71963-77-4

Basic information

• Product Name: Artemether
• Synonyms: methyl-dihydroartemisinine;[3r-(3r,5as,6s,8as,9r,10r,12s,12ar**)]-decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12h-pyrano[4,3-j]-1,2-benzodioxepin;ARTEMETHER;ARTHEMETER;Artimether;ArtemetherC16H26O5;ARTEMTHER;(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin
• CAS NO: 71963-77-4
• Molecular Formula: C₁₆H₂₆O₅
• Molecular Weight: 298.37
• EINECS: 1806241-263-5
• Product Categories: Antimalarial;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;API;Herb extract;Inhibitor;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;PALUTHER;natural product
• Mol File: 71963-77-4.mol
• Article Data: 13

Chemical Properties

• Melting Point: 86-88°C
• Boiling Point: 359.79°C (rough estimate)
• Flash Point: 140.5 °C
• Appearance: off-white to light brown/
• Density: 1.0733 (rough estimate)
• Refractive Index: 1.6200 (estimate)
• Storage Temp.: room temp
• Solubility: DMSO: ≥20mg/mL
• Merck: 14,815
• CAS DataBase Reference: Artemether(CAS DataBase Reference)
• NIST Chemistry Reference: Artemether(71963-77-4)
• EPA Substance Registry System: Artemether(71963-77-4)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Safety Statements: 24/25
• WGK Germany: 3
• RTECS: KD4165000
• Hazardous Substances Data: 71963-77-4(Hazardous Substances Data)

Usage

Description

Artemether is an antiparasitic compound and a derivative of artemisinin . It induces mortality in adult wild-type and pfatp6-mutant P. falciparum but the efficacy is decreased in the mutants (IC50s = 8.2 and 13.5 nM, respectively). Artemether reduces parasitemia in P. falciparum-infected monkeys and P. berghei-infected mice with 50% curative dose (CD50) values of 7.1 and 55 mg/kg, respectively. It also reduces the worm burden of S. mansoni trematodes in mice when used at doses ranging from 200 to 500 mg/kg. Formulations containing artemether have been used in the treatment of malaria.

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 71963-77-4 differently. You can refer to the following data:
1. Derivative of Artemisinin (A777500). Antimalarial, used to treat strains of malaria which are multi-drug resistant.
2. atypical antidepressant, norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist
3. Artemether and lumefantrine combination therapy is indicated for the treatment of acute uncomplicated malaria caused by Plasmodium falciparum, including malaria acquired in chloroquine-resistant areas. May also be used to treat uncomplicated malaria when

Definition

ChEBI: An artemisinin derivative that is artemisinin in which the lactone has been converted to the corresponding lactol methyl ether. It is used in combination with lumefantrine as an antimalarial for the treatment of multi-drug resistant strains of falcip rum malaria.

General Description

Artemisinin (ART) is a natural compound present in Artemisia annua, a traditional Chinese plant.

Biochem/physiol Actions

Artemether is a methyl ether derivative of artemisinin. It is used against multi-drug resistant strains of the malaria parasite, Plasmodium falciparum, and shows potential in treatment of schistosomiasis.

Safety Profile

Poison by intramuscular route.Experimental reproductive effects. When heated todecomposition it emits acrid smoke and irritating fumes.

InChI:InChI=1/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15-,16?/m1/s1

Synthetic route

Trimethyl orthoacetate (1445-45-0) + dihydroartemisinin (71939-50-9) → artemether (71963-77-4)

Conditions	Yield
With perchloric acid In ethanol at 0℃; for 8h; pH=2; Reagent/catalyst; pH-value; Temperature;	97.6%

trimethoxypropane (24823-81-2) + dihydroartemisinin (71939-50-9) → artemether (71963-77-4)

Conditions	Yield
With sulfuric acid In isopropyl alcohol at 0 - 12℃; for 4h; pH=2; Solvent; Temperature; Reagent/catalyst; pH-value;	97.2%

dihydroartemisinin (71939-50-9) + trimethyl orthoformate (149-73-5) → artemether (71963-77-4)

Conditions	Yield
With methanesulfonic acid In ethanol at 5 - 20℃; for 3h; pH=5; Solvent; pH-value; Temperature; Reagent/catalyst;	96.6%
toluene-4-sulfonic acid In methanol at 30℃; for 0.5h;

methanol (67-56-1) + dihydroartesiminin (81496-81-3) → artemether (71963-77-4)

Conditions	Yield
With dimethylphosphoric acid; boron trifluoride diethyl etherate at 3 - 20℃; Reagent/catalyst; Temperature;	96.2%

dihydroartesiminin (81496-81-3) + trimethyl orthoformate (149-73-5) → artemether (71963-77-4)

