AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
Dec 202016
 
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2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester
2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d‘éthyle
Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate
Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat
1206769-44-9
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)
AGN-PC-0JIRMK
AKOS016034964
ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate
MWt310.819
MFC16H23ClN2O2
Image result for MOM CAN TEACH YOU NMRNMR IS EASY
1H NMR PREDICT
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ACTUAL VALUES……..1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
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13C NMR PREDICT
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ACTUAL VALUES……..13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
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Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

Molbank 2009 m607 i001
Melting Point: 56oC.
EI-MS m/z (rel. int. %): 311 (100) [M+1]+, 236(40), 197(60), 154(45).
IR ν max (KBr) cm-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).
1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
Elemental analysis: Calculated for C16H23ClN2O2: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.
Molbank 2009, 2009(3), M607; doi:10.3390/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

1Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India
2Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India
*Author to whom correspondence should be addressed.
Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009
Bijay K Mishra

Professor at Sambalpur University, Chemistry Department

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, 1H NMR, 13C NMR and Mass spectroscopic data are reported.

 

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CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C

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Synthesis of a Precursor to Sacubitril Using Enabling Technologies

 flow synthesis, SYNTHESIS  Comments Off on Synthesis of a Precursor to Sacubitril Using Enabling Technologies
Aug 112016
 

 

Abstract Image

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

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

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

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
Novartis Pharma AG, Postfach, 4002 Basel, Switzerland
Org. Lett., 2015, 17 (21), pp 5436–5439
DOI: 10.1021/acs.orglett.5b02806, http://pubs.acs.org/doi/10.1021/acs.orglett.5b02806
Figure

LCZ696 (sacubitril/valsartan) is a first-in-class combination of the angiotensin II receptor-blocker valsartan and the neprilysin inhibitor sacubitril. A recent head-to-head comparison of LCZ696 with enalapril in a double-blind trial was stopped early because the boundary for an overwhelming benefit with LCZ696 was crossed.As a result of this, LCZ696 was reviewed under the FDA’s priority review program and was granted approval on the July 7, 2015 to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II–IV) and reduced ejection fraction.

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively

Figure

(2R, 4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 3

To a stirred solution of (2R, 4S)-5-(4-Biphenylyl)-2-methyl-4-(tert-butylsulfinylamino)valeric acid 14 (50.0 mg, 134 μmol) in absolute ethanol (0.4 mL) at 0 °C was added thionyl chloride (20 μL, 268 μmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed to yield 46.0 mg (99%) of titled compound 3 as a white solid.

1 H NMR (600 MHz, DMSO-d6) δ 8.17 (br. s, 3H), 7.66 (dd, J = 8.0, 7.4 Hz, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (2 H, t, J = 7.4 Hz, H15, 2H), 7.36 (1 H, d, J = 8.0 Hz, H15), 3.99 (q, J = 7.1 Hz, H18), 3.42 – 3.36 (m, H4, 1H), 3.04 (dd, J = 13.8, 5.5 Hz, 1H), 2.81 (dd, J = 13.8, 8.1 Hz, 1H), 2.77 – 2.70 (m, 1H), 1.86 (ddd, J = 14.3, 9.1, 5.0 Hz, 1H), 1.59 (ddd, J = 13.8, 8.1, 5.4 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.1 Hz, 3H).

13C NMR (151 MHz, CDCl3) δ 174.7, 139.7, 138.7, 135.5, 130.0, 129.0, 127.4, 126.8, 126.5, 60.1, 50.4, 38.1, 35.5, 35.0, 17.5, 13.9.

HRMS (ESI+ , m/z [M+H]+ ) Calcd for C20H26NO2 312.1964; found 312.1967;

HPLC. 97:3 d.r. (Daicel Chiralpak AD-H column; isocratic n-hexane/ethanol/methanol/trimethylamine 80/10/10/0.2; 40 o C; flow rate = 0.8 mL min-1 ; λ = 254 nm; run time = 23 mins; tR (2R, 4S) 97.07%; tR (2S,4R) 0.21%; tR (2S, 4S) 2.32%; tR (2R,4R) 0.40%)

 

13C NMR Ethyl (2R,4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoate hydrochloride 3

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////////////Synthesis, Precursor,  Sacubitril, Enabling Technologies, flow synthesis, valsartan, LCZ69

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Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

 SYNTHESIS  Comments Off on Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis
Jul 292016
 

 

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01600F, Paper
Li Chen, Jinmo Zhao, Sivaram Pradhan, Bruce E. Brinson, Gustavo E. Scuseria, Z. Conrad Zhang, Michael S. Wong
The nonselective nature of glucose pyrolysis chemistry can be controlled by preventing the sugar ring from opening and fragmenting.

