WO2009088404A1 - Procédé de préparation d'artémisinine et de ses précurseurs - Google Patents

Procédé de préparation d'artémisinine et de ses précurseurs Download PDF

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WO2009088404A1
WO2009088404A1 PCT/US2008/011662 US2008011662W WO2009088404A1 WO 2009088404 A1 WO2009088404 A1 WO 2009088404A1 US 2008011662 W US2008011662 W US 2008011662W WO 2009088404 A1 WO2009088404 A1 WO 2009088404A1
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formula
dihydroartemisinic
solvent
stereoisomer
agent
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PCT/US2008/011662
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English (en)
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Karl Fisher
Derek Mcphee
Frank Xavier Woolard
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Amyris Biotechnologies, Inc.
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Publication of WO2009088404A1 publication Critical patent/WO2009088404A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems

Definitions

  • the present invention provides processes for the preparation of artemisinin and its precursors such as amorphadiene, amorphadiene epoxide, dihydroartemisinic alcohol and dihydroartemisinic acid.
  • artemisinin is prepared by multi-step synthetic processes from amorphadiene, amorphadiene epoxide, dihydroartemisinic alcohol or dihydroartemisinic acid. Processes for the preparation of the artemisinin precursors are also disclosed.
  • artemisinin can be obtained by extracting artemisinin or its precursor artemisinic acid from Artemisia annua.
  • the extraction method provides artemisinin or artemisinic acid from the plant in inconsistent and low yields, which may not meet the worldwide demand for them. Therefore, there is a need for improved methods of producing artemisinin or its precursors in a large scale that can meet the worldwide demand.
  • artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans.
  • 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.
  • Dihydroartemisinic acid used for preparing artemisinin can be obtained from artemisinic acid by reducing its exocyclic methylene group with a variety of reducing agents.
  • Both dihydroartemisinic acid or artemisinic acid can be prepared from amorphadiene-11- 5,12-epoxide by multi-step synthetic procedures.
  • artemisinin and its precursors such as amorphadiene epoxide and dihydroartemisinic acid in a large scale. Also provided herein are processes that have better control over the stereochemistry of artemisinin and its precursors.
  • each of X'-X 12 is independently H, halo or linear or branched alkyl; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently halo or linear or branched alkyl with the proviso that at least one of X'-X 12 is not H.
  • each of X 1 -X 12 is independently H, halo or linear or branched alkyl; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently halo or linear or branched alkyl with the proviso that at least one of X'-X 12 is not H;
  • the amorphadiene- 11 -S, 12-epoxide of Formula (II) is prepared by a microorganism.
  • the amorpha-l,4-diene of Formula (IV) is prepared by a microorganism.
  • the hydroboration agent is 9-borabicyclo[3.3. ljnonane, disiamylborane, thexylborane, dicyclohexylborane, di(isopropylprenyl)borane, borane or a combination thereof.
  • the hydroboration agent is 9- borabicyclo [3.3.1] nonane .
  • each of X'-X 12 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 of the metalloporphyrin having Formula (XI) used herein is fluoro.
  • the epoxidizing agent used in the epoxidizing step or reaction disclosed herein is oxygen, a peroxide, a peracid, a hypochlorite, a peroxydisulfate, a dioxyrane, iodosylbenzene, or a combination thereof.
  • the epoxidizing agent is a peroxide.
  • the peroxide is hydrogen peroxide.
  • the epoxidizing reaction occurs in the presence of ammonium acetate and ammonium bicarbonate. In other embodiments, the epoxidizing reaction occurs in a solvent, hi further embodiments, the solvent is acetonitrile.
  • the reducing agent used in the ring-opening step or reaction disclosed herein is a hydride.
  • the hydride is sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the ring-opening reaction disclosed herein occurs in the presence of a catalyst.
  • the catalyst is boron trifluoride.
  • the ring-opening reaction occurs in a solvent.
  • the solvent is ether.
  • the ring-opening reaction disclosed herein occurs in the presence of a catalyst such as boron trifluoride and a solvent such as ether.
  • the oxidizing agent used in the oxidizing step or reaction disclosed herein is pyridine-SO 3 complex, hi some embodiments, the oxidizing reaction occurs in the presence of a base catalyst. In further embodiments, the catalyst is triethylamine. In some embodiments, the oxidizing reaction occurs in a solvent. In further embodiments, the solvent is a mixture of methylene chloride and dimethyl sulfoxide.
