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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Commercial Production of Semi-Synthetic Artemisinin


STR1

Figure 1. Production of artemisinic acid or β-farnesene by engineered yeast. The sesquiterpene alkenes β-farnesene and amorphadiene are both derived from FPP (farnesyl diphosphate) by the action of specific enzymes introduced from plants: amorphadiene synthase (ADS) generates amorphadiene and β-farnesene synthase (FS) generates β-farnesene. Production strains express either ADS or FS, not both. Oxidation of amorphadiene to artemisinic acid is accomplished by the action of five plant enzymes expressed in the engineered yeast.17 Conversion of purified artemisinic acid to artemisinin is accomplished by in vitro organic chemistry. Isoprenoid production strains make little ethanol.

 

The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast. Development of commercially viable yeast strains was a substantial challenge that was addressed by creation and implementation of an industrial synthetic biology pipeline. Using the engineered strains, production of β-farnesene from Brazilian sugarcane offers several environmental advantages. Among the many commercial applications of β-farnesene, its use as a feedstock for making biodegradable lubricants is highlighted. This example, along with others, highlight a powerful new suite of technologies that will become increasingly important for production of chemicals, spanning from pharmaceuticals through commodity chemicals.

 

STR1

Figure 2. Sanofi industrial semi-synthesis of artemisinin. The process starts with a moderate pressure catalytic diastereoselective hydrogenation of artemisinic acid to produce a high (95:5) ratio of the desired (R)-isomer. To avoid formation of a lactone byproduct, dihydro-epi-deoxyarteannuin B, during the photooxidation, the carboxylic acid is protected as a mixed anhydride. The final step combines formation of the intermediate hydroperoxide via photoxidation using a Hg vapor lamp and commercially available tetraphenylporphyin (TPP) as sensitizer with a Hock cleavage and rearrangement catalyzed by trifluoroacetic acid to give, after workup, the best yield reported to date of pure isolated artemisinin (55%).

Synthetic Biology and the Development of Commercial β-Farnesene Production Strains Semi-synthetic artemisinin is a pharmaceutical with a price point comparable to plant-derived artemisinin,20 namely above $150 per kg. β-Farnesene, however, is a specialty chemical with multiple uses (more details below); most specialty and commodity chemicals have significantly lower price points, often below $10 per kg. For these product categories, it is of paramount importance that fermentative production be as efficient as possible, with high yields (namely, grams of product made per gram of feed substrate), productivities (grams of product/liter of culture/hour) and concentration (also known as titer; grams of product per liter of culture). Developing yeast strains capable of the yield, productivity and titer required for chemical production requires extensive development, and has been enabled over the last decade by the new discipline of synthetic biology. Synthetic biology seeks to extend approaches and concepts from engineering and computation to redesign biology for a chosen function;21recent advances in the application of design automation, i.e., the use of software, hardware and robotics22 have enabled the creation and screening of hundreds of thousands of strain variants (created by both design and random mutagenesis) for the properties required for commercial production of β-farnesene. Notable enabling technologies developed for routine usage include rapid and reliable assembly of large (i.e., multiple kilobase) deoxyribonucleic acid (DNA) constructs;23-25 high throughput, cost effective, verification of structural DNA assemblies by both initial restriction digest26 and by low-cost DNA sequencing;27 and whole genome sequencing of yeast strains.28 In addition, there is a need to effectively identify the best new strains (akin to panning for gold!) through high throughput, rapid, and accurate methods to screen thousands of strains. Further, the results of small-scale (< 1 milliliter) tests must correspond to the results of large-scale (> 50,000 liter) production. Development and implementation of these technologies required considerable investment by Amyris. The outcome is a robust pipeline for efficient, cost-effective strain generation allied with screening for the properties required for commercial production of β-farnesene by fermentation (i.e., at a price point required for its use as a specialty chemical).

 

As the world’s population and economies grow, the demand for a wide variety of specialty, commodity, and pharmaceutical chemicals will outpace the supply available from current sources. There is an urgent need to develop alternative, sustainable sources of many existing chemicals and to develop abundant sources of currently scarce chemicals with novel beneficial properties. Synthetic biology and industrial fermentation, combined with synthetic chemistry, will be an increasingly important source of chemicals in the decades ahead; artemisinin and β-farnesene provide good examples of this relatively new approach to chemical production. Brazil’s plentiful sugar cane feedstock and fermentation expertise make it an excellent location for this type of manufacturing, which can expand and diversify the nation’s industrial base and international importance.

J. Braz. Chem. Soc. 2016, 27(8), 1339-1345

Developing Commercial Production of Semi-Synthetic Artemisinin, and of β-Farnesene, an Isoprenoid Produced by Fermentation of Brazilian Sugar

Kirsten R. Benjamin; Iris R. Silva; João P. Cherubim; Derek McPhee; Chris J. Paddon

How to cite this article

Genes encoding the biosynthetic pathway for production of a valuable product (e.g., farnesene) in a native organism are expressed in a heterologous microbial host (e.g., yeast). The engineered yeast produces farnesene by commercial fermentation. Copyright © 2016 Amyris, inc. All rights reserved.

http://dx.doi.org/10.5935/0103-5053.20160119

http://jbcs.sbq.org.br/imagebank/pdf/v27n8a04.pdf

Benjamin KR, Silva IR, Cherubim JP, Mcphee D, Paddon CJ. Developing Commercial Production of Semi-Synthetic Artemisinin, and of β-Farnesene, an Isoprenoid Produced by Fermentation of Brazilian Sugar. J. Braz. Chem. Soc. 2016;27(8):1339-1345

Kirsten R. Benjamin,a Iris R. Silva,b João P. Cherubim,c Derek McPheea and Chris J. Paddon*,a a Amyris, Inc., 5885 Hollis Street, Suite 100, CA 94608 Emeryville, USA b Amyris Brasil Ltda, Rua John Dalton 301-Bloco B-Edificio 3, Condominio Techno Plaza, 13069-330 Campinas-SP, Brazil c Amyris Brasil Ltda, Rodovia Brotas/Torrinha-km 7.5, 17380-000 Brotas-SP, Brazil

*e-mail: paddon@amyris.com
Chris Paddon

Chris Paddon, PhD

Dr. Paddon has a PhD in Biochemistry from Imperial College, London, but now considers himself a synthetic biologist. After postdoctoral work at the National Institutes of Health in Bethesda, MD, he worked in the pharmaceutical industry (GlaxoSmithKline), and then for two Bay Area biopharmaceutical companies (Affymax and Xenoport) before joining Amyris, Inc. in 2005 as its sixth employee and first scientist. He was project leader for the semi-synthetic artemisinin project at Amyris, Inc. and has subsequently led a number of other projects and programs there.

