemical process allowed for the preparation of a wide range of synthetic targets by Ar–Csp3, Ar–Csp2 and Ar–Csp bond-forming reactions. The use of a photochemical flow reactor, consisting of a polyfluorinated tube reactor wrapped around a 500 W Hg lamp, allowed to overcome batch limitations paving the way for metal-free arylation reactions via phenyl cations. Derivatives 14a–g were prepared with this greener flow approach (Scheme 15) starting from mesitylene 13, and haloarenes using short irradiation times (<6 h), and a 5:1 MeCN/H2O mixture.
Scheme 15: Synthesis of biaryls 14a–g under photochemical flow conditions.
The reported results show how photochemistry hold the potential to become a green tool for the development of sustainable photochemical flow synthesis.
Hazardous chemistry by using green and sustainable continuous-flow microreactors
We have already shown how continuous-flow technology could play an important role in improving chemical processes [5,71], providing different advantages over traditional batch mode. However, the hazardous nature of some chemicals makes handling at conventional lab or industrial scale difficult. The use of microreactors and continuous-flow chemistry offers the possibility to perform reactions using dangerous or hazardous materials that cannot be used in batch mode. In other word, syntheses previously “forbidden” for safety reasons, such as those involving diazo compounds, hydrazine, azides, phosgene, cyanides and other hazardous chemicals could be performed with relatively low risk using flow technology [72-76].
Several research groups investigated this aspect, as highlighted by several available reviews [77,78]. Here we describe very recent reports with the aim to highlight the potential of flow chemistry in the field of hazardous chemistry under a greener perspective.
Diazo compounds are recognized as versatile reagents in organic synthesis. Nevertheless, diazo compounds are also considered highly energetic reagents [79,80]. For this reason, the in situ generation of such reagents has been investigated under flow conditions. Moody and co-workers reported a new method for the in situ generation of diazo compounds as precursors of highly reactive metal carbenes (Scheme 16) [81].
Scheme 16: Flow oxidation of hydrazones to diazo compounds.
As reported in Scheme 16, diazo species 18 could be generated from simple carbonyls 15 and hydrazine (16). Intermediate hydrazones 17 can be converted into the corresponding diazo compounds by oxidation using a recyclable oxidant based on N-iodo-p-toluenesulfonamide potassium salt. The possibility to regenerate a functionalized resin by simple washing with aqueous KI3/KOH solution makes the process more sustainable. This method produces KI solution as waste, and it is an alternative way for the direct oxidation of hydrazones, that often requires the use of heavy metals such as HgO, Pb(OAc)4 and AgO [82,83].
The diazo compounds could be collected as solution in dichloromethane at the output of the flow system, and obtained sufficiently pure for further use without requiring handling or isolation. Further mixing of solutions containing diazo derivatives to a solution containing a Rh(II) catalyst, and reactants such as amines, alcohols or aldehydes led to a wide range of products as reported in Scheme 17.
Scheme 17: Synthetic use of flow-generated diazo compounds.
Ley’s group developed several continuous-flow approaches for generating diazo species from hydrazones [84,85]. Under flow conditions, diazo compounds were reacted with boronic acids in order to generate reactive allylic and benzylic boronic acids further employed for iterative C–C bond forming reactions [86]. The generation of unstable diazo species was possible using a cheap, recyclable and less toxic oxidant, MnO2. The flow stream was accurately monitored by in-line FTIR spectroscopy in order to maximize the formation of the diazo compound (Scheme 18) [87].
Scheme 18: Ley’s flow approach for the generation of diazo compounds.
Starting from this initial investigation, Ley and co-workers developed an elegant application of this strategy for a sequential formation of up to three C–C bonds in sequence, by an iterative trapping of boronic acid species. The sequence starts with the reaction of diazo compound 20, generated under flow conditions, and boronic acid 19 (Scheme 19). Further sequential coupling with diazo compounds 21 and 22 led to boronates 23 or protodeboronated products 24 at the end of the sequence (Scheme 19).
Scheme 19: Iterative strategy for the sequential coupling of diazo compounds.