  • the esterifying step or reaction disclosed herein is carried out by reacting the dihydroartemisinic acid of formula (IA) sequentially with thionyl chloride and an alcohol having a formula of R'OH wherein R' is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl or aralkyl.
  • the converting step or reaction disclosed herein comprises (a) peroxidizing the dihydroartemisinic acid ester of formula (V) to form a peroxide intermediate of formula (VI):
  • R' is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl or aralkyl; and (b) cyclizing the peroxide intermediate of formula (VI) with oxygen to form artemisinin.
  • the peroxidizing reaction occurs in the presence of hydrogen peroxide and sodium molybdate.
  • the cyclizing reaction occurs in the presence of benzenesulfonic acid and an ion exchange resin.
  • halo means -F, -Cl, -Br or -I.
  • alkyl or “alkyl group” means a univalent group having the general formula C n H 2n+ ] derived from removing a hydrogen atom from a saturated, unbranched or branched aliphatic hydrocarbon, where n is an integer, preferably between 1 and 20, more preferably between 1 and 8.
  • alkyl groups include, but are not limited to, (Q-C ⁇ alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2 -methyl- 1 -butyl, 3 -methyl- 1 -butyl,
  • alkyl groups include nonyl and decyl groups.
  • An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
  • the alkyl group can be branched or unbranched.
  • cycloalkyl group means a univalent group derived from a cycloalkane by removal of a hydrogen atom from a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms.
  • cycloalkyl groups include, but are not limited to, (C 3 - C 7 )cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C 3 -C 7 )cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or substituted by one or two suitable substituent
  • aryl or “aryl group” means an organic radical derived from a monocyclic or polycyclic aromatic hydrocarbon by removing a hydrogen atom.
  • Non-limiting examples of the aryl group include phenyl, naphthyl, benzyl, or tolanyl group, sexiphenylene, phenanthrenyl, anthracenyl, coronenyl, and tolanylphenyl.
  • An aryl group can be unsubstituted or substituted with one or more suitable substituents.
  • the aryl group can be monocyclic or polycyclic.
  • alkenyl or “alkenyl group” means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to (C 2 -C 8 )alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)- pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the alkenyl group can be branched or unbranched.
  • alkynyl or “alkynyl group” means monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, (C 2 - Cg)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4- methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2 -hexynyl.
  • An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the alkynyl group can be branched or unbranched.
  • substituted as used to describe a compound or chemical moiety means that at least one hydrogen atom of that compound or chemical moiety is replaced with a second chemical moiety.
  • the second chemical moiety can be any desired substituent that does not adversely affect the desired activity of the compound.
  • substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; alkyl; heteroalkyl; alkenyl; alkynyl; aryl, heteroaryl, hydroxyl; alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxo; haloalkyl (e.g., trifluoromethyl); carbocyclic cycloalkyl, which can be monocyclic or fused or non-fused polycyclic ⁇ e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or a heterocycloalkyl, which can be monocyclic or fused or non- fused polycyclic (
  • pyrrolidinyl piperidinyl, piperazinyl, morpholinyl or thiazinyl
  • carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl or benzofuranyl); amino (primary, secondary or tertiary); o-lower alkyl; o-aryl, aryl; aryl-
  • substantially free of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
  • stereochemically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • racemate means about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.
  • process(es) of the invention refers to the methods disclosed herein which are useful for preparing a compound of the invention. Modifications to the methods disclosed herein ⁇ e.g. , starting materials, reagents, protecting groups, solvents, temperatures, reaction times, purification) are also encompassed by the present invention.
  • the term “adding”, “reacting” or the like means contacting one reactant, reagent, solvent, catalyst, reactive group or the like with another reactant, reagent, solvent, catalyst, reactive group or the like.
  • Reactants, reagents, solvents, catalysts, reactive group or the like can be added individually, simultaneously or separately and can be added in any order. They can be added in the presence or absence of heat and can optionally be added under an inert atmosphere.
  • “Reacting” can refer to in situ formation or intramolecular reaction where the reactive groups are in the same molecule.
  • reaction that is “substantially complete” or is driven to “substantial completion” means that the reaction contains more than about 80% by percent yield, more preferably more than about 90% by percent yield, even more preferably more than about 95% by percent yield, and most preferably more than about 97% by percent yield of the desired product.
