80286-58-4

Basic information

• Product Name: artemisic acid
• Synonyms: artemisic acid;Artimisinic Acid;2-[[(1R)-4β,7-Dimethyl-1,2,3,4,4aβ,5,6,8aβ-octahydronaphthalen]-1α-yl]acrylic acid;Qing Hau acid;Qinghao acid;ARTEMISININIC ACID;4,11(13)-AMorphadien-12-oic acid;4,11(13)-Cadinadien-12-oic acid
• CAS NO: 80286-58-4
• Molecular Formula: C₁₅H₂₂O₂
• Molecular Weight: 234.337
• Product Categories: Miscellaneous Natural Products;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract
• Mol File: 80286-58-4.mol
• Article Data: 5

Chemical Properties

• Melting Point: 129-131℃
• Boiling Point: 373.563 °C at 760 mmHg
• Flash Point: 273.336 °C
• Appearance: /
• Density: 1.019
• Vapor Pressure: 1.31E-06mmHg at 25°C
• Refractive Index: 1.504
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 4.32±0.11(Predicted)
• CAS DataBase Reference: artemisic acid(CAS DataBase Reference)
• NIST Chemistry Reference: artemisic acid(80286-58-4)
• EPA Substance Registry System: artemisic acid(80286-58-4)

Safety Data

• Hazardous Substances Data: 80286-58-4(Hazardous Substances Data)

Usage

Uses

Artemisic Acid is a derivative of Artemisinin (A777500), an antimalarial constituent of the tradional Chinese medicinal herb Artemisia annua L., Compositae, which has been known for almost 2000 years as Qinghao. Antimalarial.

Definition

ChEBI: A monocarboxylic acid that is prop-2-enoic acid which is substituted at position 2 by a 4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl group (the 1S,4R,4aS,8aR diastereoisomer). I is a sesquiterpenoid precursor of artemisinin, obtained from sweet wormwood, Artemisia annua.

InChI:InChI=1/C15H22O2/c1-9-4-6-12-10(2)5-7-13(14(12)8-9)11(3)15(16)17/h8,10,12-14H,3-7H2,1-2H3,(H,16,17)/t10-,12?,13?,14?/m1/s1

Synthetic route

dehydroartemisinyl alcohol (125184-95-4) → artemisinic acid (80286-58-4)

Conditions	Yield
With Jones reagent In acetone at 20℃;	100%

ethanol (64-17-5) + D-glucose (50-99-7) → artemisinic acid (80286-58-4)

Conditions	Yield
With Tetradecanoic acid 1-methylethyl ester; artemisinic acid producing yeast strain In water for 123.4h; Product distribution / selectivity; Enzymatic reaction;

ethanol (64-17-5) → artemisinic aldehyde + artemisinic acid (80286-58-4) + (1R,4R,4aS,8aR)-4,7-dimethyl-1-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene (92692-39-2) + dehydroartemisinyl alcohol (125184-95-4)

Conditions	Yield
With Tetradecanoic acid 1-methylethyl ester Reagent/catalyst; Enzymatic reaction;

ethanol (64-17-5) → artemisinic acid (80286-58-4) + (1R,4R,4aS,8aR)-4,7-dimethyl-1-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene (92692-39-2) + dehydroartemisinyl alcohol (125184-95-4)

Conditions	Yield
With Tetradecanoic acid 1-methylethyl ester Reagent/catalyst; Enzymatic reaction;

diazomethane (186581-53-3, 908094-01-9) + artemisinic acid (80286-58-4) → methyl artemisinate (82869-24-7)

Conditions	Yield
In diethyl ether at 0℃;	100%
In diethyl ether at 0℃;	99%
In diethyl ether for 0.333333h; Ambient temperature;	98%

artemisinic acid (80286-58-4) → dihydroartemisinic acid (85031-59-0, 110715-68-9, 126643-10-5)