With the aim to exploit the versatility of this approach, Ley and co-workers reported the allylations of carbonyl electrophiles such as aldehydes using the above reported strategy for the generation of allylboronic acids. The flow protocol considers the reaction of diazo compounds 25 (generated in flow) with boronic acid 26 and aldehyde 27 (Scheme 20). By this new iterative coupling it was possible to obtain alcohols as products. The usefulness of the method was demonstrated with the preparation in good yield (60%) of a precursor of the natural product bakuchiol 28 (Scheme 20) [88].
Scheme 20: Integrated synthesis of Bakuchiol precursor via flow-generated diazo compounds.
The microreactor technology offers the advantage to handle hazardous components such as hydrazine and molecular oxygen, which represent alternative reagents for selective reduction of C=C double bonds. In fact, combination of hydrazine hydrate (N2H4·H2O) and O2 provide diimide (HN=NH) as reducing agent. Nevertheless, this strategy is rarely used in traditional batch chemistry for safety reason. Kappe and co-workers recently developed a reduction of the alkene to the corresponding alkane, by a catalyst-free generation of diimide by oxidation of hydrazine monohydrate (N2H4·H2O) with molecular oxygen [89,90]. The flow system set-up is reported in Scheme 21, and consists in a HPLC pump for delivering the alkene and hydrazine monohydrate, while O2 was delivered by a mass-flow controller (MFC) from a standard compressed-gas cylinder. After combination of the reagent streams, the resulting segmented flow was pumped through a heated residence unit (RTU) consisting in a fluorinated tube with low gas permeability (Scheme 21).
Scheme 21: Kappe’s continuous-flow reduction of olefines with diimide.
The flow system reported in Scheme 21 was able to reduce alkenes with high yields and selectivity by using residence times in the range of 10 to 30 min at 100 °C, and by employing a slight excess of hydrazine. Importantly, this strategy is compatible with sensitive functional groups such as silyl ether, halogenes, and benzyl groups. A very nice application of this approach was the highly selective reduction of artemisinic acid to dihydroartemisinic acid, which are of interest in the synthesis of the antimalarial drug artemisinin. This industrially relevant reduction was executed by using O2 at 20 bar, four residence units at 60 °C and consecutive feedings with N2H4·H2O in order to obtain full conversion in dihydroartemisinic acid (29, DHAA, Scheme 22).
Scheme 22: Multi-injection setup for the reduction of artemisinic acid.
Continuous-flow sustainable production of APIs
With the aim to demonstrate the potential of microreactor technology and flow chemistry in sustainable synthesis, recent outstanding “proof of concepts” will be described. Kobayashi and co-workers reported a multistep continuous-flow synthesis of a drug target via heterogeneous catalysis. The developed process not requiring any isolation of intermediates, separation of the catalyst or other work-up procedures can be considered sustainable [91]. The syntheses of (S)-rolipram and a γ-aminobutyric acid (GABA) derivative were accomplished. Readily available starting materials and columns containing chiral heterogeneous catalysts to produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde derivative which undergoes a Henry-type reaction with nitromethane in the first flow step (Flow I). The resulting nitroalkene undergoes an asymmetric addition catalyzed by a supported PS–(S)-pybox–calcium chloride catalyst at 0 °C using two columns (Flow II). This is the enantio-determining step of the process. The stereochemistry of the adduct can be simply switched to the opposite enantiomer, by using the enantiomeric supported catalyst PS–(R)-pybox–calcium chloride. The enantiomeric excess of the products was about 96%. Two more steps consisting in a Pd-catalyzed hydrogenation reaction and a decarboxylation (Flow III and Flow IV) led to the target (S)-rolipram in 50% overall yield. The systems was designed in order to keep the level of the palladium in solution as low as possible (<0.01 ppm).
Scheme 23: Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).