  • a catalyst comprising a porphyrin, a phthalocyanine, a corrole or a combination thereof.
  • the amorpha-4, 11 -diene of Formula (IV) can be prepared by any known chemical or biological method.
  • the amorpha-4, 11 -diene of Formula (IV) can be obtained by extraction from biological materials such as plants and microbes.
  • the amorpha-4,11-diene of Formula (IV) can be prepared by a biological method as described in U.S. Patent No. 7,172,886, which is incorporated herein by reference.
  • the amorpha-4,11-diene of Formula (IV) can be prepared by any known chemical synthetic method.
  • the catalyst is a porphyrin. Any hydrogen or metal porphyrin that can act as a catalyst for epoxidizing olefins can be used herein.
  • the catalyst is a porphyrin having formula (X):
  • Q 1 is two hydrogens or M 1 (L 1 ) n (L 2 ) m ;
  • M 1 is a metal such as Ge, Sn, Al, Ga, Zn, Cd, Cu, Ni, Pd, Pt, Co, Rh, Fe, Ru, Os, Mn, Cr, Mo, W, V, Ti, Zr, Sc, Mg, or U;
  • each of L 1 and L 2 is independently O, PPh 3 , OEt 2 , pyridine, H 2 O, or halo such as fluoro or chloro;
  • each of n and m is independently an integer from 0 to 6;
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently H, linear alkyl, branched alkyl or cycloalkyl group; and each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X
  • At least one of X'-X 12 is not H.
  • each of X'-X 12 and R*-R 8 of the metalloporphyrin is halo such as fluoro, chloro, bromo or iodo.
  • Q 1 is M ⁇ L 1 ),, ⁇ 2 )TM where M 1 is Mn; n is 0; m is 1; and L 2 is chloro.
  • porphyrin disclosed herein is represented by
  • Q 1 is two hydrogens or M 1 QJ) n (L ) m ;
  • M is chromium, manganese, iron, cobalt, nickel, copper, zinc, osmium, ruthenium, or palladium;
  • each of n and m is independently an integer from 0 to 2;
  • each of L 1 and L 2 is independently Cl or O;
  • each of R 1 - R 8 is independently H, linear alkyl, branched alkyl or cycloalkyl group;
  • each of X'-X 12 is independently halo or linear or branched alkyl.
  • the porphyrin is a metalloporphyrin having formula
  • each of X'-X 12 is independently H, halo or linear or branched alkyl; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently halo or linear or branched alkyl. In some embodiments, at least one of X'-X 12 is not H. In other embodiments, each of X*-X 12 and R 1 - R 8 of the metalloporphyrin is halo such as fluoro, chloro, bromo or iodo.
  • the manganese (III) complexed porphyrins can be obtained commercially or prepared according to the following multistep synthetic scheme where Ar is substituted or unsubstituted aryl.
  • Ar is 2,6- dichlorophenyl, pentafiuorophenyl or 2,4,6-trimethylphenyl.
  • the catalyst is a phthalocyanine. Any hydrogen or metal phthalocyanine that can act as a catalyst for epoxidizing olefins can be used herein.
  • the phthalocyanine has formula (XII):
  • Q 3 is two hydrogens or M 2 (L 3 ) p (L 4 ) q ;
  • M 2 is Ge, Sn, Al, Ga, Zn, Cd, Cu, Ni, Pd, Pt, Co 5 Rh, Fe, Ru, Os, Mn, Cr, Mo, W, V, Ti, Zr, Sc, Mg, or U;
  • each of L 3 and L 4 is independently O or Cl;
  • each of p and q is independently an integer from 0 to 6;
  • each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 is independently hydrogen, linear or branched alkyl, cycloalkyl, alkaryl, aralkyl, aryl, or sulfo group.
  • M 2 is Ni, Cu, Ti, Ge 5 V, Zr 5 Mo, Rh or
  • the catalyst is a corrole. Any hydrogen or metal corrole that can act as a catalyst for epoxidizing olefins can be used herein.
