Improving the efficiency of the Diels-Alder process by using flow chemistry and zeolite catalysis

• Improving the efficiency of the Diels-Alder process by using flow chemistry and zeolite catalysis
• Green Chem., 2017, Advance Article
  DOI: 10.1039/C6GC02334G, Paper

  S. Seghers, L. Protasova, S. Mullens, J. W. Thybaut, C. V. Stevens
  The industrial application of the Diels-Alder reaction for the synthesis of (hetero)cyclic compounds constitutes an important challenge. To tackle the reagent instability problems and corresponding safety issues, the use of a high-pressure and zeolite catalysed microreactor process is presented.

The industrial application of the Diels–Alder reaction for the atom-efficient synthesis of (hetero)cyclic compounds constitutes an important challenge. Safety and purity concerns, related to the instability of the polymerization prone diene and/or dienophile, limit the scalability of the production capacity of Diels–Alder products in a batch mode. To tackle these problems, the use of a high-pressure continuous microreactor process was considered. In order to increase the yields and the selectivity towards the endo-isomer, commercially available zeolites were used as a heterogeneous catalyst in a microscale packed bed reactor. As a result, a high conversion (≥95%) and endo-selectivity (89:11) were reached for the reaction of cyclopentadiene and methyl acrylate, using a 1:1 stoichiometry. A throughput of 0.87 g h⁻¹during at least 7 h was reached, corresponding to a 3.5 times higher catalytic productivity and a 14 times higher production of Diels–Alder adducts in comparison to the heterogeneous lab-scale batch process. Catalyst deactivation was hardly observed within this time frame. Moreover, complete regeneration of the zeolite was demonstrated using a straightforward calcination procedure

Improving the efficiency of the Diels–Alder process by using flow chemistry and zeolite catalysis

S. Seghers,^a   L. Protasova,^b   S. Mullens,^b  J. W. Thybaut^c and   C. V. Stevens*^a  

*

Corresponding authors

^a

SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
E-mail: chris.stevens@ugent.be

^b

VITO, Vlaamse Instelling voor Technologisch Onderzoek, Boeretang 200, 2400 Mol, Belgium

^c

Laboratory for Chemical Technology, Department of Chemical Engineering and Technical Chemistry, Faculty of Engineering and Architecture, Ghent University, Technologiepark 914, 9052 Ghent, Belgium

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02334G
http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02334G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

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A robust and recyclable polyurea-encapsulated copper(I) chloride for one-pot ring-opening/Huisgen cycloaddition/CO2 capture in water

 

 

 

 

 

Green Chem., 2016, 18,6357-6366
DOI: 10.1039/C6GC01956K, Paper

Yun Chen, Wei-Qiang Zhang, Bin-Xun Yu, Yu-Ming Zhao, Zi-Wei Gao, Ya-Jun Jian, Li-Wen Xu
One-pot ring-opening/Huisgen cycloaddition reactions combined with CO₂ capture were carried out successfully in the presence of polyurea-encapsulated CuCl.

A robust and recyclable polyurea-encapsulated copper(I) chloride for one-pot ring-opening/Huisgen cycloaddition/CO2 capture in water

A robust and recyclable polyurea-encapsulated copper(I) chloride for one-pot ring-opening/Huisgen cycloaddition/CO2 capture in water
Yun Chen,a Wei-Qiang Zhang,a Bin-Xun Yu,a Yu-Ming Zhao,a Zi-Wei Gao,*a Ya-Jun Jiana and Li-Wen Xu*ab
*Corresponding authors
aKey Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education (MOE) and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710062, P. R. China
E-mail: liwenxu@hznu.edu.cn, zwgao@snnu.edu.cn
bKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, No 1378, Wenyi West Road, Science Park of HZNU, Hangzhou 311121, P. R. China
Green Chem., 2016,18, 6357-6366
DOI: 10.1039/C6GC01956K

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01956K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

 

Multicomponent ring-opening/Huisgen cycloaddition reactions combined with CO₂ capture with a polyurea-encapsulated copper salt as a catalyst that in situ formed from simple CuCl and soluble polyurea during the reaction were carried out successfully for the synthesis of β-hydroxytriazoles under exceptionally mild conditions, in which the polyurea-encapsulated copper(I) chloride proved to be a robust and recyclable catalyst system with high yields as well as excellent chemoselectivity in this reaction.