Chris Paddon is a Principal Scientist at Amyris, Inc. in Emeryville, CA. He was project leader for the Semi-Synthetic Artemisinin project, and subsequently led a number of projects at Amyris using synthetic biology for the production of natural products. He received his Bachelor’s degree in Microbiology from The University of Surrey (UK), and doctorate in Biochemistry from Imperial College (London, UK). Following postdoctoral work at The National Institutes for Health (Bethesda, MD) he joined the pharmaceutical industry, working for GSK (London, UK). He subsequently worked for Affymax (Palo Alto, CA) and Xenoport (Santa Clara, CA) before joining Amyris.

//////////// Commercial Production, Semi-Synthetic , Artemisinin,  farnesene, fermentation, natural product, lubricant

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New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd


 

 

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.


acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50°C, and the crude mass degassed under vacuum at 50-55°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10°C. Ethyl acetate (60 ml) was added to the reaction mass at 10°C and stirred for 15 minutes at 15-20°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45°C and the obtained crude mass was degassed at 50-55°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85°C till reaction completion. The reaction mass was cooled up to 0-5°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer,  Parasitic infection,  Plasmodium falciparum infection,  Viral infection, artemether artemisinin,  artemotil,  artenimol,  artesunate,

ARTEMISININ


Ijms 13 05060f1 1024

Artemisinin  is a sesquiterpene lactone with an endoperoxide function. It was first isolated from the Chinese traditional herb—Artemisia annua L. and its structure was first confirmed by Chinese scientists in the 1970s. Artemisinin and its derivatives or analogues are currently regarded as the most promising weapons against multidrug-resistant malaria . Its unique 1,2,4-trioxane structure is entirely incompatible with the traditional antimalarial structure-activity theory, which attracted the interest of many researchers

(+) Artemisinin is a sesquiterpene endoperoxide lactone with an unprecedented structure is a natural medicine for the treatment of malaria in particular drug against drug resistant malaria and cerebral malaria. The total synthesis of this novel sesquiterpene is described using an intermolecular radical reaction on important intermediate iodolactone starting from terpene (+) isolimonene.

Malaria is probably as old as mankind and continues to affect millions of people throughout the world. Today some 500 million people in Africa, India, South East Asia and South America are exposed to endemic malaria and it is estimated to cause two and half million deaths annually, one million of which are children. Certainly malaria is a serious problem all over the globe. As a consequence, effective therapeutic agents against malaria are continuously being sought, especially against those strains of Plasmodium falciparum, which are resistant to conventional quinine and acridine based drugs. Artemisinin, which has been isolated from Artemisia Annua L. Compositae (Qinghao), is an active constituent of traditional Chinese herbal medicine which is used for the treatment of malaria in China for more than 1000 years.

a sesquiterpene endoperoxide lactone with an unprecedented structure is a natural medicine for the treatment of malaria, in particular drug against drug resistant and cerebral malaria. The exceptional pharmacological potential and extreme scarcity of the natural material together with its complex structure prompted us to study the total synthesis of (+) Artemisinin. The architectural complexity is attributed to the presence of 7 chiral centers with tetracyclic framework with an endoperoxide unit. Though many valuable contributions5-9 have been made towards the total synthesis of this unique structurally complex molecule, the need for a simple strategic route still remains, encouraging us to take up the total synthesis of this potent antimalarial drug.

Schimid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105, 624. 6. Xu, X. X.; Zhu, J.; Huang, D. Z.; Zhou, W. S. Tetrahedron 1986, 42, 819. 7. (a) Avery, M. A.; Chong, W. K. M.; White, C. J. J. Am. Chem. Soc. 1992, 114, 974. (b) Avery, M. A.; White, C. J.; Chong, W. K. M. Tetrahedron Lett. 1987, 28, 4629. 8. Ravindranathan, T.; Kumar, M. A.; Menon, R. B.; Hiremath, S. V. Tetrahedron Lett. 1990, 31, 755. 9. Liu, H. J.; Yeh, W. L.; Chew, S. Y. Tetrahedron Lett. 1993, 34, 4435.

IUPAC (3R,5aS,6R,8aS,9R,12S,12aR)-octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10(3H)-one
Structure C15H22O5
CAS # 63968-64-9
Mol. Mass 282.33 g/mol
Density 1.24 ± 0.1 g/cm³
Melting Point 151-154 °C

Ijms 13 05060f4 1024

Ijms 13 05060f5 1024

Ijms 13 05060f6 1024

Ijms 13 05060f7 1024

http://www.mdpi.com/1422-0067/13/4/5060/htm

……………

1,5,9-Trimethyl-(1R,4S,5R,8S,9R,12S,13R)-11,14,15,16-tetraoxatetracyclo [10.3.1.O4,13.O8,13] hexadecan-10-one (Artemisinin)

purified on preparative TLC (eluent petroleum ether/ethyl acetate, 90/10) to give 1 (6 mg) in 10% yield. 


1 H NMR (500MHz, CDCl3): δ 1.00 (d, J = 6.0 Hz, 3H), 1.01-1.13 (m, 2H), 1.21 (d, J = 7.4 Hz, 3H), 1.34-1.43 (m, 3H), 1.44 (s, 3H), 1.74-1.79 (m, 2H), 1.86-1.90 (m, 1H), 1.97-2.07 (m, 2H), 2.40-2.46 (qxd, J = 3.8, 8.9 Hz, 1H), 3.36-3.41 (qxd, J = 1.7, 5.3, 5.4 Hz, 1H), 5.84 (s, 1H). 


MS (FAB): m/z 283 (M+1). 