Another outstanding proof of concept, which demonstrates the potential of flow chemistry for sustainable pharmaceutical manufacturing, has been recently reported by Jensen and his research team. The research team set up a compact and reconfigurable manufacturing platform for the continuous-flow synthesis and formulation of active pharmaceutical ingredients (APIs) [92]. The “mini” plant (reported in Figure 3) was very compact in size [1.0 m × 0.7 m × 1.8 m, (W × L × H)], and low-weighing (about 100 kg) and was able to perform complex multistep synthesis, work-up procedures as well as purification operations such as crystallization. This platform was also equipped with devices for real-time monitoring and final formulation of high purity APIs. For the preparation of target molecules, commercially available starting materials were employed. The platform was tested for the production and supply of hundreds to thousands doses per day of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam and fluoxetine hydrochloride.
Remarkably, for future applications of the platform, the produced medicines also met the U.S. Pharmacopeia standards.
Figure 3: Reconfigurable modules and flowcharts for API synthesis. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).
The future use of this kind of platform would concern the “on-demand” production or the “instantaneous” production of short-lived pharmaceuticals (Figure 4). Other advantageous concerns of this reconfigurable platform are the lower production costs, the higher safety, the automation (computer controlled processes), the reduced waste (production could be done where is needed and in the right amount).
Figure 4: Reconfigurable system for continuous production and formulation of APIs. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).
Conclusion
Flow chemistry and manufacturing engineering have become largely acknowledged as viable and very often superior alternative to batch processing. Continuous-flow techniques offer increased safety, scalability, reproducibility, automation, reduced waste and costs, and accessibility to a wide range of new chemical possibilities, seldom not accessible through classic batch chemistry. All those benefits are even more noteworthy and outstanding than what they might seem, because they widely fulfil most of the green chemistry principles. In this short overview, we tried to highlight progresses and potential of flow chemistry in the field of sustainable synthesis. Thus, it is expected that flow chemistry and microreactor technology could deeply change the way to perform sustainable chemical production in the near future [93].
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How to cite this article:
Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Beilstein J. Org. Chem.2017,13, 520–542. doi:10.3762/bjoc.13.51
As an organic chemist I’m involved in the development of new sustainable synthetic methodologies for the construction of new molecules with defined stereochemistry and functional properties.
Jointly with my coworkers we are involved in three main research themes:
1. Heterosubstituted Organolithiums. We mainly explore the reactivity of lithiated 3,4,5,6-membered N,S,O-heterocycles (aziridines, azetidines, oxazetidines, thietanes, oxazolines, piperazines, morfolines) and their utility in stereoselective synthesis. Our approach is focused in establishing the chemical and configurational stability of the lithiated intermediates as well as their structure in solution by using modern spectrometric and spectroscopic techniques such as in line -IR, in line-MS, NMR and DOSY.
2. Microreactor Technology and Flow-Chemistry. With the aim to design more sustainable synthetic processes, we set up, at the Depatment of Pharmacy, a well equipped “flow chemistry laboratory” named FLAME-Lab, for the development of continuous-flow microreactor-mediated organometallic and organocatalytic synthesis in both homegenous and heterogenous conditions.
3. Molecular Dynamics. As a “curiosity driven” research activity, we investigate the dynamic behavior of small molecules that could function as molecular switches with “on-off” states and as versatile scaffolds useful in catalysis and in “dynamic-controlled and predictable reactivity”.
aDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK
bDepartment of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Via Torino 155, 30172 Venezia Mestre, Italy E-mail:selva@unive.it
Giulia Fiorani
Postdoctoral Research Fellow presso University of Oxford
Dr. Fiorani earned her PhD in Chemical Sciences from the University of Rome “Tor Vergata” (2010) on synthesis and applications of ionic liquids. After several post-doctoral experiences (University of Padua, Italy 2010-2012, Ca’ Foscari University of Venice 2012-2013), Giulia was awarded a Marie Curie Intra-European Fellow in 2014 at ICIQ (Institute of Chemical Research of Catalonia, Tarragona, Spain) working under the supervision of Prof. Arjan W. Kleij on the preparation of cyclic organic carbonates from CO2 and terpene based oxiranes. Giulia joined the Williams group in 2016 and is working on renewable based polymers.