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

*Corresponding authors
aDepartment of Chemical and Biomolecular Engineering, Rice University, Houston, USA
E-mail: mswong@rice.edu
bDepartment of Chemistry, Rice University, Houston, USA
cDalian National Laboratory of Clean Energy, Dalian Institute of Chemical Physics, Dalian, China
E-mail: zczhang@dicp.ac.cn
dDepartment of Civil and Environmental Engineering, Rice University, Houston, USA
eDepartment of Materials Science and NanoEngineering, Rice University, Houston, USA
Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01600F

The selective production of platform chemicals from thermal conversion of biomass-derived carbohydrates is challenging. As precursors to natural products and drug molecules, anhydrosugars are difficult to synthesize from simple carbohydrates in large quantities without side products, due to various competing pathways during pyrolysis. Here we demonstrate that the nonselective chemistry of carbohydrate pyrolysis is substantially improved by alkoxy or phenoxy substitution at the anomeric carbon of glucose prior to thermal treatment. Through this ring-locking step, we found that the selectivity to 1,6-anhydro-β-D-glucopyranose (levoglucosan, LGA) increased from 2% to greater than 90% after fast pyrolysis of the resulting sugar at 600 °C. DFT analysis indicated that LGA formation becomes the dominant reaction pathway when the substituent group inhibits the pyranose ring from opening and fragmenting into non-anhydrosugar products. LGA forms selectively when the activation barrier for ring-opening is significantly increased over that for 1,6-elimination, with both barriers affected by the substituent type and anomeric position. These findings introduce the ring-locking concept to sugar pyrolysis chemistry and suggest a chemical-thermal treatment approach for upgrading simple and complex carbohydrates.

////////Ring-locking ,  selective anhydrosugar, carbohydrate pyrolysis, synthesis

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Synthesis and Low Temperature Spectroscopic Observation of 1,3,5-Trioxane-2,4,6-Trione: The Cyclic Trimer of Carbon Dioxide

 spectroscopy, SYNTHESIS  Comments Off on Synthesis and Low Temperature Spectroscopic Observation of 1,3,5-Trioxane-2,4,6-Trione: The Cyclic Trimer of Carbon Dioxide
Jun 172016
 
Abstract Image
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1,3,5-Trioxane-2,4,6-trione (cyclic trimer of CO2) is the product of a four-step synthesis: chlorination of isobutyraldehyde; cyclotrimerization of 2-chloro-2-methylpropanal; dehydochlorination of 2,4,6-tris(2-chloropropan)-2-yl-1,3,5-trioxane; ozonolysis at −80 °C of 2,4,6-tri(propan-2-ylidene)-1,3,5-trioxane. This trioxane-trione is detected in solution at temperatures between −80 to −40 °C, and its conversion to CO2 is monitored by 13C NMR and FTIR. The CO2 trimer has a half-life of approximately 40 min at −40 °C.