IR (KBr): 1740 (δ-lactone) cm-1. 


Optical rotation [α]D : (+) 87.94 (c=0.1, Dioxane). 


http://www.arkat-usa.org/get-file/18950/

ARKIVOC 2003 (iii) 125-139

Total synthesis of (+) Artemisinin J. S. Yadav,

* R. Satheesh Babu and G. Sabitha Organic Chemical Sciences, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, India E-mail: yadav@iict.ap.nic.in

………….

Total Synthesis

In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which is then converted to methoxymethyl ether (3). The ether is hydroborated and then undergoes oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which then is oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.6

6 G. Schmid, W. Hofheinz. “Total Synthesis of qinghaosu” J. Am. Chem. Soc.; 1983; 105 (3); 624-625

……………….

Produce artemisinin with biosynthesis and chemical synthesis. The World Health Organization estimates that in 2010 there were >200 million cases of malaria worldwide that accounted for >650,000 deaths. Many promising strategies to combat malaria require use of artemisinin-based combination therapies, but artemisinin production—from natural sources or laboratory biosynthesis—is insufficient and expensive.

C. J. Paddon and J. D. Newman at Amyris (Emeryville, CA) and almost 50 colleagues in the United States, Canada, and China engineered a new strain ofSaccharomyces cerevisiae (baker’s yeast) to improve the production of artemisinic acid (1, a precursor for artemisinin) from glucose. This research was sponsored by the Institute for OneWorld Health with the support of the Bill & Melinda Gates Foundation.

The authors studied the biochemical pathway to 1 in S. cerevisiae. They then overexpressed the genes involved in artemisinin production and suppressed those related to other products. They also added isopropyl myristate oil to solubilize 1 and drive the equilibrium toward the product. They produced 1 in 25 g/L concentration.

The authors then developed a synthesis of artemisinin (2) from 1 that is suitable for large-scale production (see figure). Among the improvements are

  • the use of hydrogen to reduce the double bond in artemisinic acid,
  • esterification of the carboxylic acid group to avoid side reactions,
  • chemical generation of singlet oxygen (1O2) from H2O2, and
  • in the last step, the use of air, a safer and less expensive source of triplet oxygen (3O2) than pure oxygen.

Artemisinin was obtained in 50% overall yield with higher purity than is usually found in commercial samples. This process is simple, scalable, and economically viable. It can potentially supply worldwide requirements of artemisinin to combat malaria. The process is not patented and is therefore freely available. (Nature 2013, 496, 528–532José C. Barros)

……………….

Friedrich Wöhler’s early syntheses of oxalic acid and urea heralded the age of synthetic organic chemistry. These reactions demonstrated the potential for man to generate compounds that had previously only been obtained from the extraction of biological substances. Remarkably, despite huge advances in chemical synthesis, almost all natural products synthesised to date have relied upon similar apparatus and techniques to those used by Wöhler in the 1820s. Steve Ley and his group are among the pioneers of the use of flow chemistry in synthesis, and have demonstrated the use of machines in place of the antiquated round-bottomed flasks still used in chemistry labs the world over.

GA?id=C3CS60246JThe number of sequential operations required in traditional approaches to making molecules can make synthesis time-consuming. In particular, downstream processes such as purification of the desired compound from waste products can take much longer than the actual reaction. Importantly, flow chemistry can also offer significant improvements to work health and safety as hazardous chemicals can be manipulated in a closed system and therefore, risks associated with exposure are reduced.

In flow chemistry (at its most basic), a reaction is performed in a continuous flowing stream where substrates and reagents are combined inside inert tubing and pumped around a coil of tubing before being quenched or treated with the chemical required for the next stage of the transformation.

Ley and coworkers have recently published a review that presents some highlights from the use of flow chemistry in natural product synthesis. One of the notable examples featured in this review is the continuous flow, semi-synthesis of artemisinin bySeeberger and Lévesque. Artemisinin is a sesquiterpene that represents the frontline treatment for plasmodium falciparummalaria when used in combination with other therapeutics. The supply of artemisinin from natural sources is problematic as is the scalability of existing synthetic approaches.

Dihydroartemisinic acid 2, (derived from artemesinic acid 1) represents the starting point for this flow synthesis and first undergoes photooxidation to yield hydroperoxide 3. Subsequent treatment of 3 with strong acid, followed by oxidation provided hydroperoxide 5, which underwent a spontaneous cycloaddition sequence, leading to the generation of artemisinin6.

The use of a continuous flow reactor particularly enhanced the challenging photochemical transformations associated with the synthesis. Issues such as low mass transfer of oxygen gas into solution and low penetration of light were resolved by coiling the reaction tubing around a lamp to enabled effective generation of the singlet-oxygen required for the reaction. Additionally, improved mixing and temperature control could also be achieved. Crucially, this synthesis provides a low cost method to meet the escalating demand for artemisinin at affordable prices for patients in the developing world.

The elegant syntheses described in this review span a range of natural product classes and highlight the advantages that mechanisation of chemical processes can offer. As chemists seek to address medicinal and environmental challenges, perhaps greater emphasis should be placed on rational design rather than labour-intensive and repetitive tasks. The effective implementation of flow systems and technology could revolutionise the chemical sciences, and this review provides some exciting food for thought.

For more, read this Chem Soc Rev article in full:

Flow chemistry syntheses of natural products

Julio C. Pastre, Duncan L. Browne and Steven V. Ley

Chem. Soc. Rev., 2013, Advance Article

DOI: 10.1039/C3CS60246J

….

Although photocatalytic chemistry has been the subject of intense interest recently, the rate of these reactions is often slow due to the limited penetration of light into typical reaction media. Peter H. Seeberger at the Max-Planck Institute for Colloids and Surfaces in Potsdam and the Free University of Berlin showed (Chem. Sci. 20123, 1612. DOI: 10.1039/C2SC01016J) that Ru(bpy)32+ catalyzed reactions such as the reduction of azide 1 to 2 can be achieved in as little as 1 min residence time using continuous flow, as opposed to the 2 h batch reaction time previously reported. The benefits of flow on a number of strategic photocatalytic reactions, including the coupling of 3 and 4 to produce 5, was also demonstrated (Angew. Chem. Int. Ed. 201251, 4144. DOI: 10.1002/anie.201200961) by Corey R. J. Stephenson at Boston University and Timothy F. Jamison at MIT. In this case, a reaction throughput of 0.914 mmol/h compares favorably with 0.327 mmol/h for the batch reaction.