Abstract
Dimethyl carbonate (DMC) is an environmentally sustainable compound which can be used efficiently for the upgrading of several promising renewables including glycerol, triglycerides, fatty acids, polysaccharides, sugar-derived platform molecules and lignin-based phenolic compounds. This review showcases a thorough overview of the main reactions where DMC acts as a methylating and/or methoxycarbonylating agent for the transformation of small bio-based molecules as well as for the synthesis of biopolymers. All processes exemplify genuine green archetypes since they couple innocuous reactants of renewable origin with non-toxic DMC. Each section of the review provides a detailed overview on reaction conditions and scope of the investigated reactions, and discusses the rationale behind the choice of catalyst(s) and the proposed mechanisms. Criticism and comments have been put forward on the pros and cons of the described methods and their perspectives, as well as on those studies which still require follow-ups and more in-depth analyses.
University of Oxford · Department of Chemistry · Prof. Charlotte K. Williams
United Kingdom
Polymer chemistry and catalysis applied to polymers preparation.
Mar 2016–Sep 2016
Post Doctoral Research Assistant
Imperial College London · Department of Materials · Prof. Charlotte K. Williams
United Kingdom · London, England
Polymer chemistry and catalysis applied to polymers preparation.
Mar 2014–Feb 2016
Marie Curie Intra-European Fellow
ICIQ Institute of Chemical Research of Catalonia · Prof. Arjan W. Kleij
Spain
Novel applications of renewable based molecules for the preparation of cyclic carbonate and polycarbonates (FP7-PEOPLE-2013-IEF, project RENOVACARB, Grant Agreement no. 622587).
Apr 2012–Oct 2013
Post Doctoral Research Assistant
Università Ca’ Foscari Venezia · Department of Molecular Science and Nanosystems · Prof. Maurizio Selva, Prof. Alvise Benedetti
Italy
Synthesis and characterization of luminescent Ionic Liquids.
Jan 2011–Feb 2012
Post Doctoral Research Assistant
Italian National Research Council · Institute on Membrane Technology ITM · Prof. Marcella Bonchio, Dr Alberto Figoli
Italy · Rome
Project BioNexGen – development of a new generation of membrane reactors.
Jan 2010–Dec 2010
Research Assistant
University of Padova · Department of Chemical Sciences · Dr Mauro Carraro
Italy · Padova
Hybrid nanostructures organized by hybrid ligands for the preparation of new functional materials.
Teaching experience
Sep 2016–Oct 2016
Visiting Scholar
Università degli Studi di Sassari · Department of Chemistry and Pharmacy
Italy · Sassari
10 hour course on terpene chemistry for PhD students.
Education
Nov 2006–Mar 2010
University of Rome Tor Vergata
Chemical Sciences · PhD
Italy
Oct 2004–Jul 2006
University of Rome Tor Vergata
Chemistry · Master of Science
Italy
Sep 2001–Oct 2004
University of Rome Tor Vergata
Chemistry · BSc
Italy
Other
Languages
English, Italian, Spanish
Scientific Societies
Member of the Italian Chemical Society since 2007.
Delegato per il Dipartimento all’Internazionalizzazion
Currently: Associate professor of Organic Chemistry with tenure.
Department of Molecular Sciences and Nanosystems, University Ca’ Foscari Venice.
Born in Venice in 1965. Married to Paola, two children: Alberto (2000) and Marta (2002).
Career
– 2011, was offered the senior position as Associate professor of Chemistry with Tenure at UMAss Boston.
– 2005-2014 Assistant professor of Organic Chemistry with tenure (SSD CHIM/06), University Ca’ Foscari Venice.
– 2007 Visiting scientist, University of Sydney.
– 1996-2005 Post-doctoral researcher University Ca’ Foscari Venice.
Education
– 1996 Ph.D. in Chemistry, Case Western Reserve University, Cleveland OH, USA.
– 1992 Laurea in Industrial Chemistry @ University Ca’ Foscari Venice.
Fellowships
– 2007 Endeavour Research Fellow (Austrlian Government, Department of Education, Employment and Workplace Relations) at the University of Sydney.
– 1992-1996 Fulbright Fellow (U.S. Department of State, International Educational Exchange Program) at Case Western Reserve University.