As a product of combustion and respiration whose accumulation in the atmosphere has become a cause for significant concern, carbon dioxide has been the subject of much research directed at its reutilization. Various approaches toward this CO2 reutilization goal have been described in excellent reviews over the past two decades.Important processes involve reduction with hydrogen,coupling with other small molecules, incorporation into polymers and artificial photosynthesis. The main products include fuels, solvents, chemical intermediates and polymers.
The efficiency of these commercial processes in terms of reagent usage is relatively low with respect to the fraction of CO2 incorporated into the product; the highest being for urea (57%), and decreasing for salicylic acid (36%) and methanol (10%). This could be raised to 100% if a CO2 self-fixation chemistry could be developed. Ideally with a sufficient input of energy, CO2 would react with itself to yield a liquid or solid product from which this energy could be extracted when needed for useful work. Such chemistry has been the subject of theoretical calculation for structures representing the linear polymer and cyclic oligomers of CO2.
With respect to thermodynamic stability, the cyclic trimer has been described as “feasible” although energetically less stable than three CO2 molecules by 27 kJ/mol per CO2 unit.(10)Regarding kinetic stability of the cyclic trimer toward fragmentation to CO2, calculated barriers for this decomposition have ranged from activation energies of 61 to 172 kJ/mol depending on the computational method with calculated half-lives ranging from days to milliseconds at ambient conditions and substantially longer at lower temperatures.
 The cyclic trimer of CO2has also been proposed as a low-energy intermediate in the transformation of CO2 to an extended solid.
The formation of an orthocarbonate extended covalent structure of interconnected six-membered rings was predicted by model calculation with the finding of a stabilization energy that increased with molecular size. Later experimental work found under extreme pressure/temperature (40 GPa/1800 K), CO2 will transform to a metastable extended solid which has been characterized as a Phase V form of CO2 with a sigma bonded quartz-like structure.
 It has also been proposed that sorption of CO2 into the isolated nanoscale confined spaces of sulfur- or nitrogen-treated porous carbon at 30 bar pressure can produce a polymeric structure of carbon dioxide as has been reported for other molecules in nanoconfined spaces.
The 1,3,5-trioxane-2,4,6-trione structure of the CO2 cyclic trimer, 1, may represent an important intermediate or product in the self-fixation of gaseous CO2. Theoretical studies on this molecule have indicated a possibility of kinetic stability at room temperature and as well as a possibility for it to be thermodynamically feasible.To date, no experimental evidence has been reported for its existence. The objective of this work is to synthesize compound 1 and to make an assessment of its stability. The approach is that of a model compound synthesis where the trioxane ring is first generated from substituted aldehydes and then the peripheral carbonyl structures are incorporated at low temperature in the final step. As will be shown, compound 1does not possess the stability for facile isolation and storage

Synthesis and Low Temperature Spectroscopic Observation of 1,3,5-Trioxane-2,4,6-Trione: The Cyclic Trimer of Carbon Dioxide

Chemistry Division, Naval Research Laboratory, Washington, D. C. 20375, United States
§Mettler-Toledo AutoChem, Inc., Columbia, Maryland 21046, United States
J. Org. Chem., Article ASAP
DOI: 10.1021/acs.joc.6b00647
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Figure
 Figure

2,4,6-Tri(propan-2-ylidene)-1,3,5-trioxane (2a)

 crude product was purified by vacuum distillation (10 mmHg at 185 °C) to yield the title compound as a colorless liquid (2.32 g, 71%). 1H NMR (CDCl3, 300 MHz) δ = 1.63 (s, 18 H,) ppm; 13C NMR (CDCl3, 75 MHz) δ = 15.0, 86.9, 144.7 ppm; IR νmax (liquid) 2991, 2919, 2863, 1726, 1284, 1212 cm–1; UV (CH3CN) λmax = 210 nm (ε = 1.57 × 104 L/mol·cm); HRMS (ESI) m/z calcd for C12H18O3 [M + H]+ 211.1334, found 211.1342. Anal. Calcd for C12H18O3: C, 68.54; H, 8.68; O, 22.83. Found: C, 68.48; H; 8.76.

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/////////Synthesis, Low Temperature,  Spectroscopic Observation, of 1,3,5-Trioxane-2,4,6-Trione,  The Cyclic Trimer,  Carbon Dioxide

 

EXTRAS

1,3,5-Trioxane

 

1,3,5-Trioxane, sometimes also calledtrioxane or trioxin, is a chemicalcompound with molecular formula CHO. It is a white solid with a chloroform-like odor. It is a stable cyclictrimer of formaldehyde, and one of the three trioxaneisomers; its molecular backbone consists of a six-membered ring with three carbon atoms alternating with three oxygen atoms. Thus, cyclotrimerization of formaldehyde affords 1,3,5-trioxane:

The mechanism can be explained in an acidic catalyzed reaction:

Uses

In chemistry, 1,3,5-trioxane is used as a stable, easily handled source of anhydrousformaldehyde. In acidic solutions, it decomposes to generate three molecules of formaldehyde. It may also be used in polymerization to form acetal resins, such aspolyoxymethylene plastic. It is a feedstock for certain types of plastic, is an ingredient in some solid fuel tablet formulas, and is used in chemical laboratories as a stable source of formaldehyde.

Trioxane is combined with hexamine and compressed into solid bars to makehexamine fuel tablets, used by the military and outdoorsmen as a cooking fuel.