ORGANIC SPECTROSCOPY INTERNATIONAL

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ACTs (Artemisinin) drugs to treat malaria .

Earlier this year Francois Levesque and Peter Seeberger laid out their plans for scaling up the production of the important anti-malarial drug artemisinin (DOI). Their vision: the industrial production from dihydroartemisinic acid in a single continuous flow reaction. This month in Science, science writer Kai Kupferschmidt is not so sure.

Current artemisinin industrial production completely relies on extraction from thesweet wormwood plant. But help is on the way. Biotech company Amyris has trained special yeast cells to produce a precursor called artemisinic acid. The dihydro acid can then be obtained from artemisinic acid via reduction with hydroxylamine-O-sulfonic acid / MeOH (diazene).

In the Levesque/Seeberger procedure the next step to artemisinin is a photochemical reaction with singlet oxygen forming a hydroperoxide using teraphenylporphyrin asphotosensitizer followed by an ene reaction. This step is then followed by a thermal Hock rearrangement initiated by trifluoroacetic acid. Another round of oxygen adds another hydroperoxide unit and another rearrangement forms artemisinin itself. This sequence takes place in a continuous flow reactor and in the photochemical step all the tubing is wrapped around the lamp for maximum exposure to light.

So far so good but as Kupferschmidt found out, Amyris with backing from several charities and non-profits exclusively licensed the yeast cells to chemical company Sanofi. This company has decided the final chemical steps will take place via old-fashioned batch chemistry not flow chemistry. This is bad news for Seeberger but the man is not going to give up that easily. He is looking at two alternative ways to lay his hands on artemisinic acid: it is present in waste from sweet wormwood cultivation or better still, the plant can be engineered to produce it in larger quantities than artemisinin itself.

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As reported back in 2012 here chemical company Sanofi and the Bill and Melinda Gates Foundation have joined forces (Sanofi the know-how and Bill the money) to increase production of the important antimalarial drugartemisinin. In a recent OPRD publication Sanofi chemists present a commercial-scale (no-loss no profit) production line with a capacity of 60 tonnes, starting from yeast-produced artemisinic acid. Here is the summary.
In step one from artemisinic acid to dihydroartemisinic acid (a dehydrogenation) the Wilkinson catalyst was deemed too expensive and replaced by ruthenium chloride (R)-DTBM-Segphis (a modified segphos). Scale: 600 Kg, 90% diastereoselectivity. The compound was next activated with ethylchloroformate and potassium carbonate in dichloromethane to the anhydride. The photochemical step consisted of addingtetraphenylporphyrin as a sensitizer and trifluoroacetic acid in dichloromethane. The subsequent Schenck ene reaction / Hock rearrangement requires two equivalents of singlet oxygen. Where the prior art yielded 41% of product, this photochemical solution pushes out 55%. Side note: the article does not really explain why the acid was activated, the Seeberger procedure does not include this step. Remaining challenge: product isolation was accomplished by simultaneous DCM distillation – solvent replacement with n-heptane and crystallisation. Pretty amazing when considering this is still industrial production at the hundreds of kilogram scale and the final product is a labile peroxide!
Figure
Nature2013, 496 ( 7446) 528532
J. Am. Chem. Soc., 2012, 134 (33), pp 13577–13579
DOI: 10.1021/ja3061479

Abstract

Abstract Image

Malaria represents one of the most medically and economically debilitating diseases present in the world today. Fortunately, there exists a highly effective treatment based on the natural product artemisinin. Despite the development of several synthetic approaches to the natural product, a streamlined synthesis that utilizes low-cost chemical inputs has yet to materialize. Here we report an efficient, cost-effective approach to artemisinin. Key to the success of the strategy was the development of mild, complexity-building reaction cascades that allowed the use of readily available, affordable cyclohexenone as the key starting material.

Rf = 0.2 (hexanes/ethyl acetate, 5/1).

IR (film) ν/cm-1 2956 (m), 2933 (m), 2884 (m), 2861 (m), 1739 (s), 1201 (m), 1114 (s), 1033 (m), 1028 (m), 995 (s), 883 (m).

[α]D 20 = +64.0 (c 1.20, CHCl3) (nat. [α]D 20 = +66.6 (c 0.90, CHCl3)).

1H NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 3.38 (dq, J = 7.4, 5.5 Hz, 1H), 2.41 (ddd, J = 14.4, 12.9, 3.9 Hz, 1H), 2.06-1.92 (m, 2H), 1.90-1.82 (m, 1H), 1.79-1.70 (m, 2H), 1.52-1.31 (m, 3H), 1.42 (s, 3H), 1.18 (d, J = 7.4 Hz, 3H), 1.10-1.00 (m, 2H), 0.98 (d, J = 5.9 Hz, 3H).

13C NMR (100 MHz, CDCl3) δ 172.7, 106.0, 94.3, 80.1, 50.7, 45.6, 38.2, 36.5, 34.2, 33.5, 25.8, 25.5, 24.0, 20.5, 13.2.

HRMS calcd. for C15H22O5Na [M+ Na] 305.1365, found 305.1356.

ART10 ART11 ART12 ART13

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http://pubs.acs.org/doi/abs/10.1021/op4003196

Org. Process Res. Dev., 2014, 18 (3), pp 417–422
DOI: 10.1021/op4003196

Abstract

Abstract Image

A new commercial-scale alternative manufacturing process to produce a complementary source of artemisinin to supplement the plant-derived supply is described by conversion of biosynthetic artemisinic acid into semisynthetic artemisinin using diastereoselective hydrogenation and photooxidation as pivotal steps. This process was accepted by Prequalification of Medicines Programme (PQP) in 2013 as a first source of nonplant-derived-artemisinin in industrial scale from Sanofi production facility in Garessio, Italy.