Conditions	Yield
Stage #1: dihydroartesiminin; trimethyl orthoformate In methanol at 20℃; for 0.25h; Stage #2: With acetyl chloride In methanol at 10 - 15℃; Stage #3: With sodium hydrogencarbonate In methanol; water at 0 - 5℃; for 2h; Product distribution / selectivity;	74.67%

Methyl (R)-3-hydroxybutyrate (3976-69-0) + dihydroartemisinin (71939-50-9) → 9,10-dehydrodihydroartemisinin (82596-30-3) + artemether (71963-77-4) + C20H32O7 (120020-67-9)

Conditions	Yield
With boron trifluoride diethyl etherate In diethyl ether for 24h; Ambient temperature;	A n/a B n/a C 70%

(S)-3-hydroxybutyric acid methyl ester (53562-86-0) + dihydroartemisinin (71939-50-9) → 9,10-dehydrodihydroartemisinin (82596-30-3) + artemether (71963-77-4) + C20H32O7 (119946-74-6)

Conditions	Yield
With boron trifluoride diethyl etherate In diethyl ether for 24h; Ambient temperature;	A n/a B n/a C 56%

methanol (67-56-1) + dihydroartemisinin (71939-50-9) → artemether (71963-77-4) + α-artemether

Conditions	Yield
In benzene at 20℃; for 24h; Product distribution; Further Variations:; Reaction partners; Solvents; reaction times;
With hydrogenchloride In acetic acid methyl ester; water at 20 - 23℃; for 4.5h; Temperature; Concentration; Solvent;

2-Methoxypropene (116-11-0) + dihydroartesiminin (81496-81-3) → artemether (71963-77-4)

Conditions	Yield
Stage #1: 2-Methoxypropene; dihydroartesiminin In methanol at 20℃; for 0.25h; Stage #2: With methanesulfonyl chloride In methanol at 10 - 20℃; Stage #3: With sodium hydrogencarbonate In methanol at 20℃; for 2h; Product distribution / selectivity;

2,2-dimethoxy-propane (77-76-9) + dihydroartesiminin (81496-81-3) → artemether (71963-77-4)

Conditions	Yield
Stage #1: 2,2-dimethoxy-propane; dihydroartesiminin In methanol at 20℃; for 0.25h; Stage #2: With chloro-trimethyl-silane In methanol at 10 - 20℃; Stage #3: With sodium hydrogencarbonate In methanol at 20℃; for 2h; Product distribution / selectivity;

Trimethyl orthoacetate (1445-45-0) + dihydroartesiminin (81496-81-3) → artemether (71963-77-4)

Conditions	Yield
Stage #1: Trimethyl orthoacetate; dihydroartesiminin With sulfuric acid In methanol Stage #2: With sulfuric acid In methanol Stage #3: With sodium hydrogencarbonate In methanol; water Product distribution / selectivity;
With boron trifluoride diethyl etherate In methanol at 10 - 20℃; for 4h;	98 g

α-artemether → artemether (71963-77-4)

Conditions	Yield
With chloro-trimethyl-silane In toluene at 25 - 30℃; for 12h;

methanol (67-56-1) + dihydroartesiminin (81496-81-3) → artemether (71963-77-4) + α-artemether

Conditions	Yield
Stage #1: dihydroartesiminin With dodecatungstophosphoric acid hydrate In dichloromethane at 20℃; for 0.0833333h; Stage #2: methanol In dichloromethane at 20℃; for 3h; optical yield given as %de;

C12H13O2(CH3)3(O)(OO) (63968-64-9) → artemether (71963-77-4) + α-artemether

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / methanol 2.1: dodecatungstophosphoric acid hydrate / dichloromethane / 0.08 h / 20 °C 2.2: 3 h / 20 °C View Scheme

methanol (67-56-1) + C12H13O2(CH3)3(O)(OO) (63968-64-9) → artemether (71963-77-4) + α-artemether

Conditions	Yield
With sodium tetrahydroborate; cellulose sulfuric acid; trimethyl orthoformate In tetrahydrofuran at -5 - 20℃; for 2.5h;	A n/a B n/a

methanol (67-56-1) + dihydroartemisinin (71939-50-9) → artemether (71963-77-4)

Conditions	Yield
With amberlyst-15 In 2-methyltetrahydrofuran at 20℃; for 4h; Kinetics; Reagent/catalyst; Temperature; Flow reactor;

methanol (67-56-1) + dihydroartemisinin (71939-50-9) → artemether (71963-77-4)