Conditions	Yield
With lithium borohydride; nickel dichloride In methanol for 2h; Ambient temperature;	100%
With C48H50Cl4N2O2P2Ru3; hydrogen; sodium hydrogencarbonate In methanol at 0℃; under 22502.3 Torr; for 36h; Autoclave;	98%
With palladium on activated charcoal; hydrogen In chloroform at 20℃; under 750.075 Torr; Solvent; Pressure; Reagent/catalyst;	98%

diazomethane (186581-53-3, 908094-01-9) + artemisinic acid (80286-58-4) → (S)-3-((1R,4R,4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-naphthalen-1-yl)-4,5-dihydro-3H-pyrazole-3-carboxylic acid methyl ester (150665-64-8)

Conditions	Yield
In diethyl ether at 0℃; for 10h;	98%

artemisinic acid (80286-58-4) → (S)-dihydroartemisinic acid (110715-68-9)

Conditions	Yield
With C48H50Cl4N2O2P2Ru3; hydrogen; sodium hydrogencarbonate In methanol at 0℃; under 22502.3 Torr; for 36h; Autoclave;	98%
With dihydrogen peroxide; hydrazine hydrate In ethanol at 0 - 20℃;	86%

artemisinic acid (80286-58-4) → dihydroartemisinic acid (161022-41-9)

Conditions	Yield
With hydrogen; potassium hydroxide In water; toluene at 0 - 60℃; under 76005.1 Torr; for 12h; Reagent/catalyst; Solvent; Autoclave; enantioselective reaction;	97.4%
With hydrogen; Wilkinson's catalyst In methanol under 1551.49 - 1913.5 Torr; for 289h; Product distribution / selectivity; Parr apparatus;
With tris(triphenylphosphine)ruthenium(II) chloride; C48H50N2O2P2Ru; hydrogen; triethylamine In methanol at 0℃; under 15001.5 Torr; for 24h; Autoclave; enantioselective reaction;	n/a

artemisinic acid (80286-58-4) + Propargylamine (2450-71-7) → 2-((1R,4R,4aS,8aR)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl)-N-(prop-2-yn-1-yl)acrylamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 6h; Inert atmosphere;	95%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 6h; Inert atmosphere;	95%

artemisinic acid (80286-58-4) + methyl p-toluene sulfonate (80-48-8) → methyl artemisinate (82869-24-7)

Conditions	Yield
With potassium carbonate In acetone for 1h; Heating;	94%

artemisinic acid (80286-58-4) + propargyl alcohol (107-19-7) → prop-2-yn-1-yl 2-((1R,4R,4aS,8aR)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl)acrylate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 25℃; for 12h;	94%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 25℃; for 12h;	94%

2-phenethyl iodide (17376-04-4) + artemisinic acid (80286-58-4) → 2-((1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-naphthalen-1-yl)-5-phenyl-pentanoic acid

Conditions	Yield
With triethyl borane; tri-n-butyl-tin hydride In hexane at 20℃; for 16h; Addition;	72%

artemisinic acid (80286-58-4) → dehydroartemisinyl alcohol (125184-95-4)

Conditions	Yield
Stage #1: artemisinic acid With lithium aluminium tetrahydride In tetrahydrofuran at 70℃; for 15h; Heating / reflux; Stage #2: With sodium hydroxide; water In tetrahydrofuran for 0.166667h;	65%
With diisobutylaluminium hydride
Multi-step reaction with 2 steps 1: 99 percent / diethyl ether / 0 °C 2: 82 percent / DIBAL / CH2Cl2 / -78 °C View Scheme

artemisinic acid (80286-58-4) → 3-β-hydroxyartemisinic acid (118059-19-1) + 3β,15-dihydroxyartemisinic acid

Conditions	Yield
With endophytic fungus Trichothecium roseum CIMAPN1 In aq. phosphate buffer; acetone at 28℃; for 336h; pH=6; Microbiological reaction; stereoselective reaction;	A 51.1% B 37.3%

artemisinic acid (80286-58-4) → 3β-hydroxyartemisinic acid + 3β,15-dihydroxyartemisinic acid + 9-oxo-arteannuinic acid