Analytical Data of Semisynthetic Artemisinin

Optical Rotation: [α]20D = +74–78 [10 mg/mL in ethanol].
The melting point of the crystalline artemisinin was found to be about 159 °C.
The theoretical mass of [M + H]+ is 283.1545 amu. The high-resolution mass spectrum shows the [M + H]+ at m/z = 283.1557 amu. This measured mass is consistent with the [M + H]+formula C15H22O5 within an deviation of 4.2 ppm. (amu: atomic mass unit)
Figure
Scheme 5. Manufacturing of semisynthetic artemisinin in production scale

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http://pubs.acs.org/doi/abs/10.1021/op200373m

Org. Process Res. Dev., 2012, 16 (5), pp 1039–1042
DOI: 10.1021/op200373m
Publication Date (Web): February 21, 2012
Copyright © 2012 American Chemical Society
*Email: a.lapkin@warwick.ac.uk. Fax: (+44) 24764 18922.
This article is part of the Continuous Processes 2012 special issue.

Abstract

Abstract Image

Stoichiometric reduction of artemisinin to dihydroartemisinin (DHA) has been successfully transferred from batch to continuous flow conditions with a significant increase in productivity and an increase in selectivity. The DHA space-time-yield of up to 1.6 kg h–1 L–1 was attained which represents a 42 times increase in throughput compared to that of conventional batch process.

World Drug Tracker: Antimalarial flow synthesis closer to …

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The processes yields several artemisinin-derived APIs that are key components in Artemisinin Combination Therapies

Artemisinin (Cook, 2012).

(+)-Artemisinin (41) is currently the most effective drug against Plasmodium falciparum malaria as part of an artemisinin-based combination therapy (ACT). Although it can be isolated on an industrial scale from Artemisia annua, the market price of artemisinin (41) has fluctuated widely and traditional extraction does not provide enough material to meet the worldwide demand. Interestingly, recent efforts towards a cheaper and more efficient production of artemisinin (41) have mainly taken place in the areas of synthetic biology, semisynthesis and plant engineering, while there has been a lack of practical approaches using a straightforward total synthesis. Despite the fact that all the total syntheses of artemisinin, until 2010, were impressive from a feasibility point of view, none of them provided a solution for the low-cost synthesis of 41. This changed when Cook’s group recently published a scalable synthesis of artemisinin (41), which provides a blueprint for the cost-effective production of 41 and its derivatives below Key to their successful strategy was the use of reaction cascades that rapidly built complexity, starting from the cheap feedstock chemical, cyclohexenone (42). The latter was first subjected to a one-pot conjugate addition/alkylation sequence, to give ketone 43. A three-step sequence consisting of formylation, cycloaddition and a Wacker-type oxidation, yielded 9.4 g of methyl ketone 44. The challenging formation of the unusual peroxide bridge was initially met with failure, but was eventually realized by a reaction with singlet oxygen to give 41 amongst other oxidized intermediates. The entire synthetic sequence was conducted on a gram scale, required only three chromatographic purifications and was carried out in only five flasks. Considering the low cost of the commodity chemicals used and the conciseness of Cook’s synthesis, it is certainly worth being further investigated.

2015 January » All About Drugs

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7 Semi-synthesis of artemisinin using continuous flow. The Seeberger group has recently developed a continuous flow approach to the production of …

…………

http://pubs.acs.org/doi/abs/10.1021/ol2015434

http://pubs.acs.org/doi/suppl/10.1021/ol2015434/suppl_file/ol2015434_si_001.pdf

Org. Lett., 2011, 13 (16), pp 4212–4215
DOI: 10.1021/ol2015434
Publication Date (Web): July 15, 2011
Copyright © 2011 American Chemical Society

Abstract

Abstract Image

Attachment of H2O2 onto the highly hindered quaternary C-12a in an advanced qinghaosu (artemisinin) precursor has been achieved through a facile perhydrolysis of a spiro epoxy ring with the aid of a previously unknown molybdenum species without involving any special equipment or complicated operations. The resultant β-hydroxyhydroperoxide can be further elaborated into qinghaosu, illustrating an entry fundamentally different from the existing ones to this outstanding natural product of great importance in malaria chemotherapy.

QHS: M.p. 153-155 ºC (nat. m.p. 154-156 ºC).

[α]D 25 +67.6 (c 1.75, CHCl3), (nat. [α]D 24 +66.6 (c 1.57, CHCl3)).

1 H NMR (400 MHz, CDCl3) δ 5.83 (s, 1H), 3.36 (br dq, J = 7.2, 5.5 Hz, 1H), 2.40 (br ddd, J = 14.8, 13.8, 3.9 Hz, 1H), 2.06-1.93 (m, 2H), 1.90-1.82 (m, 1H), 1.78-1.67 (m, 2H), 1.50-1.30 (m, 3H), 1.41 (s, 3H), 1.17 (d, J = 7.3 Hz, 3H), 1.09-1.00 (m, 2H), 0.97 (d, J = 5.7 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 171.9, 105.3, 93.6, 79.4, 49.9, 44.8, 37.4, 35.8, 33.5, 32.8, 25.1, 24.7, 23.3, 19.7, 12.4.

FT-IR (film) 2959, 2933, 2884, 2861, 1738, 1450, 1378, 1212, 1201, 1114, 1033, 997, 882, 831 cm–1.

ESI-MS 283.1 ([M+H]+ ), 305.0 ([M+Na]+ ), 337.0 ([M+MeOH+Na]+ ); EI-HRMS: calcd for C15H22O5 (M+ ) 282.1467, found 282.1461.

ART31 ART30

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Ind. Eng. Chem. Res., 2013, 52 (22), pp 7157–7169
DOI: 10.1021/ie302495w
Publication Date (Web): March 26, 2013
Copyright © 2013 American Chemical Society
*Tel.: +45 6550 7481. E-mail: bgr@kbm.sdu.dk.
This article is part of the PSE-2012 special issue..http://pubs.acs.org/doi/abs/10.1021/ie302495w

Abstract

Abstract Image

A systematic method of conceptual process synthesis for recovery of natural products from their biological sources is presented. This methodology divides the task into two major subtasks namely, isolation of target compound from a chemically complex solid matrix of biological source (crude extract) and purification of target compound(s) from the crude extract. Process analytical technology (PAT) is used in each step to understand the nature of material systems and separation characteristics of each separation method. In the present work, this methodology is applied to generate process flow sheet for recovery of artemisinin from the plant Artemisia annua (A. annua). The process flow sheet is evaluated on the basis of yield and purity of artemisinin obtained in bench scale experiments. Yields of artemisinin obtained in individual unit operations of maceration, flash column chromatography, and crystallization are 90.0%, 87.1% and 47.6%, respectively. Results showed that the crystallization step is dominant to the overall yield of the process which was 37.3%.

update……..