– 1993 CNR Research Fellow (1993) at Case Western Reserve University, Cleveland OH, USA.
Awards
– Ca’ Foscari Research Prize (2014, category Advanced Research).
– Royal Society of Chemistry International Journal Grants Awards (2007, 2009).
– CNR prize for research (1994).
– Outstanding teaching award CWRU (1993).
– Prize for the Laurea thesis from the Consorzio Venezia Ricerche (1992).
Editorial Board memberships
– Advisory Board of the journal “Green Chemistry” (Royal Society of Chemistry, UK).
– Editorial Advisory Board of the journal “ACS Sustainable Chemistry and Engineering” (American Chemical Society, USA).
Training and editorial activities.
– Scientific coordinator and organizer of the Summer School on Green Chemistry from 1998 to 2006 (funded by the European Commission, UNESCO, and NATO).
– Editor of the volume “Methods and Reagents for Green Chemistry” Wiley Interscience 2007.
– Editor of “Green Nanoscience”, volume 8 of the 12 volume set of the “Handbook of Green Chemistry” P. Anastas Ed., Wiley-VCH 2011.
– Author of over 60 scientific papers and chapters and of one patent in the field of organic chsmistry, with emphasis on green chemistry. Hirsch index (Scopus, Feb. 2014) = 21.
Invited talks
– Green chemistry applied to the upgrading of bio-based chemicals: towards sustainable chemical production. University of Sydney, 19 March 2014.
– Sustainable (Chemical) Solutions, Rethinking Nature in Contemporary Japan, Università Ca’ Foscari, Venezia, 25-26 February 2013
– Carbonate based ionic liquids and beyond, Green Solvents Conference, Frankfurt am Main, Dechema Gesellschaft fur Chemische Technik und Biotechnologie e. V., pp. 27, Green Solvents for Synthesis, Boppard, 8-10 Ottobre 2012
– Chemicals e Fuels da Fonti Rinnovabili, Bioforum. Biotecnologie: dove scienza e impresa si incontrano, Milano, ITER, vol. VII Edizione, Bioforum, Confindustria Venezia, 24.02.2011
– Green Chemistry for Sustainability: Teaching ionic liquids new tricks & A breath of oxygen for bio-based chemicals., Slovenian-Italian conference on Materials and Technologies for Sustainable Growth, Ajdovscina, Slovenia, 4-6 Maggio 2011
– Benign molecular design, WORKSHOP ON ECOPHARMACOVIGILANCE, Verona, 26-27 Marzo 2009
– Not merely solvents: task specific ionic liquids made by green syntheses, COIL-3 Pre-symposium workshop, Cairns, Australia, 31/05/2009
– Multiphase catalysis: a tool for green organic synthesis, Royal Australian Chemical Institute NSW Organic Chemistry Group, 28th Annual One-Day Symposium, MacQuarie University, Sydney, Australia, 5 December 2007
– Catalytic Reactions in Liquid Multiphasic Systems The acronym talk, INTAS Project on POPs, Moscow, 12-14 Giugno 2005
– Catalytic reactions in liquid multiphasic systems, Convegno: Eurogreenpol – First European Summer School on Green Chemistry of Polymers, Iasi – Rumania, 21-27 Agosto 2005
– Mechanism and Synthetic Applications of the Multiphase Catalytic Systems, International Workshop on Hazardous Halo-Aromatic Pollutants: Detoxification and Analysis, Venezia, 14-16 Maggio 2002
– The multiphase catalytic hydrodehalogenation of haloaromatics, European Summer School on Green Chemistry, Venezia, 10-15 September 2001
Academic committees
– Quality assurance board of Ca’ Foscari University
– Teaching council of the International College, Ca’ Foscari merit school.
– Academic Council of Venice International University VIU.
– Delegate for international relations of the Department of Molecular Sciences and Nanosystems.
– Scientific board of Edizioni Ca’ Foscari – Digital Publishing.
– Research committee of the Department of Molecular Sciences and Nanosystems.
– Teaching board of the Doctorate in Chemical Sciences (2012-2014).