  • the corrole has formula (XIII):
  • Q 3 is M 3 (L 5 ) r (L 6 ) s ;
  • M 3 is Ge, Sn, Al, Ga, Zn, Cd, Cu, Ni, Pd, Pt, Co, Rh, Fe, Ru, Os, Mn, Cr, Mo, W, V, Ti, Zr, Sc, Mg, or U;
  • L 5 and L 6 is independently Cl, PPh 3 , OEt 2 , C 5 H 5 N, or O; each of r and s is independently an integer from 0 to 6;
  • each of R 45 , R 46 , and R 48 is independently H, SO 2 Cl, SO 3 H, SO 2 NR 49 R 50 , CO 2 H 5 CO 2 R 51 , COCl, CONR 52 R 53 , CHO, or NO 2 , where R 49 -R 53 is independently H 5 linear or branched alkyl, or aryl; R 47 is H or CHO;
  • each of R 30 - R 44 is independently H, linear or branched alky
  • the epoxidizing agent used in the epoxidizing step or reaction disclosed herein is oxygen, a peroxide, a peracid, a hypochlorite, a peroxydisulfate, a dioxyrane, iodosylbenzene, or a combination thereof.
  • suitable peroxides include hydrogen peroxide and t-BuOOH.
  • suitable peracid is meta-chloroperbenzoic acid (mCPBA).
  • suitable peroxidisulfate include sodium peroxidisulfate, potassium peroxidisulfate and ammonium peroxidisulfate.
  • the epoxidizing agent is a peroxide.
  • the peroxide is hydrogen peroxide.
  • the epoxidizing agent is used in a stoichiometric amount. In some embodiments, the epoxidizing agent is used in a stoichiometric excess. In other embodiments, the epoxidizing agent is used in a stoichiometric excess of about 1.1 to about 10 equivalents. In further embodiments, the epoxidizing agent is used in a stoichiometric excess of about 4 to 6 equivalents.
  • the epoxidizing reaction occurs in the presence of at least one ammonium salt.
  • suitable ammonium salts include ammonium acetate and ammonium bicarbonate.
  • the epoxidizing reaction occurs in a solvent such as acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide and combinations thereof.
  • the solvent is acetonitrile.
  • the amorphadiene-1 l-S ⁇ -epoxide of Formula (II) can react with a reducing agent to open the epoxy ring reductively so as to form a dihydroartemisinic-1 l-i?-alcohol of formula (III A):
  • amorphadiene- 11,12-epoxide of Formula (II) to dihydroartemisinic-1 l-i?-alcohol of formula (IIIA) can be achieved using a reducing agent.
  • suitable reducing agents include metal aluminum hydrides and their derivatives, metal borohydrides and their derivatives, borane and its derivatives and asymmetric hydrogenation.
  • suitable metal aluminum hydrides and borohydrides are described in J. Seyden-Penne, "Reductions by the Alumino- and Borohydrides in Organic Synthesis, " VCH- Lavoisier, Paris (1991); and F. A. Carey et ah, "Advanced Organic
  • the reducing agent is or comprises a metal aluminum hydride.
  • Any metal aluminum hydride that can be used to open in regiospecifically epoxy ring to form an alcohol can be used herein.
  • metal aluminum hydrides include sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), lithium tri-t- butoxyaluminum hydride and diisobutylaluminium hydride (DIBAL).
  • Red-Al sodium bis(2-methoxyethoxy)aluminum hydride
  • DIBAL diisobutylaluminium hydride
  • metal aluminum hydrides suitable for the ring-opening reaction disclosed herein are disclosed in D.Tanner et ah, Tetrahedron, 53, 16319-16146 (1997), which is incorporated herein by reference.
  • the reducing agent is or comprises a metal borohydride.
  • Any metal borohydride that can give acceptable stereospecific yields of primary alcohol from aliphatic epoxides can be used herein.
  • suitable metal borohydrides include lithium triethylborohydride (LiEt 3 BH), lithium tri-sec-butylborohydride (L-Selectride), sodium tri-sec-butylborohydride (N-Selectride), potassium tri-sec- butylborohydride (K-Selectride), triisoamylborohydride, potassium triphenyl borohydride (KPh 3 BH), sodium triacetoxyborohydride and sodium cyanoborohydride with boron trifluoride etherate (NaBH 3 CN with BF 3 -Et 2 O).
  • Suitable metal borohydride is zinc borohydride (ZnBH 4 ) in combination with zeolite, as disclosed in R. Sreekumar et al, " Regioselective Reduction of Epoxides and Conjugated Carbonyl Compounds Using Zeolite Supported Zinc Borohydride, " Tetrahedron, 39, 5151-5154 (1998), which is incorporated herein by reference.