Amalgamation of Synthetic Biology and Chemistry for High-Throughput Nonconventional Synthesis of the Antimalarial Drug Artemisinin

Chemistry Research and Development, Plot Number 123-AB, Ipca Laboratories Limited, Kandivali Industrial Estate, Kandivali West, Mumbai 400067, India
Research and Development, Amyris Inc., 5885 Hollis Street, Suite 100, Emeryville, California 94608, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00414

(3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one (Artemisinin, 1)

The melting point of artemisinin batch 1 (AM2/AM2/16260 P2) was found to be 152.6–153.7 °C, and that of batch 2 (AM2/AM2/16260 Crop II) was 153–154 °C.(53)
The specific optical rotation of artemisinin batch 1 was [α]D20 = +76.55 [10 mg/mL in ethanol], and that of artemisinin batch 2 was [α]D20 = +76.51 [10 mg/mL in ethanol].(54)
  1. 53 Monographs for pharmaceutical substances (A–O). The International Pharmacopoeia, 4th ed. Vol. 1; World Health Organization: Geneva, 2006.

  2. 54.Monographs for pharmaceutical substances (A–O). The International Pharmacopoeia, 6th ed.; World Health Organization: Geneva, 2016.

Figure

Abstract Image

The development of a cost-effective process for the production of artemisinin, the precursor of all artemisinin-derived drugs, the first-line treatment for malaria, has been a long-pursued endeavor. The breakthrough achievement of coaxing genetically engineered yeast to express Artemisia annua genes for the commercial production of artemisinic acid, an advanced intermediate in the synthesis of artemisinin, has yet to fully realize an affordable malaria treatment for the poor because of the lack of a cost-effective chemical conversion into artemisinin. We describe herein a commercially feasible and pragmatic synthesis of artemisinin from amorpha-4,11-diene, an early-stage intermediate produced in 2-fold higher molar yield than engineered yeast cells can process into artemisinic acid. The key to this novel approach is an exceedingly effective functionalization of the isopropenyl group of amorphadiene via endo-epoxyamorphadiene to give dihydroartemisinic acid, which upon esterification followed by oxidation and cyclicization furnishes pure artemisinin in approximately 60% yield.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00414

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Recovery of Artemisinin from a Complex Reaction Mixture Using Continuous Chromatography and Crystallization


Figure

Figure

Recovery of Artemisinin from a Complex Reaction Mixture Using Continuous Chromatography and Crystallization

Articles ASAP (As Soon As Publishable)
Publication Date (Web): May 8, 2015 (Article)
DOI: 10.1021/acs.oprd.5b00048
*E-mail: seidel-morgenstern@mpi-magdeburg.mpg.de. Tel.: +49-(0)391-6110 401. Fax: +49-(0)391-6110 521.
Artemisinin, a secondary metabolite of sweet wormwood, is the basis for the production of the most effective antimalarial drugs. Since the amount of artemisinin currently produced from plants is not sufficient to treat the worldwide malaria cases, an effective semisynthetic method was developed recently that is capable of producing artemisinin from dihydroartemisinic acid (DHAA). DHAA is a byproduct obtained during the extraction of artemisinin from plant leaves. The photocatalytic reaction to convert DHAA to artemisinin can be performed continuously in a tubular reactor using toluene as a solvent. The reactor effluent contains besides artemisinin the photocatalyst (dicyanoanthracene) and several compounds that are structurally similar to artemisinin, including unreacted DHAA starting material. To isolate artemisinin from the reaction mixture, two separation techniques were applied, crystallization and chromatography. The solid obtained by seeded cooling crystallization was highly enriched in artemisinin but contained also traces of the photocatalyst. In contrast, using a variant of continuously operated multicolumn simulated moving bed (SMB) chromatography, which splits the feed into three fractions, we were able to recover efficiently the photocatalyst in the raffinate stream. The extract stream provided already almost pure artemisinin, which could be finally further purified in a simple crystallization step.
Magdeburg, Germany
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This Little Known Chinese Herb Kills 12,000 Cancer Cells For Every Healthy Cell


WORMWOOD PLANT
This Little Known Chinese Herb Kills 12,000 Cancer Cells For Every Healthy Cell
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Today, odds are that you have had/have cancer, or know somebody who does. In Canada, approximately one million Canadians that were alive at…
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A little known Chinese herb might be eligible for the growing list of cancer killers via alternative methods of treatment. According to  studies published  in Life Sciences, Cancer Letters and Anticancer Drugs, artemesinin, a derivative of the wormwood plant commonly used in Chinese medicine, can kill off  cancer cells, and do it at a rate of 12,000 cancer cells for every healthy cell.
Artemisinin is currently FDA approved for the treatment of malaria, it’s very safe and easy to use. It’s inexpensive and works on all cancers but has yet to find it’s way into the mainstream. It’s really time to move beyond just radiation, surgery and chemotherapy for the treatment of cancer.
Artemisinin.svgartemisinin
“Artemisinin reacts with iron to form free radicals that kill cells. Since cancer cells uptake relatively larger amounts of iron than normal cells, they are more susceptible to the toxic effect of artemisinin. In previous research, we have shown that artemisinin is more drawn to cancer cells than to normal cells. In the present research, we covalently attached artemisinin to the iron-carying plasma glycoprotein transferrin.Transferrin is transported into the cells via receptor-mediated endocytosis and cancer cells express significantly more transferrin receptors on their cell surface and endocytose more transferrin than normal cells. Thus, we hypothesize that by tagging artemisinin to transferrin, both iron and artemisinin would be transported into cancer cells in one package. Once inside a cell, iron is released and can readily react with artemisinin close by tagged to the transferrin. This would enhance the toxicity and selectivity of artemisinin towards cancer cells. We found that holotransferrin-tagged artemisinin, when compared with artemisinin, was very potent and selective in killing cancer cells. Thus, this ‘tagged-compound’ could potentially be developed into an effective chemotherapeutic agent for cancer treatment.” 