– Teaching board of the degree course Bio- and Nanomaterials science and Technology.
– Erasmus selection committee.
– Overseas selection committee
– Post-doctoral selection committees.
Referee, reviewer, and examiner for:
– Valutazione della Qualità della Ricerca (VQR), ANVUR
– Progetti di Rilevante Interesse Nazionale (PRIN), MIUR
– American Chemical Society Petroleum Research Fund (USA).
– Ph.D. Theses, University of Nottingham (UK) and University of Sydney (Aus).
– European Science Foundation
– Journals published by: Royal Society of Chemistry, American Chemical Society, Wiley, Elsevier, Springer, IUPAC
Funded projects
– Coordinator of a Cooperlink project funded by the Italian Ministry for Education, University and Research, 2011, 12 months, entitled “Joint PhD between Università Ca’ Foscari and the University of Sydney: integration of experiment and theory towards the green synthesis of self-assemblying materials and the use of renewable resources”.
– Participant in the Project of Relevant National Interest (PRIN) “Green organic syntheses mediated by new catalytic systems”, 2010, 24 months.
– Tutor of a PhD scholarship funded by the Regione Veneto through the European Social Fund, entitled “Organic syntheses of active principles and chemicals for the pharmaceutical industry using green solvents “ 2009-2011, 36 months.
– Principal Scientist of a post-doctoral fellowship funded by the Regione Veneto through the European Social Fund entitled “New reduced environmental impact chemical synthesesfor the preparation of monomers for advanced polymers, April 2012, 12 months.
– Principal Scientist of a post-doctoral fellowship funded by the Regione Veneto through the European Social Fund entitled “Environmentally compatible chemical syntheses of fluorinated monomers for advanced materials” April 2013, 12 months.
– Principal Scientist of a post-doctoral fellowship funded by the Regione Veneto through the European Social Fund entitled “Valorisation of renewable substrates from biomass, such as glycerol and its derivatives, using green chemistry” April 2014, 12 Months
– Principal Scientist of a research contract between the chemical company Aussachem (Santandrà di Povegliano, TV), entitled: “Green Chemistry for the valorisation of glycerol and of its derivatives: new ecofriendly products” December 2013.
International collaborations and networks
– Teaching and research collaboration with the University of Sydney, School of Chemistry Laboratory for Advanced Catalysis and Sustainability prof. Thomas Maschmeyer. A joint PhD program in Chemistry was established and is currently running. Up to date 5 students (3 outgoing, 2 incoming) have benefited from this agreement The first joint PhD has been awarded in December 2013 (Marina Gottardo). Four joint publications have already been produced, and others are in preparation.
– Research collaboration with the Queen’s University of Belfast, Queen’s University Ionic Liquids Laboratory, prof. Kenneth R. Seddon, for the exchange of Erasmus students who carry out research towards their MS thesis. Currently the student Riccardo Zabeo is in Belfast w research towards his thesis, tutor dr. Perosa. Previously, the PhD student Marco Noè (tutor Perosa) spent 4 months in Belfast carrying out research that was published on an international journal.
– In the framework of a scientific collaboration with prof. Janet Scott of the Centre for Sustainable Chemical Technologies of the University of Bath, an Erasmus Mundus Joint Doctorate project entitled “Bio-Based Chemicals and Materials” was submitted in 2011 and was evaluated positively albeit not funded. Nonetheless the collaboration has already produced a joint publication.
– Summer School on Green Chemistry Network. Following the 8 editions of the “Summer school on Green Chemistry” (1998-2005) coordinated and organized by the applicant, a Green Chemistry Network was initiated that involves the following institutions: RWTH-Aachen, QUB-QUILL Belfast, UNSW-Sydney, ARKEMA-France, University of Groningen-NL, Dow Europe-CH, Universite de Poitiers, ETH-Zurich, TU-Darmstadt, Universidad Politecnica de Valencia, Delft University of Technology, TU-Munchen.
– Since 1993 Alvise Perosa is a member of the American Chemical Society.
MoU’s and International agreements
– Alvise Perosa started the Joint PhD degree in Chemistry between the University of Sydney and the Università Ca’ Foscari Venezia.