  • ZnBH 4 zinc borohydride
  • the reducing agent is or comprises a borane or one of its derivatives. Any borane or derivative that can perform stereospecific epoxide ring openings can be used herein.
  • suitable boranes are morpholine borane (MPB) with BF 3 . Et 2 O and diborane (B 2 H 6 ). Further suitable boranes are disclosed in W. Smith, J. Ore. Chem.. 49, 3219 (1984), which is incorporated herein by reference.
  • the reducing agent is hydrogen coupled with an asymmetric hydrogenation catalyst to form stereospecific hydrogenated ring-opened products substantially free of other stereoisomers.
  • asymmetric hydrogenation catalyst is the rhodium-DIPAMP catalyst.
  • the rhodium-DIPAMP catalyst and other asymmetric hydrogenation catalysts are disclosed in Vineyard et ah, J. Am. Chem.
  • asymmetric hydrogenation catalyst is Perlman's catalyst that can couple with a reducing agent to perform epoxide ring openings can be used herein.
  • An application of Pearlman's catalyst in epoxy ring opening reaction is disclosed in J. Garcia et ah, "Stereoselective Carbohydrate Synthesis via Palladium Hydroxide Cataylzed Epoxide Hvdrosenolvsis" Tetrahedron., 39, 5273-5276 (1991), which is incorporated herein by reference.
  • the reducing agent is a hydride.
  • the hydride is sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the hydride is sodium triacetoxyborohydride.
  • the ring opening reaction occurs in the presence of a catalyst.
  • the catalyst is boron trifluoride.
  • the catalyst is boron trifluoride etherate.
  • the ring-opening reaction occurs in a solvent such as diethyl ether, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide and combinations thereof.
  • the solvent is diethyl ether.
  • dihydroartemisinic-1 l-i?-alcohol (IIIA) can be prepared from amorphadiene according to the hydroboration reaction as shown below.
  • Any hydroboration reagent that can convert an olefin into an alcohol can be used herein.
  • suitable hydroboration reagents include 9- borabicyclo[3.3.1]nonane (9-BBN), disiamylborane, thexylborane, dicyclohexylborane, di(isopropylprenyl)borane, borane and other organoboranes.
  • the hydroboration reagent is 9-borabicyclo[3.3.1]nonane (9-BBN).
  • sodium hydroxide and hydroperoxide are added at the end of the hydroboration reaction.
  • the desirable dihydroartemisinic-1 l-i?-alcohol (III A) can be separated from its isomer(s) by conventional separation techniques. Hydroboration reactions are disclosed in Ra ⁇ jit S. Dhillon, "Hydroboration and Organic Synthesis: 9-Borabicyclo [3.3.1] nonane (9-BBN),” Springer (2007), which is incorporated herein by reference.
  • the dihydroartemisinic- 11 -i?-alcohol of formula (III A) reacts with one or more oxidizing agents to form a dihydroartemisinic acid of formula (IA) or a dihydroartemisinic aldehyde of formula (VII):
  • Any oxidizing agent can oxidize a primary alcohol to the corresponding aldehyde or carboxylic acid can be used herein to convert the dihydroartemisinic-1 I -R- alcohol of formula (IIIA) to dihydroartemisinic acid of formula (IA), or the intermediate dihydroartemisinic aldehyde of formula (VII).
  • the dihydroartemisinic-1 l-/?-alcohol is first oxidized to the dihydroartemisinic aldehyde before being further oxidized to the dihydroartemisinic acid.
  • the alcohols are directly oxidized to the dihydroartemisinic acid in one step.
  • the oxidizing agent for oxidizing the dihydroartemisinic-1 l-i?-alcohol of formula (IIIA) to the dihydroartemisinic acid of formula (IA) is or comprises KMnO 4 , RuO 4 , pyridinium dichromate (PDC) in DMF, MnO 2 , Jones reagent, i.e., a solution of chromium trioxide in concentrated sulfuric acid, Heyns oxidation reagent, 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO) or combinations thereof.
  • the dihydroartemisinic-11 -i?-alcohol of formula (IIIA) is first oxidized to the dihydroartemisinic aldehyde of formula (VII) which can then be further oxidized to the dihydroartemisinic acid of formula (IA).
  • the oxidizing agent for oxidizing the dihydroartemisinic-1 ⁇ -R -alcohol to the dihydroartemisinic aldehyde is or comprises dimethyl sulfoxide (DMSO) activated with an electrophile.