Wormwood

Other common name(s): absinthium, absinth wormwood

Scientific/medical name(s): Artemisia absinthium

Description

Wormwood is a shrubby perennial plant whose upper shoots, flowers, and leaves are used in herbal remedies and as a bitter flavoring for alcoholic drinks. It is native to Europe, northern Africa, and western Asia, and now also grows in North America.

Overview

Available scientific evidence does not support claims that wormwood is effective in treating cancer, the side effects of cancer treatment, or any other conditions. The plant contains a volatile oil with a high level of thujone (see Thuja). There are reports that taking large doses of wormwood internally can cause serious problems with the liver and kidneys. It can also cause nausea, vomiting, stomach pain, headache, dizziness, seizures, numbness of the legs and arms, delirium, and paralysis.

Wormwood, or Artemisia absinthium, should not be confused with sweet wormwood, or Artemisia annua. Although wormwood is related to sweet wormwood, they are used in different ways. Extracts of sweet wormwood have been used in traditional herbal medicine, and an active ingredient, artemisinin, is now used in conventional medical treatment of malaria.

How is it promoted for use?

Wormwood is promoted as a sedative and anti-inflammatory. There are also claims that it can treat loss of appetite, stomach disorders, and liver and gallbladder complaints. In folk medicine it is used for a wide range of stomach disorders, fever, and irregular menstruation. It is also used to fight intestinal worms. Externally, it is applied to poorly healing wounds, ulcers, skin blotches, and insect bites. It is used in Moxibustion treatments for cancer (seeMoxibustion). Available scientific evidence does not support these claims.

What does it involve?

Wormwood is taken in small doses for a short period of time, usually a maximum of 4 weeks. It is available as a capsule and as a liquid that can be added to water to make a tincture. The whole herb is sometimes brewed as a tea. Wormwood oil, washes, or poultices can also be used on the skin. Although pure wormwood is not available, “thujone-free” wormwood extract has been approved by the US Food and Drug Administration (FDA) for use in foods and as a flavoring in alcoholic drinks such as vermouth.

What is the history behind it?

Artemisia absinthium was used by Hippocrates, and the earliest references to wormwood in Western civilization can be found in the Bible. Extract of wormwood was also used in ancient Egypt. The herb is mentioned often in first-century Greek and Roman writings and reportedly was placed in the sandals of Roman soldiers to help soothe their sore feet. It was taken as a treatment for tapeworms as far back as the Middle Ages.

In 1797, Henri Pernod developed absinthe, an alcoholic drink containing distilled spirits of wormwood, fennel, anise and sometimes other herbs. Absinthe became very popular in Europe and the United States in the nineteenth century. It was eventually banned in several countries in the early twentieth century due to its purported ill effects and addictive qualities. More recent analysis has suggested that, when properly prepared and distilled, the thujone content in these drinks was very low. It appears more likely that the addictiveness and other ill effects of absinthe were due to its alcohol content, which is around 60% to 85%. Varying additives or impurities from different distillers may have also produced some of these effects. Even though absinthe is illegal in some countries, various types can be found in some European countries. However, their thujone content is strictly limited. Wormwood is also an ingredient in vermouth and other drinks.

What is the evidence?

Available scientific studies do not support the use of wormwood for the treatment of cancer or the side effects of conventional cancer treatment. There is not enough evidence available to support its use for other conditions. Wormwood oil has been tested in laboratory studies and appears to inhibit the growth of some fungi. However, human tests have not been completed.

Some derivatives of Artemisia annua, or sweet wormwood, a relative of wormwood, have been shown to be effective in the treatment of malaria. In fact, the World Health Organization approved artemisinin for use against malaria in Africa in 2004. These extracts also show some promise in laboratory studies as cancer treatment drugs. Further studies are required to find out whether the anti-cancer results apply to people. It is important to remember that extracted compounds are not the same as the whole herb, and study results are not likely to show the same effects.

Are there any possible problems or complications?

This product is sold as a dietary supplement in the United States. Unlike companies that produce drugs (which must be tested before being sold), the companies that make supplements are not required to prove to the Food and Drug Administration that their supplements are safe or effective, as long as they don’t claim the supplements can prevent, treat, or cure any specific disease.
Some such products may not contain the amount of the herb or substance that is on the label, and some may include other substances (contaminants). Actual amounts per dose may vary between brands or even between different batches of the same brand. In 2007, the FDA wrote new rules to improve the quality of manufacturing for dietary supplements and the proper listing of supplement ingredients. But these rules do not address the safety of the ingredients or their effects on health.
Most such supplements have not been tested to find out if they interact with medicines, foods, or other herbs and supplements. Even though some reports of interactions and harmful effects may be published, full studies of interactions and effects are not often available. Because of these limitations, any information on ill effects and interactions below should be considered incomplete.

Wormwood should be avoided, especially by women who are pregnant or breast-feeding, by people who have had seizures, and by those with ulcers or stomach irritation. Thujone, a component of wormwood, is known to cause muscle spasms, seizures, and hallucinations if taken internally. In high doses it is known to damage the liver and the kidneys.

Because of its thujone content, large doses of wormwood taken internally can lead to vomiting, stomach and intestinal cramps, headaches, dizziness, nervous system problems, and seizures. Wormwood can also lead to liver failure. The New England Journal of Medicine reported that a man who ordered essential oil of wormwood over the Internet, thinking he had purchased absinthe, suffered liver failure shortly after drinking the oil. Wormwood may also make seizures more likely and may interfere with the anti-convulsant effects of medicines such as phenobarbital.

The plant is a relative of ragweed and daisies. Those with allergies to these types of plants may also be allergic to wormwood. Contact with wormwood can cause rash in some people.