1,3,5-Trioxane is a mortician‘s restorative chemical that maintains the corpse’s contours after postmortem tissue constriction.

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

 PROCESS, spectroscopy, SYNTHESIS  Comments Off on Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process
Jun 032016
 
Abstract Image

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

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

Zhiguo J. Song*et al
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00141
Publication Date (Web): May 25, 2016
Copyright © 2016 American Chemical Society
Benzofurans are important building blocks for the synthesis of biologically active compounds in the pharmaceutical industry and compound 3 has been an important intermediate in Merck’s hepatitis C program.(1, 2)

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

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

19F NMR (376 MHz DMSO-d6) δ 109.9

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

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

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

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

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

    (e) McComas, C. C.,Liverton, N. J., Habermann, J., Koch, U., Narjes, F., Li, P., Peng, X., Soll, R., Wu, H., Palani, A., He, S.,Dai, X., Liu, H., Lai, Z., London, C., Xiao, D., zorn, N., and Nargund, R. WO 2013033971.

  2. He, S.; Li, P.; Dai, X.; McComas, C. C.; Du, C.; Wang, P.; Lai, Z.; Liu, H.; Yin, J.; Bulger, P. G.; Dang, Q.;Xiao, D.; Zorn, N.; Peng, X.; Nargund, R. P.; Palani, A. Tetrahedron Lett. 2014, 55, 22122216, DOI: 10.1016/j.tetlet.2014.02.051

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

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Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

 flow synthesis  Comments Off on Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor
May 312016
 
image file: c6re00059b-f1.tif

 

 

React. Chem. Eng., 2016, Advance Article
DOI: 10.1039/C6RE00059B, Paper
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Nicholas Holmes, Geoffrey R. Akien, A. John Blacker, Robert L. Woodward, Rebecca E. Meadows, Richard A. Bourne
Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.

Paper

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

*Corresponding authors
aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: r.a.bourne@leeds.ac.uk
bDepartment of Chemistry, Faraday Building, Lancaster University, Lancaster, UK
cSchool of Chemical and Process Engineering, University of Leeds, Leeds, UK
dAstraZeneca Pharmaceutical Development, Silk Road Business Park, Macclesfield, UK
React. Chem. Eng., 2016, Advance Article

DOI: 10.1039/C6RE00059B

http://pubs.rsc.org/en/Content/ArticleLanding/2016/RE/C6RE00059B#!divAbstract

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Scheme 1 Synthesis of the model acrylamide 6 via the β-chloroamide 5 intermediate.

image file: c6re00059b-s1.tif

 

Scheme 2 Proposed mechanisms to dimers 8a and 8b. The observation of a peak corresponding to 7suggested a Rauhut–Currier mechanism to 8b but subsequent LC-MS-MS analysis showed the major dimer to most likely be 8a. All observed peaks from offline LC-MS are displayed.

image file: c6re00059b-s2.tif

 

 

///////Self-optimisation, synthesis, EGFR kinase inhibitor, AZD9291,  automated flow reactor

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Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

 spectroscopy, SYNTHESIS  Comments Off on Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation
Mar 312016
 

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC00157B, Paper
Hamideh Ahankar, Ali Ramazani, Katarzyna Slepokura, Tadeusz Lis, Sang Woo Joo
In this study, we reported a simple and efficient route for the one-pot sonochemical synthesis of substituted 3-pyrrolin-2-ones by citric acid as an additive.

Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

The ultrasound-promoted one-pot multicomponent synthesis of substituted 3-pyrrolin-2-ones using citric acid as a green additive in a green solvent is reported. Citric acid catalyzed the reaction efficiently without the need for any other harmful organic reagents. Clean reaction profile, easy work-up procedure, excellent yields and short reaction times are some remarkable features of this method. The utilization of ultrasound irradiation makes this method potentially very useful, fast, clean and convenient.