  • Suitable electrophiles include oxalyl chloride (Swern oxidation), carbodiimide (Pfitzner-Moffatt oxidation), sulfur trioxide-pyridine complex (Parikh-Doering oxidation) and combinations thereof.
  • the oxidizing agent is or comprises sulfur trioxide-pyridine complex with DMSO.
  • the oxidizing agent for oxidizing the dihydroartemisinic-1 l-i?-alcohol to the dihydroartemisinic aldehyde is or comprises tetrapropylammonium perruthenate (TPAP).
  • TPAP tetrapropylammonium perruthenate
  • the TPAP is combined with a co-oxidant.
  • suitable co-oxidants include trimethylamine N-oxide (TMAO) and N-methylmorpholine N-oxide (NMO).
  • TMAO trimethylamine N-oxide
  • NMO N-methylmorpholine N-oxide
  • a catalytic amount of TPAP is used in combination with a co-oxidant.
  • the ratio of the amount of TPAP to the amount of co-oxidant is from about 1 : 1 to about 1 :30, about 1 :5 to about 1 :30, about 1 : 10 to about 1 :30, or from about 1 :15 to about 1 :30.
  • the oxidizing agent for oxidizing the dihydroartemisinic-1 l-i?-alcohol to the dihydroartemisinic aldehyde is or comprises a chromium-based reagent.
  • suitable chromium-based reagents include Collins reagent, i.e., the complex of chromium(VI) oxide with pyridine in dichloromethane, pyridinium dichromate (PDC), pyridinium chlorochromate (PCC) and combinations thereof.
  • the pyridinium dichromate (PDC) is dissolved in solvent such as N,N-dimethylformamide (DMF) before use.
  • the oxidizing agent for oxidizing the dihydroartemisinic-1 l-i?-alcohol to the dihydroartemisinic aldehyde is or comprises 2,2,6,6- tetramethylpiperidine-1-oxyl (TEMPO) in combination with sodium hypochlorite (NaOCl).
  • TEMPO 2,2,6,6- tetramethylpiperidine-1-oxyl
  • NaOCl sodium hypochlorite
  • the NaOCl is used in an excess amount.
  • the oxidizing agent for oxidizing the dihydroartemisinic-11- ⁇ -alcohol to the dihydroartemisinic aldehyde is or comprises a hypervalent iodine compound.
  • hypervalent iodine compounds include 1,1,1 -triacetoxy- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 ( 1 H)-one (Dess-Martin periodinane), dichloroiodobenzene, diarylchloroiodanes, (bis(trifluoroacetoxy)iodo)benzene, 2-iodoxybenzoic acid and combinations thereof.
  • the dihydroartemisinic aldehyde can be subsequently oxidized to the dihydroartemisinic acid of formula (IA) using a suitable oxidizing agent.
  • suitable oxidizing agents include metal chlorite, potassium permanganate, nitric acid, chromium(VI) oxide, acidified potassium dichromate and combinations thereof.
  • the oxidizing agent is a metal chlorite.
  • the metal is an alkali metal, alkaline metal, or transitional metal.
  • the metal is K, Na, Li, Cs, Ag, Au, Ca, Mg, Ca, Ba, Al, Ni, Co, Zn, Pb or Fe.
  • the oxidizing agent is sodium chlorite.
  • the oxidizing agent is sodium chlorite in combination with a chlorine scavenger.
  • the oxidizing reaction occurs in the presence of a base catalyst.
  • the base catalyst is an organic amine.
  • suitable organic amines include triethylamine, pyridine, DBU, N ,N- diisopropylethylamine (DIPEA), imidazole and combinations thereof.
  • the catalyst is triethylamine.
  • the oxidizing reaction occurs in a solvent such as methyl acetate, acetonitrile, ethyl acetate, ethers such as diethyl ether and tetrahydrofuran, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, ionic liquids and combinations thereof.
  • the solvent is a mixture of dichloromethane and dimethyl sulfoxide.
  • the dihydroartemisinic acid of formula (IA) can be prepared according to the following procedure where amorpha-l,4-diene is converted to artemisinic acid by a microorganism and the artemisinic acid is then hydrogenated to form dihydroartemisinic acid of formula (IA).