 

 

////////A robust and recyclable,  polyurea-encapsulated, copper(I) chloride,  one-pot,  ring-opening/Huisgen cycloaddition/CO2 capture in water

Continuous-Flow Diazotization

Mp: 118–120 °C. MS (M + H⁺): 314.

HRMS (ESI) m/z: Calcd for C₁₆H₁₅N₃NaO₄, (M + Na⁺): 336.0960. Found: 336.0899.

IR (KBr) ν/cm^–1: 3447, 3339, 1717, 1714, 1699, 1594.

¹H NMR (CDCl₃, 400 MHz) δ/ppm: 8.50 (s, 1H, Ar–H), 7.88 (d, J = 8.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.6 Hz, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 1H, Ar–H), 7.54 (t, J = 7.2 Hz, 1H, Ar–H), 7.41 (t, J = 7.2 Hz, 1H, Ar–H), 6.71 (d, J = 9.2 Hz, 1H, Ar–H), 6.28 (br s, 2H, −NH₂), 3.91 (s, 3H, −CH₃), 3.89 (s, 3H, −CH₃).

¹³C NMR (CDCl₃, 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4, 128.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.

    

Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

Zhiqun Yu^†, Hei Dong^†, Xiaoxuan Xie^†, Jiming Liu^‡, and Weike Su^*†‡

^† National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China

^‡ Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00238

Publication Date (Web): November 17, 2016

Copyright © 2016 American Chemical Society

*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00238

Abstract

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

//////////////chlorosulfonylation, continuous-flow,  diazotization,  parallel side reaction

o-Methylphenylphenylacetylene

o-Methylphenylphenylacetylene 3b

100.0 mg, 52%; oil; 

IR (film): 2360, 2335, 1599, 1571, 1493, 1455, 1379, 1157, 1103, 1069, 912, 754, 714, 689, 554, 521, 449 cm–1;

1H NMR (400 MHz, CDCl3, TMS, ppm): δ 7.45 (s, 2H), 7.41 (s, 1H), 7.25 (s, 3H), 7.14 (s, 2H), 7.07 (s, 1H), 2.431 (s, 3H); 

13C NMR (100 MHz, CDCl3, ppm): δ 140.2, 131.9, 131.6, 129.5, 128.4 (d), 128.2, 125.6, 123.6, 123.1, 93.4, 88.4, 20.8; 

MS (EI, 70 eV):m/z (%) 192(97) [M+], 191 (100) [M+ – 1], 189 (36), 65 (26); known compound (14309-60-5).(12a)

12 a) Kakusawa, N.; Yamaguchi, K.; Kurita, J. J. Organomet. Chem. 2005, 690, 2956– 2966, DOI: 10.1016/j.jorganchem.2005.03.021 

Gram-Scale Preparation of Pd@PANI: A Practical Catalyst Reagent for Copper-Free and Ligand-Free Sonogashira Couplings

Lei Yu*, Zhe Han, and Yuanhua Ding

Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Jiangsu Key Laboratory of Zoonosis, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002,People’s Republic of China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00322

Publication Date (Web): November 18, 2016

Copyright © 2016 American Chemical Society

*E-mail: yulei@yzu.edu.cn.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00322

Abstract

Palladium nanoparticles on the polyaniline (Pd@PANI) catalyst are now easily prepared on a gram scale through the oxidative polymerization of aniline in the presence of PdCl2 by using air as a clean oxidant. The material is found to be very stable and can be stored for more than one year without deactivation. Thus, it may become a commercial reagent in organic synthesis, depending on its application scopes. This article reported the first example of Pd@PANI-catalyzed Sonogashira couplings free of copper and ligands.