Conditions	Yield
With cell culture of endophytic fungus Trichothecium roseum In acetone for 336h; Microbiological reaction;	A 50.4% B 32.2% C 5.2%

D-glucose (50-99-7) + artemisinic acid (80286-58-4) → artemisinic acid glucose ester

Conditions	Yield
With whole-cell of E. coli BL21 culture at 25℃; for 72h; pH=7.0; aq. buffer; Enzymatic reaction;	18.6%

diazomethane (186581-53-3, 908094-01-9) + artemisinic acid (80286-58-4) → methyl <2'R,4a'S,5'R,8'R>-2-(2',5'-dimethyl-2'-hydroperoxy-2',3',4',4a',5',6',7',8'-octahydronaphthalen-8'-yl)propenoate (129165-35-1)

Conditions	Yield
With oxygen; rose bengal 1.) acetonitrile, -30 deg C, irradiation, 2.) ether, 0 deg C; Yield given. Multistep reaction;

diazomethane (186581-53-3, 908094-01-9) + artemisinic acid (80286-58-4) → 2-(4,7-dimethyl-(1α-H),2,3,(4β-H),(4aα-H),5,6,(8aα-H)-octahydronaphthalen-1-yl)propionic acid methyl ester (87391-99-9) + 11S-methyl arteannuinate (85788-54-1, 87391-99-9, 98575-64-5)

Conditions	Yield
With sodium tetrahydroborate; nickel dichloride 1.) MeOH, -15 deg C, 2.) 30 min; Multistep reaction;

artemisinic acid (80286-58-4) → dehydroqinghaosu (101020-89-7)

Conditions	Yield
With oxygen; copper(II) bis(trifluoromethanesulfonate); rose bengal 1.) acetonitrile, -30 deg C, 2.) from -20 deg C to RT, 12 h; Yield given. Multistep reaction;

artemisinic acid (80286-58-4) → C12H13O2(CH3)3(O)(OO) (63968-64-9) + (1R,5S,8R,9S,12R,14R)-8,12-dimethyl-4-methylidene-2,13-dioxatetracyclo[7.5.0.01,5.012,14]tetradecan-3-one (50906-56-4)

Conditions	Yield
In water at 30℃; for 2h; cell-free extract from Artemisia annua L. (Asteraceae), EDTA, HEPES with DDT buffer, pH 7.15; Title compound not separated from byproducts;

artemisinic acid (80286-58-4) → arteannuin B

Conditions	Yield
With oxygen; methylene blue In ethanol at 22℃; for 4h; Irradiation; Yield given;

artemisinic acid (80286-58-4) → 2-((1S,4R,4aS,6S,8aR)-6-Hydroxy-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-naphthalen-1-yl)-acrylic acid

Conditions	Yield
microbial fermentation by Mucor mucedo; Yield given;

artemisinic acid (80286-58-4) → 2-((1S,4R,4aS,6S,8aR)-6-Hydroxy-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-naphthalen-1-yl)-acrylic acid + 3-α-hydroxyartemisinic acid

Conditions	Yield
microbial fermentation by Aspergilus flavipes; var. organism; Yield given. Yields of byproduct given;

artemisinic acid (80286-58-4) → 2-((1R,4R,4aS,7R)-7-Hydroxy-4,7-dimethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-1-yl)-acrylic acid (128261-36-9)

Conditions	Yield
With dihydrogen peroxide; oxygen; triethyl phosphite; methylene blue 1.) irradiation, CH2Cl2, -78 deg C, 2.5 h; 2.) Et2O-petrol, rt, 30 min; 3.) t-BuOH; Yield given. Multistep reaction;

artemisinic acid (80286-58-4) → 2-((1R,4R,4aS,7R)-7-Hydroxy-4,7-dimethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-1-yl)-acrylic acid (128261-36-9) + epi-deoxyarteannuin B