– Erasmus, Alvise Perosa is the contact person for the following Erasmus agreements: Universitat Autonoma de Barcelona, Universidad Rey Juan Carlos, Universidad Rovira i Virgili,UNIVERSITE D’AVIGNON ET DES PAYS DE VAUCLUSE, ARISTOTLE UNIVERSITY THESSALONIKI, Queen’s University of Belfast.
Academic tutoring
– Marco Noè (PhD 2009-11: 24° cycle)
– Jessica N. G. Stanley (PhD cotutelle University of Sydney, 2012-2014)
– Alessio Caretto (PhD 2012-14: 27° cycle)
– Manuela Facchin (PhD 2014-16: 29° cycle)
– Tutor if BSc and MSc level students of the degree corse in Sustainable Chemistry and Technologies and, and of the MSc degree course in Science and Technolgy of Bio- and Nanomaterials.
Teaching
– 1992-94, Case Western Reserve University, Chemistry BS: Organic Chemistry 1 Laboratory (teaching assistant award in 1993).
– 2006-09, Università Ca’ Foscari Venezia, degree course in Chemical Sciences and Technologies for Cultural Heritage Conservation and Restoration: Organic Chemistry Laboratory.
– 2006-07, Università Ca’ Foscari Venezia, degree course in Chemistry, Industrial Chemistry, Materials Chemistry, Environmental Sciences: Organic Chemistry 1 and Laboratory for part-time students.
– 2005-06, 2011-12, 2012-13, 2013-14: Università Ca’ Foscari Venezia, degree course in Chemistry and in sustainable Chemical Technologies: Organic Chemistry 2 and Laboratory.
– 2011-12, Università Ca’ Foscari Venezia, degree course in Chemistry and in sustainable Chemical Technologies: Green Organic synthesis Laboratory.
– 2012-13, 2013-14 Università Ca’ Foscari Venezia, MS degree course in Bio e Nanomaterials: Colloids and Interfaces.
– 2013-14 Università Ca’ Foscari Venezia, Graduate course in Organic syntheses from renewable building blocks.
An efficient green protocol for the synthesis of tetra-substituted imidazoles catalyzed by zeolite BEA: effect of surface acidity and polarity of zeolite
Jenifer J Gabla has obtained her MSc degree in Organic Chemistry, in the year 2013 from Uka Tarsadia University, Bardoli, Gujarat. She is currently pursuing her PhD in the area of solid acid catalyzed multicomponent reactions for the synthesis of biologically active drug molecules, at Applied Chemistry Department (ACD), S. V. National Institute of Technology (SVNIT) under the guidance of Kalpana Maheria, Assistant Professor & Head, ACD, SVNIT, Surat, Gujarat, India. Her research focuses on development of novel zeolite based catalytic materials and exploring their utility in the green process development for the synthesis of medicinal compounds. She has presented her research in several national and international conferences.
aApplied Chemistry Department, S. V. National Institute of Technology, Ichchhanath, Surat – 395007, India E-mail:kcmaheria@gmail.com
bMandvi Science College, Mandvi – 394160, Surat, India
Abstract
In the present study, the catalytic activity of various medium (H-ZSM-5) and large pore (H-BEA, H-Y, H-MOR) zeolites were studied as solid acid catalysts. The zeolite H-BEA is found to be an efficient catalyst for the synthesis of 1-benzyl-2,4,5-triphenyl-1H-imidazoles through one-pot, 4-component reaction (4-CR) between benzil, NH4OAc, substituted aromatic aldehydes and benzyl amine. The hydrophobicity, Si/Al ratio and acidic properties of zeolite BEA were well improved by controlled dealumination. The synthesized materials were characterized by various characterization techniques such as XRD, ICP-OES, BET, NH3-TPD, FT-IR, pyridine FT-IR, 27Al and 1H MAS NMR. It has been observed that the dealumination of the parent zeolite H-BEA (12) results in the enhanced strength of Brønsted acidity up to a certain Si/Al ratio which is attributed to the inductive effect of Lewis acidic EFAl species, leading to the higher activity of the zeolite BEA (15) catalyst towards the synthesis of 1-benzyl-2,4,5-triphenyl-1H-imidazoles under thermal solvent-free conditions with good to excellent yields. Using the present catalytic synthetic protocol, diverse tetra-substituted imidazoles, which are among the significant biologically active scaffolds, were synthesized in high yield within a shorter reaction time. The effect of polarity, surface acidity and extra framework Al species of the catalysts has been well demonstrated by means of pyridine FT-IR, and 27Al and 1H MAS NMR. The solvent-free synthetic protocol makes the process environmentally benign and economically viable.