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copper-free, nanoparticles, palladium; polyaniline, Sonogashira coupling

Doxercalciferol, доксэркальциферол , دوكساركالسيفيرول , 度骨化醇

doxercalciferol

• Molecular FormulaC₂₈H₄₄O₂
• Average mass412.648 

доксэркальциферол [Russian] 

دوكساركالسيفيرول [Arabic] 

度骨化醇 [Chinese] 

1,3-Cyclohexanediol, 4-methylene-5-[(2E)-2-[(1R,3aS,7aR)-octahydro-7a-methyl-1-[(1R,2E,4R)-1,4,5-trimethyl-2-hexen-1-yl]-4H-inden-4-ylidene]ethylidene]-, (1R,3S,5Z)- 

54573-75-0

Title: Doxercalciferol CAS Registry Number: 54573-75-0 CAS Name: (1a,3b,5Z,7E,22E)-9,10-Secoergosta-5,7,10(19),22-tetraene-1,3-diol Additional Names: 1a-hydroxyvitamin D2; 1-hydroxyergocalciferol Trademarks: Hectorol (Bone Care) Molecular Formula: C28H44O2 Molecular Weight: 412.65 Percent Composition: C 81.50%, H 10.75%, O 7.75% Literature References: Synthetic vitamin D prohormone. Prepn: H.-Y. P. Lam et al., Science 186, 1038 (1974); eidem, Steroids30, 671 (1977); H. E. Paaren et al., J. Org. Chem. 45, 3253 (1980). Comparative activity and toxicity: G. Sjöden et al., Proc. Soc. Exp. Biol. Med. 178, 432 (1985). Metabolism to bioactive form: J. C. Knutson et al., Endocrinology 136, 4749 (1995). Pharmacology: J. W. Coburn et al., Nephrol. Dial. Transplant. 11, Suppl. 3, 153 (1996). Clinical trial for suppression of secondary hyperparathyroidism in hemodialysis: J. M. Frazao et al., ibid. 13, Suppl. 3, 68 (1998). Properties: Crystals, mp 138-140°. uv max (ethanol): 265 nm (e 18300). LD50 orally in rats: 3.5-6.5 mg/kg (Sjöden). Melting point: mp 138-140° Absorption maximum: uv max (ethanol): 265 nm (e 18300) Toxicity data: LD50 orally in rats: 3.5-6.5 mg/kg (Sjöden) Therap-Cat: Antihyperparathyroid. Keywords: Antihyperparathyroid.

CLIP

Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photoisomerization of a known vitamin D intermediate as the key step, thus circumventing the limitations of batch photoisomerization processes. Doxercalciferol is produced in an overall yield of about 10% from ergocalciferol.

Doxercalciferol

1H NMR (CDCl3) δ 6.40 (d, 1H, J = 11.2), 6.04 (d, 1H, J = 11.2), 5.35 (s, 1H), 5.15–5.29 (m, 2H), 5.03 (s, 1H), 4.45 (dd, 1H, J = 7.3, 4.0), 4.21–4.31 (m, 1H), 2.81–2.90 (m, 1H), 2.62 (d, 1H, J = 13.3), 2.34 (dd, 1H, J = 13.3, 6.5), 1.83–2.11(m, 6H), 1.42–1.79 (m, 7H), 1.21–1.40 (m, 3H), 1.04 (d, 3H, J = 6.6), 0.94 (d, 3H, J = 6.8), 0.86 (t, 6H, J = 7.3), 0.58 (s, 3H) ppm.

Doxercalciferol (trade name Hectorol) is drug for secondary hyperparathyroidism and metabolic bone disease.^[1] It is a synthetic analog of ergocalciferol (vitamin D₂). It suppresses parathyroid synthesis and secretion.^[2]

PATENT

https://www.google.com/patents/US20130023681

CLIP

References

1. Jump up^ Sprague S M; Ho L T (2002). "Oral doxercalciferol therapy for secondary hyperparathyroidism in a peritoneal dialysis patient".Clinical nephrology. 58 (2): 155–160. PMID 12227689.