  • the artemisinic acid can be reduced to form dihydroartemisinic acid with hydrogen in the presence of a catalyst selected from Pd, Pd/C, Pt, PtO 2 , Ru(PPh 3 ) 2 Cl2, Raney nickel, Wilkinson's catalyst, 5% iridium carbonate in methanol, (R)-Xyl-PhanePhos-RuCl 2 -(DMF) 2 in an aprotic solvent and combinations thereof.
  • the catalyst is Wilkinson's catalyst.
  • the catalyst is a Pd catalyst.
  • the catalyst is 5% Pd/C.
  • the catalyst is 10% Pd/C in a high pressure reaction vessel and the reaction is allowed to proceed until completion. Generally, after completion, the reaction mixture can be washed, concentrated, and dried to yield the corresponding hydrogenated product.
  • the artemisinic acid may be hydrogenated by treatment with hydrazine in the presence of a catalyst, such as 5-ethyl-3-methyllumiflavinium perchlorate, under oxygen atmosphere to give the corresponding hydrogenated products.
  • a catalyst such as 5-ethyl-3-methyllumiflavinium perchlorate
  • the artemisinic acid can be converted to dihydroartemisinic acid by asymmetric hydrogenation of artemisinic acid with a noble metal catalyst, following the procedure described in Noyori, Ryoji, Asymmetric Catalysis In Organic Synthesis. Wiley- Interscience (1994), which is incorporated herein by reference.
  • the dihydroartemisinic acid of formula (IA) reacts with an esterification agent to form a dihydroartemisinic acid ester of formula (V):
  • R' of dihydroartemisinic acid ester of formula (V) is an alkyl group.
  • R' is a Ci -22 alkyl group such as methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, stearyl and behenyl.
  • R' is methyl.
  • the dihydroartemisinic acid of formula (IA) can be esterified directly into the dihydroartemisinic acid ester of formula (V) in one step.
  • the dihydroartemisinic acid of formula (IA) can be halogenated first into the corresponding acyl halide of formula (VIII), which can subsequently react with an alcohol having formula R'OH to form the dihydroartemisinic acid ester of formula (V).
  • the dihydroartemisinic acid of formula (IA) is converted first into the acyl halide of formula (VIII) by reacting with a halogenating agent.
  • the halogenating agent can be, for example, PX 3 , PX 5 or SOX 2 where X can be F, Cl, Br or I.
  • the halogenating agent is a chlorinating agent such as SOCl 2 or PCl 5 .
  • the halogenating agent is a brominating agent such as PBr 5 .
  • the halogenating agent is SOCl 2 .
  • the halogenating reaction can occur in a solvent, such as toluene, benzene, cyclohexane, xylene, decane, and mixtures thereof.
  • the solvent is toluene.
  • the reaction temperature of the halogenating reaction can be between 20 0 C and 140 0 C. In some embodiments of interest, the reaction temperature is between 40 0 C and 120 0 C. In other embodiments of interest, the reaction temperature is between 60 0 C and 110
  • the reaction time can vary from 1 to 24 hours, depending on the reaction temperature. In general, the higher the reaction temperature, the shorter is the reaction time. In one embodiment, the reaction time is from about 1 hour to about 2 hours at a reaction temperature between 100 0 C and 110 0 C.
  • the acyl halide of formula (VIII) can subsequently react with an alcohol having formula R'OH to form the dihydroartemisinic acid ester of formula (V) where R' is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl or aralkyl.
  • the reaction can occur in the presence of a base catalyst.
  • the base catalyst is an organic amine.
  • Suitable organic amine include triethylamine, pyridine, DBU, N,N-diisopropylethylamine (DIPEA), imidazole and combinations thereof, hi some embodiments, the catalyst is triethylamine.
  • the dihydroartemisinic acid of formula (IA) is esterified directly into the dihydroartemisinic acid ester of formula (V) in one step with an esterification agent.
  • Any esterification agent that can convert the -CO 2 H group of the dihydroartemisinic acid of Formula (IA) into a -CO 2 R' group can be used for the esterification reaction disclosed herein.
  • the esterification reaction can be catalyzed or promoted with a Bronsted acid, a Lewis acid, an ion exchange resin, a zeolite or the like.
  • the esterification reaction can be catalyzed or promoted with a base catalyst such as an amine, a metal carbonate, a metal hydrogen carbonate, a metal hydroxide or the like.
  • a base catalyst such as an amine, a metal carbonate, a metal hydrogen carbonate, a metal hydroxide or the like.