Conditions	Yield
With oxygen; sodium carbonate; triphenylphosphine; methylene blue 1.) irradiation, CH2Cl2, -78 deg C, 2.5 h; 2.) to -15 deg C, 30 min; 3.) water, 100 deg C, 2h; Yield given. Multistep reaction. Yields of byproduct given;

artemisinic acid (80286-58-4) → epi-deoxyarteannuin B

Conditions	Yield
With oxygen; methylene blue In dichloromethane at -78℃; for 2.5h; Irradiation;

chloro-trimethyl-silane (75-77-4) + artemisinic acid (80286-58-4) → C18H30O2Si (195060-78-7)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h;
With n-butyllithium 1) THF, 0 deg C, 15 min, 2) THF, 0 deg C, 15 min; Multistep reaction;

triisopropylsilyl chloride (13154-24-0) + artemisinic acid (80286-58-4) → C24H42O2Si (195060-80-1)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h;
With n-butyllithium 1) THF, 0 deg C, 15 min, 2) THF, 0 deg C, 15 min; Multistep reaction;

artemisinic acid (80286-58-4) + tert-butyldimethylsilyl chloride (18162-48-6) → C21H36O2Si (195060-79-8)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h;
With n-butyllithium 1) THF, 0 deg C, 15 min, 2) THF, 0 deg C, 15 min; Multistep reaction;

triisopropylsilyl chloride (13154-24-0) + artemisinic acid (80286-58-4) → C21H36O2Si (195060-79-8)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h;

artemisinic acid (80286-58-4) + tert-butyldimethylsilyl chloride (18162-48-6) → C24H42O2Si (195060-80-1)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at 0℃; for 0.25h;

Upstream product

• 64-17-5 ethanol 
• 50-99-7 D-glucose 
• 125184-95-4 dehydroartemisinyl alcohol 

Downstream Products

• 474326-29-9 12-(p-vinyl)homobenzyldihydroartemisinyl alcohol 
• 474326-32-4 12-(p-vinyl)homobenzyldeoxoartemisinin 
• 126189-95-5 (+)-deoxyartemisinin 
• 127924-95-2 (1R,2S,3R,6S)-1-Hydroperoxy-6-((R)-2-hydroxy-1-methyl-ethyl)-3-methyl-2-(3-oxo-butyl)-cyclohexanecarbaldehyde 
• 110715-68-9 (S)-dihydroartemisinic acid 
• 85031-59-0 dihydroartemisinic acid 
• 63968-64-9 C₁₂H₁₃O₂(CH₃)3(O)(OO) 
• 63968-64-9 qinghaosu 
• 87322-21-2 (R)-2-{(1S,3S,4R)-2-[1-Methoxy-meth-(Z)-ylidene]-4-methyl-3-[2-(2-methyl-[1,3]dithian-2-yl)-ethyl]-cyclohexyl}-propionic acid methyl ester 
• 106623-24-9 (R)-2-{(1R,2S,3S,4R)-2-Formyl-4-methyl-3-[2-(2-methyl-[1,3]dithian-2-yl)-ethyl]-cyclohexyl}-propionic acid methyl ester 

Relevant articles and documents

High-level semi-synthetic production of the potent antimalarial artemisinin

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

CONVERSION OF AMORPHA-4,11-DIENE TO ARTEMISININ AND ARTEMISININ PRECURSORS

The present invention relates to methods for the conversion of amorpha-4,11-diene to artemisinin and various artemisinin precursors.

Method of preparing (+)-deoxoartemisinin and selected analogues of (+)-deoxoartemisinin

This invention is a new method for preparing compounds useful as antimalarial agents having the formula; STR1 wherein R is hydrogen, a linear, branched or cyclo lower alkyl group having 1 to 8 carbon atoms; aminoalkyl; branched aminoalkyl; hydroxyalkyl: alkylcarboxylate or alkylbenzoate groups having 1 to 5 carbon atoms in the alkyl chains; aryl; alkoxy-substituted aryl; heteroaryl; and pyridinium groups. The method comprises treating artemisinic acid with a methylating agent followed by a stereoselective reduction of the methylated compound, subjecting the reduced compound to a Grignard addition followed by chiral photoxidation with subsequent treatment with a cyclization agent.