Doxercalciferol

Names
IUPAC name (1S,3R,5Z,7E,22E)-9,10-Secoergosta-5,7,10,22-tetraene-1,3-diol
Other names 1-Hydroxyergocalciferol; 1-Hydroxyvitamin D2; 1α-Hydroxyergocalciferol; 1α-Hydroxyvitamin D2; Hectorol; TSA 840
Identifiers
CAS Number	54573-75-0
3D model (Jmol)	Interactive image
ChEMBL	ChEMBL1200810
ChemSpider	4444554
DrugBank	DB06410
ECHA InfoCard	100.170.997
IUPHAR/BPS	2790
PubChem	5281107
UNII	3DIZ9LF5Y9
InChI[show]
SMILES[show]
Properties
Chemical formula	C28H44O2
Molar mass	412.66 g·mol−1
Pharmacology
ATC code	H05BX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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Acetylcholine Chloride

Acetylcholine Chloride
2-acetyloxyethyl(trimethyl)azanium;chloride
60-31-1

Molecular Formula:	C7H16ClNO2
Molecular Weight:	181.66 g/mol

Acetylcholine chloride is obtained as white or off-white hygroscopic crystals, or as a crystalline powder. The salt is odorless, or nearly odorless, and is a very deliquescent powder. Acetylcholine bromide is obtained as deliquescent crystals, or as a white crystalline powder. The substance is hydrolyzed by hot water and alkali

Acetylcholine is an organic chemical that functions in the brain and body of many types of animals, including humans, as a neurotransmitter—a chemical released by nerve cells to send signals to other cells. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that interfere with acetylcholine activity are called anticholinergics.

Acetylcholine is the neurotransmitter used at the neuromuscular junction—in other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also used as a neurotransmitter in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system.

Inside the brain, acetylcholine functions as a neuromodulator—a chemical that alters the way other brain structures process information rather than a chemical used to transmit information from point to point. The brain contains a number of cholinergic areas, each with distinct functions. They play an important role in arousal, attention, and motivation.

Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous system and brain, a large number of important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as Sarin, cause harm by inactivating or hyperactivating muscles via their influences on the neuromuscular junction. Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems. Scopolamine, which acts mainly on muscarinic receptors in the brain, can cause delirium and amnesia. The addictive qualities of nicotine derive from its effects on nicotinic acetylcholine receptors in the brain.

Chemistry

Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the presence of a highly polar, charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier. A synonym of this drug is miochol.

History

Acetylcholine (ACh) was first identified in 1915 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name Vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work. Acetylcholine was also the first neurotransmitter to be identified.

CLIP

http://drugsynthesis.blogspot.in/2011/11/laboratory-synthesis-of-acetylcholine.html

Laboratory Synthesis Of Acetylcholine chloride

Acetylcholine chloride Chemical Name: 2- (acetyl oxy)- N ,N ,N- tri methyl ethan aminium chloride
Acetylcholine chloride Use: parasympathomimetic, miotic, vasodilator (peripheral)
Acetylcholine chloride MW: 181.66
Acetylcholine chloride MF: C7H16ClNO2
Acetylcholine chloride LD50: 10 mg/kg (M, i.v.); 3 g/kg (M, p.o.);
22 mg/kg (R, i.v.); 2500 mg/kg (R, p.o.)
Reference(s):

1. Baeyer, A. v.: Justus Liebigs Ann. Chem. (JLACBF) 142, 235 (1867).
2. Nothnagel: Arch. Pharm. (Weinheim, Ger.) (ARPMAS) 232, 265 (1894).
3. Fourneau, E.; Page, H.J.: Bull. Soc. Chim. Fr. (BSCFAS) [4] 15, 544 (1914).
4. DE 801 210 (BASF; appl. 1948).
5. US 1 957 443 (Merck & Co.; 1934; appl. 1931).
6. US 2 012 268 (Merck & Co.; 1935; appl. 1931).
7. US 2 013 536 (Merck & Co.; 1935; appl. 1931).

Acetylcholine
IUPAC name	2-Acetoxy-N,N,N-trimethylethanaminium
Abbreviation	ACh
Sources	motor neurons, parasympathetic nervous system, brain
Targets	skeletal muscles, brain, many other organs
Receptors	nicotinic, muscarinic
Agonists	nicotine, muscarine, cholinesterase inhibitors
Antagonists	tubocurarine, atropine
Precursor	choline, acetyl-CoA
Synthesizing enzyme	choline acetyltransferase
Metabolizing enzyme	acetylcholinesterase
Database links
CAS Number	51-84-3
PubChem	CID: 187
IUPHAR/BPS	294
DrugBank	EXPT00412
ChemSpider	182
KEGG	C01996

1H NMR PREDICT

13 C NMR PREDICT

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