S. V. National Institute of Technology, Ichchhanath, Surat
Mandvi Science College, Mandvi – 394160, Surat, India
////////
DISCLAIMER
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
K. P. Rakesh, C. S. Shantharam, M. B. Sridhara, H. M. Manukumar, Hua-Li Qin
The benzisoxazole analogs represent one of the privileged structures in medicinal chemistry and there has been an increasing number of studies on benzisoxazole-containing compounds.
Benzisoxazole: a privileged scaffold for medicinal chemistry
aDepartment of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, PR China E-mail:qinhuali@whut.edu.cn Fax: +86 27 87749300
bDepartment of Chemistry, Pooja Bhagavath Memorial Mahajana Education Centre, Mysuru-570016, India E-mail:shantharamcs@gmail.com Tel: +91 8904386977
cDepartment of Chemistry, Rani Channamma University, Vidyasangama, Belagavi-591156, India
dDepartment of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysuru-570006, India
Abstract
The benzisoxazole analogs represent one of the privileged structures in medicinal chemistry and there has been an increasing number of studies on benzisoxazole-containing compounds. The unique benzisoxazole scaffold also exhibits an impressive potential as antimicrobial, anticancer, anti-inflammatory, anti-glycation agents and so on. This review examines the state of the art in medicinal chemistry as it relates to the comprehensive and general summary of the different benzisoxazole analogs, their use as starting building blocks of multifarious architectures on scales sufficient to drive human drug trials. The number of reports describing benzisoxazole-containing highly active compounds leads to the expectation that this scaffold will further emerge as a potential candidate in the field of drug discovery.
Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, PR China
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
† CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
Cross-coupling of (hetero)arylthiols with arylzinc reagents via C–S cleavage was performed under transition-metal-free conditions. The reaction displays a wide scope of substrates and high functional-group tolerance. Electron-rich and -deficient (hetero)arylthiols and arylzinc reagents can be employed in this transformation. Mg2+ and Li+ ions were demonstrated to facilitate the reaction.
In summary, we developed a transition-metal-free coupling reaction of (hetero)arylthiols with arylzinc reagents to form bi(hetero)aryls. The reaction exhibited wide substrate scope and good compatibility of functional groups. Electron-rich and -poor aryl or heteroaryl thiols can be converted. Various arylzinc reagents, including electron-rich and electron-poor reagents, can be employed as the coupling partners. Preliminary mechanistic studies suggest a nucleophilic aromatic substitution pathway, and Mg2+ and Li+ ions play important roles in the process of reaction. This study provides an example of S2– as a leaving group in an aromatic system and an effective methodology for the synthesis of bi(hetero)aryls including pharmaceutical molecules without transition-metal impurities.
Zhong-Xia WANG
Department：
Department of Chemistry
Mailing Address：
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Rd, Hefei, Anhui, 230026, PR China
Zhong-Xia Wang is a professor in the Department of Chemistry at the University of Science and Technology
of China. He received his BS degree (1983) and MS degree (1986) from Nankai University,
and PhD degree (1997) from the University of Sussex, UK. Since July 1986, Wang has been working
at the University of Science and Technology of China (USTC) successively as Assistant,
Lecturer, Associate Professor, and Professor. From Aug. 1993 to Oct. 1996, he pursued his doctoral
studies at the University of Sussex, UK, and from Oct. 1999 to Oct. 2000, he was a Research Associate
at the Chinese University of Hong Kong.
学 系Department of Chemistry
Predicts
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
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学 系