Synthesis of pyrrolidinone derivatives from aniline, an aldehyde and diethyl acetylenedicarboxylate in an ethanolic citric acid solution under ultrasound irradiation

*Corresponding authors
aDepartment of Chemistry, University of Zanjan, P O Box 45195-313, Zanjan, Iran
E-mail: aliramazani@gmail.com
bFaculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland
cSchool of Mechanical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
E-mail: swjoo@yu.ac.kr
Green Chem., 2016, Advance Article

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00157B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract
DOI: 10.1039/C6GC00157B

Ethyl 4-hydroxy-5-oxo-1,2-diphenyl-2,5-dihydro-1H-pyrrole-3-carboxylate
ethyl 4-hydroxy-5-oxo-1,2-diphenyl-2,5-dihydro-1H-pyrrole-3-carboxylate
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//////Synthesis, pyrrolidinone derivatives, aniline,  aldehyde,  diethyl acetylenedicarboxylate,  ethanolic citric acid solution,  ultrasound irradiation

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Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin

 PROCESS, spectroscopy, SYNTHESIS  Comments Off on Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin
Mar 212016
 

 

Green Chem., 2016, 18,1807-1818
DOI: 10.1039/C6GC00090H, Paper
Elisabetta Zerazion, Roberto Rosa, Erika Ferrari, Paolo Veronesi, Cristina Leonelli, Monica Saladini, Anna Maria Ferrari
LCA of the synthesis of curcumin and its direct conventional and microwave assisted extractions fromCurcuma longa L. were compared.

Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin

Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin

*Corresponding authors
aDipartimento di Scienze e Metodi dell’Ingegneria, Università degli Studi di Modena e Reggio Emilia, via Amendola 2, 42100 Reggio Emilia, Italy
bDipartimento di Ingegneria “Enzo Ferrari”, Università degli Studi di Modena e Reggio Emilia, via Pietro Vivarelli 10, 41125 Modena, Italy
E-mail: roberto.rosa@unimore.it
Fax: +390592056243
Tel: +390592056224
c
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41125 Modena, Italy
Green Chem., 2016,18, 1807-1818

DOI: 10.1039/C6GC00090H

Natural compounds represent an extremely wide category to be exploited, in order to develop new pharmaceutical strategies. In this framework, the number of in vitro, in vivo and clinical trials investigating the therapeutic potential of curcumin is exponentially increasing, due to its antioxidant, anti-inflammatory and anticancer properties. The possibility to obtain this molecule by both chemical synthesis and extraction from natural sources makes the environmental assessments of these alternative production processes of paramount importance from a green chemistry perspective, with the aim, for both industries and academia, to pursue a more sustainable development. The present work reports detailed and quantitative environmental assessments of three different curcumin production strategies: synthesis, conventional Soxhlet-based extraction (CE) and microwave-assisted extraction (MAE). The chemical synthesis of curcumin, as recently optimized by the authors, has been firstly evaluated by using the EATOS software followed by a complete “cradle to the grave” study, realized by applying the Life Cycle Assessment (LCA) methodology. The life cycles of CE and MAE were then similarly assessed, considering also the cultivation of Curcuma longa L., the production of the dried rhizomes as well as their commercialization, in order to firstly investigate the widely claimed green character of MAE with respect to more conventional extraction procedures. Secondly, the results related to the two different extraction strategies were compared to those obtained by the chemical synthesis of curcumin, with the aim to determine its greenest preparation procedure among those investigated. This work represents the first example of an environmental assessment comparison between different production strategies of curcumin, thus smoothing the way towards the highly desirable establishment of environmentally friendly rankings, comprising all the existing alternatives to the chemical synthesis of a target chemical compound.

/////Phytochemical compounds,  synthesis,  extraction, curcumin

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Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

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Jan 052016
 

 

Abstract Image

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

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

 

1  Diphenhydramine Hydrochloride

Figure
Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Figure
Scheme 2. Continuous Flow Synthesis of Olanzapine
Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.
In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd2dba3 as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H2O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et3SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.
The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)4 as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

 

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00325
Publication Date (Web): November 26, 2015
Copyright © 2015 American Chemical Society

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

Riccardo Porta

Riccardo Porta

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

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Synthesis of Phospholipopeptides

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Jun 102015
 

thumbnail image: Synthesis of Phospholipopeptides

Synthesis of Phospholipopeptides

A crosslinking approach for the synthesis of phospholipopeptides under mild conditions

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http://www.chemistryviews.org/details/news/7984971/Synthesis_of_Phospholipopeptides.html

Bonan Li and Jun F. Liang, Stevens Institute of Technology, Hoboken, NJ, USA, report an approach to synthesize phospholipopeptides. They use a crosslinker with a thiol-reactive maleimide and an amine-reactive N-hydroxysuccinimide ester (pictured). Hence, the molecule is able to link the thiol group of the amino acid cystein in the peptide and the amine group of the phospholipid (phosphatidylamine).

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