Conditions	Yield
With perchloric acid In dichloromethane at 30 - 38℃; for 0.166667h; Temperature; Large scale;	756 g

Trimethyl orthoacetate (1445-45-0) + C12H13O2(CH3)3(O)(OO) (63968-64-9) → artemether (71963-77-4)

Conditions	Yield
Stage #1: C12H13O2(CH3)3(O)(OO) With methanol; sodium tetrahydroborate at -10 - -5℃; for 3h; Stage #2: Trimethyl orthoacetate With sulfuric acid; boron trifluoride diethyl etherate In methanol at 20℃; for 4h; pH=6 - 8; Catalytic behavior; Temperature;	101.9 g

artemether (71963-77-4) → deoxy-β-artemether

Conditions	Yield
With zinc In acetic acid for 1h; Ambient temperature;	72%

artemether (71963-77-4) → 9α-acetoxy-10β-methoxyartemethin-I + 3α-hydroxydeoxydihydroqinghaosu + 3α-hydroxy-12β-methoxyartemethin-III

Conditions	Yield
With iron(II) sulfate In water; acetonitrile at 37℃;	A 37% B 4% C 44%

DL-cysteine hydrochloride (10318-18-0) + artemether (71963-77-4) → 9α-acetoxy-10β-methoxyartemethin-I + 3α-hydroxy-12β-methoxyartemethin-III + Acetic acid (1R,3S,4R,4aS,7R,8S,8aR)-8-ethyl-8a-hydroxy-3-methoxy-4,7-dimethyl-octahydro-isochromen-1-yl ester + 3-[2-((1R,3S,4R,4aS,7R,8S,8aR)-1-Acetoxy-8a-hydroxy-3-methoxy-4,7-dimethyl-octahydro-isochromen-8-yl)-ethylsulfanyl]-2-amino-propionic acid

Conditions	Yield
With sodium hydrogencarbonate; iron(II) sulfate In acetonitrile at 20℃; for 4h; Further byproducts given;	A 26% B 44% C 10% D 3.2%

artemether (71963-77-4) + 1,4-diacetylbenzene bis(trimethylsilyl) enol ether → 10-m-acetylphenylartemisinin dimer

Conditions	Yield
Stage #1: artemether With titanium tetrachloride In dichloromethane at -78℃; for 0.0833333h; Metallation; Stage #2: 1,4-diacetylbenzene bis(trimethylsilyl) enol ether In dichloromethane at -78℃; for 1h; Condensation;	33%

artemether (71963-77-4) → 3α-hydroxydeoxy-β-artemether + 2-[(R)-4-Methyl-2-oxo-3-(3-oxo-butyl)-cyclohexyl]-propionaldehyde + 9α-acetoxy-10β-methoxyartemethin-I

Conditions	Yield
With iron(II) chloride In acetonitrile for 0.0333333h; Ambient temperature;	A 23% B 16% C 32%

artemether (71963-77-4) + 1,4-diacetylbenzene bis(trimethylsilyl) enol ether (183060-22-2) → 10-p-acetylphenylartemisinin dimer (229981-82-2)

Conditions	Yield
Stage #1: artemether With titanium tetrachloride In dichloromethane at -78℃; for 0.0833333h; Metallation; Stage #2: 1,4-diacetylbenzene bis(trimethylsilyl) enol ether In dichloromethane at -78℃; for 1h; Condensation;	26%

DL-cysteine hydrochloride (10318-18-0) + artemether (71963-77-4) → C18H29NO6S

Conditions	Yield
With sodium hydrogencarbonate; iron(II) sulfate In acetonitrile at 20℃; for 4h;	1.4%

Mn(TPP)Cl (32195-55-4) + artemether (71963-77-4) → Acetic acid (1R,3S,4R,4aS,7R,8S,8aR)-8a-hydroxy-3-methoxy-4,7-dimethyl-8-[2-((4Z,10Z,15Z,19Z)-(S)-5,10,15,20-tetraphenyl-2,3,22,24-tetrahydro-porphin-2-yl)-ethyl]-octahydro-isochromen-1-yl ester

Conditions	Yield
With tetra(n-butyl)ammonium borohydride; cadmium(II) nitrate 1.) CH2Cl2, r.t., 1 h, 2.) CH2Cl2, DMF, 30 min; Yield given. Multistep reaction;

artemether (71963-77-4) → β-2-deoxy-9-epidihydroartemisinin (1356857-18-5) + (2S, 3R, 6S)-2-(3-oxobutyl)-3-methyl-6-<(R)2-propanal>-cyclohexanone (107466-88-6) + deoxydihydroqinghaosu (72807-92-2)