Relying on this type of treatment alone and avoiding or delaying conventional medical care for cancer may have serious health consequences.

OPRD PAPER-An Improved Manufacturing Process for the Antimalaria Drug artemether


Abstract Image

Novartis Pharma AG, Chemical and Analytical Development and Chemical Operations, CH-4002 Basel, Switzerland.
Org. Process Res. Dev., 2007, 11 (3), pp 336–340
DOI: 10.1021/op0602425
Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was reinvestigated. The most important factor for obtaining optimal yields is to ensure low levels of contamination of potassium hydroxide in potassium borohydride. Application of a lower reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with acid are further important parameters in guaranteeing a robust process. In the redesign of the conversion of dihydroartemisinin to artemether, the yield was increased, and dichloromethane was replaced by the ecologically friendlier methyl acetate. A robust manufacturing process forartemether is now at hand, allowing the production of this important medicine reliably and in good quality and yield.

OPRD PAPER-Streamlined Process for the Conversion of Artemisinin to Artemether


Abstract Image
Clinton Health Access Initiative, 383 Dorchester Avenue, Suite 400, Boston, Massachusetts 02127, United States
Org. Process Res. Dev., 2012, 16 (5), pp 764–768
DOI: 10.1021/op300037e
PAPER reports an improvement to the previously published manufacturing process for artemether, a key antimalarial drug, utilizing readily available reagents, easily controlled manufacturing conditions, and a greatly simplified workup and isolation. New analytical methods and in-process controls allow for optimization of yield through control of side product formation. A 70% overall yield from the two-step conversion of naturally or synthetically derived artemisinin to pure β-artemether is obtained. This corresponds to a usage factor of 1.35 kg of artemisinin needed to produce 1 kg of β-artemether, compared to the current industry average of 1.59 kg.
Org. Process Res. Dev.201216 (8), pp 1455–1455
Publication Date (Web): August 1, 2012 (Addition/Correction)
DOI: 10.1021/op300201z
Correction to A Streamlined Process for the Conversion of Artemisinin toArtemether … The structure for β-artemether is shown above, with the correct stereochemistry shown at the anomeric (8a) position. … Assignments are correct for the α- and β-anomers of artemether and dihydroartemisinin as discussed in the text; only the structure drawings are in error. …
ACTs (Artemisinin) is extracted from the plant Artemisia annua out sesquiterpene lactones, is specific for malaria. With its discoverer Tu Yo Yo in 2011 received the Lasker Award for Clinical Medicine (Lasker Award), and because a number of the Lasker Award winners also won the Nobel Prize, artemisinin and its discoverer Tu Yo Yo won the Chinese public and widespread media attention.
The total synthesis of artemisinin from the Isopulegol ((-)-Isopulegol) began [JACS, 1983, 624].Contrast extracted from plants, is not an economical total synthesis method, but activity was found in the total synthesis of analogues are better practical significance of a thing. In this type of terpene total synthesis of natural products stereochemical conformation analysis is also very interesting. Hu menthol with MOMCl protected hydroxy, and get a double borohydride alcohol 1. Hydroboration Addition of anti-Markovnikov rule, which is replaced by hydrogen atoms added to the side of Quito, and the boron atoms added to the less substituted side. As the front side of the double bond MOM large steric hindrance, from the double rear borane adduct, resulting product1 . Compound 1 with a benzyl group protecting the primary alcohol, HCl removal of MOM protecting, PCC oxidation of the secondary alcohol to the ketone 3 . 3 with the hydrogen generating pull enolates LDA 4 , because of steric hindrance than hydrogen methyl, the nucleophilic reaction occurs in the torus , the form compound 5 . Ketone 5 and lithium reagent 6 an addition reaction, if one equivalent of lithium reagent, the resulting product was a 1:1 8 and 9 , if the 10-fold excess of lithium reagent, the resulting product was 8:1 8 and 9 . Lithium reagent 6 as a nucleophile large volume, its addition of cyclohexanone from the equatorial position to attack (such as an intermediate state 7 as shown), so that the generated key in an upright position hydroxyl group. Equivalent of lithium reagent no stereoselectivity of the reaction, but when a large excess of lithium, when chiral ketone 5 lithium reagent of the racemic 6 kinetic resolution becomes possible. Intermediate state 7 in, R configuration of the lithium reagent to Ketones speed is faster than its enantiomer S configuration lithium reagent. So generate eight faster than 9 , and finally get 8 and 9 of the ratio of 8:1. Lithium reagent 6, TMS air resistance maximum (A-value = 2.5 kcal / mol), OMe second air resistance (A-value = 0.75 kcal / mol), so that when the attack is downward TMS, OMe and H is determined by the relative position of cyclohexanone 2,6 substituent to the size and conformation of the decision, and should also be considered in the attack Burgi-Dunitz angle, so that the stereochemistry of the product unpredictable. Compound 8after removal of the benzyl protecting the primary alcohol with excess oxidized to carboxyl groups PCC automatically generate a macrolide 10 . 10 of the vinyl silane with m -CPBA and TFA into one11 , and then generate the enol methyl desilication TBAF ethers 12 , 12 and singlet oxygen reacts13 directly after treatment with acid artemisinin.
ACTs (Artemisinin) drugs to treat malaria
ACTs (Artemisinin) drugs to treat malaria

ACTs (Artemisinin) drugs to treat malaria

ACTs (Artemisinin) drugs to treat malaria

WHO approves synthetic source of artemisinin


 

Artemesininby

Rachel Mundy

 13 May 2013

A genetically engineered source of the chemical required to make antimalarial drugs has received WHO approval, paving the way for improved access to affordable treatment against malaria in developing countries.

http://www.scidev.net/en/health/malaria/news/who-approves-synthetic-source-of-artemisinin.html?goback=%2Egmp_165490%2Egde_165490_member_240860517

ARTEMISININ AN ACE ANTIMALARIAL


Artemisinin

by on Jan 20, 2012

  • 956 views as on 12 may2013

Anthony Melvin Crasto presents Artemisinin, Glenmark scientist helping millions

amcrasto@gmail.com

http://www.slideshare.net/anthonycrasto64/anthony-melvin-crasto-presents-artemisinin-11174931

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