Conditions	Yield
With 1-Benzyl-1,4-dihydronicotinamide; lumiflavin In acetonitrile at 20℃; for 2.5h; pH=7.4; aq. phosphate buffer; Inert atmosphere;

artemether (71963-77-4) → β-2-deoxy-9-epidihydroartemisinin (1356857-18-5) + deoxydihydroqinghaosu (72807-92-2)

Conditions	Yield
With 1-Benzyl-1,4-dihydronicotinamide; riboflavin In acetonitrile at 20℃; for 3h; pH=7.4; aq. phosphate buffer; Inert atmosphere;	A 52 %Spectr. B 12 %Spectr.

artemether (71963-77-4) → 9α-acetoxy-10β-methoxyartemethin-I + 3α-hydroxy-12β-methoxyartemethin-III

Conditions	Yield
With oxygen; methylene blue; ascorbic acid In acetonitrile at 20℃; for 24h; pH=7.4; aq. phosphate buffer;

Upstream product

• 67-56-1 methanol 
• 81496-81-3 dihydroartesiminin 
• 71939-50-9 dihydroartemisinin 
• 71939-50-9 dihydroartemisinin 
• 63968-64-9 C₁₂H₁₃O₂(CH₃)3(O)(OO) 
• 1445-45-0 Trimethyl orthoacetate 
• 77-76-9 2,2-dimethoxy-propane 
• 149-73-5 trimethyl orthoformate 
• 116-11-0 2-Methoxypropene 
• 3976-69-0 Methyl (R)-3-hydroxybutyrate 
• 53562-86-0 (S)-3-hydroxybutyric acid methyl ester 
• 24823-81-2 trimethoxypropane 

Downstream Products

• 181528-64-3 9α-acetoxy-10β-methoxyartemethin-I 
• 174097-70-2 3α-hydroxy-12β-methoxyartemethin-III 
• 1356857-18-5 β-2-deoxy-9-epidihydroartemisinin 
• 72807-92-2 deoxydihydroqinghaosu 
• 107466-88-6 (2S, 3R, 6S)-2-(3-oxobutyl)-3-methyl-6-<(R)2-propanal>-cyclohexanone 

Relevant articles and documents

One-pot green synthesis of β-artemether/arteether

An efficient one pot green synthesis of β-artemether/arteether from artemisinin has been developed using a sodium borohydride-cellulose sulfuric acid (CellSA) catalyst system. The green methodology is high yielding and the catalyst has good recyclability.

A process for preparing β - pedic ether process

The invention discloses a technology for preparing beta-artemether. The technology comprises the following steps: reducing an initial raw material artemisinin in the presence of a reducing agent to generate dihydroartemisinin, and carrying out an etherification reaction on dihydroartemisinin and trimethyl orthoacetate in the presence of a catalyst to prepare beta-artemether. Experiments prove that the technology allows the content of alpha-artemether generated in the methyl etherification reaction to be smaller than 3%, the HPLC purity of the obtained beta-artemether to be improved to above 99.8%, the content of single impurities to be smaller than 0.1% respectively and the quality of the above product to accord with requirements of United States Pharmacopeia; and the total mole yield of the product by artemisinin can reach 95% or above. The technology can avoid tedious intermediate processing links in the prior art, realizes simple-operation low-cost high-yield preparation of highly pure beta-artemether, accords with industrial production demands of beta-artemether, and has industrial application values.

Method for producing artesunate

The invention relates to a method for producing artesunate. The method is characterized by comprising the following steps: (a) carrying out a reaction: adding dihydroartemisinin into dichloromethane, then, adding methanol and perchloric acid, carrying out the reaction for 10 to 15 minutes, adding anhydrous sodium carbonate to terminate the reaction, and filtering the reaction solution; (b) carrying out concentration: concentrating the filtered reaction solution in a water bath with the temperature of about 55 DEG C; (d) carrying out crystallization: subjecting the concentrated mother liquor to freeze-crystallizing, and carrying out centrifugal filtration, so as to obtain crude crystals; (e) carrying out refining: dissolving the crude crystals with methanol at the temperature of 65 DEG C so as to obtain a saturated solution, carrying out cooling-crystallization, and carrying out centrifugal filtration; and (f) carrying out baking: subjecting the crystals to vacuum drying for 120 minutes at the temperature of 55 DEG C, thereby obtaining a finished product. According to the method, the yield can reach 76% in case of not treating the generated mother liquor, the reaction time is short, energy is saved, and the production cost is reduced.