  • suitable esterification agents include alcohols (e.g., R'OH where R' is as defined above), metal alkoxides (e.g., M(0R') n where M is alkali metal, alkaline metal or a transitional metal; n is from 1 to 6; and R' is as defined above), esters derived from an acid and R'OH, alkyl halides (e.g., R'OH where R' is as defined above; and X is F, Cl, Br or I), diazomethane and orthoesters.
  • alcohols e.g., R'OH where R' is as defined above
  • metal alkoxides e.g
  • Non- limiting examples of suitable orthoesters include trimethyl orthoacetate, trimethyl orthoformate, triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate and the like.
  • the esterification agent is an orthoester.
  • the orthoester is trimethyl orthoacetate.
  • the reaction temperature of the esterification can be any temperature useful for reaction between the esterification agent and the dihydroartemisinic acid of Formula (IA) according to a person of ordinary skill in the art. For instance, in certain embodiments, the esterification reaction temperature is from about 0 0 C to about 120 0 C.
  • the esterification reaction temperature is from about 20 0 C to about 100 0 C. In other embodiments of interest, the esterification reaction temperature is from about 80 0 C to about 120 0 C.
  • the reaction time can be any time useful for the reaction between the esterification agent and the dihydroartemisinic acid of Formula (IA) according to a person of ordinary skill in the art. In general, the higher the reaction temperature, the shorter is the reaction time. For instance, in certain embodiments, the reaction time is from about 1 to about 24 hours. In some embodiments of interest, the reaction time is between about 1 and about 10 hours.
  • the mole ratio of the esterification agent to the dihydroartemisinic acid of Formula (IA) is between about 2:1 and about 0.5:1. In other embodiments, the mole ratio is between 1.75:1 and about 0.75 : 1. In further embodiments, the mole ratio is between 1.5:1 and about 1:1.
  • the esterification reaction can occur in the absence or presence of a solvent. In some embodiments, the esterification reaction occurs in the absence of a solvent. In other embodiments, the esterification reaction occurs in the presence of a solvent. Any solvent that does not react with the esterification agent can be used. Non-limiting examples of suitable solvents include methyl acetate, acetonitrile, ethyl acetate, ethers such as diethyl ether and tetrahydrofuran, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, ionic liquids and combinations thereof.
  • an ionic liquid can be any organic salt with a low melting point, preferably lower than 100 0 C, and more preferably lower than room temperature. It has been reported that the use of an ionic liquid as the solvent can improve the yield of esterification reactions.
  • Non-limiting examples of suitable ionic liquids include halogen-free ionic liquids ⁇ e.g., l-ethyl-3-methylimidazolium tosylate, l-butyl-3-methylimidazolium octyl sulfate, and l-butyl-3-methylimidazolium 2-(2- methoxyethoxy)ethyl sulfate), imidazolium compounds (e.g., l-ethyl-3-methylimidazolium bromide, l-ethyl-3-methylimidazolium hexafluorophosphate, and l-butyl-3- methylimidazolium hexafluorophosphate) and pyridinium compounds (e.g., l-Butyl-4- methylpyridinium chloride and l-butyl-4-methylpyridinium hexafluorophosphate), phosphonium compounds, te
  • the dihydroartemisinic acid ester of formula (V) can be converted into artemisinin by any method known to a skilled artisan. Some non-limiting examples of such known methods are disclosed in U.S. Patent No. 4,992,561 and U.S. Patent Publication No. 2006/0270863, both of which are incorporated herein by reference.
  • the converting step or reaction disclosed herein comprises (a) peroxidizing the dihydroartemisinic acid ester of formula (V) to form a peroxide intermediate of formula (VI):
  • R' is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl or aralkyl; and (b) cyclizing the peroxide intermediate of formula (VI) with oxygen to form artemisinin.
  • the peroxidizing reaction occurs in the presence of hydrogen peroxide and sodium molybdate.
  • the cyclizing reaction occurs in the presence of benzenesulfonic acid and an ion exchange resin.
  • artemisinin is prepared according to a process comprising the steps of:
  • each of X'-X 12 is independently H, halo or linear or branched alkyl; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently halo or linear or branched alkyl with the proviso that at least one of X'-X 12 is not H;
  • artemisinin is prepared according to a process comprising the steps of:
  • a dihydroartemisinic acid of formula (IA) is prepared according to a process comprising the steps of:
  • an amorphadiene- 11 -S, 12-epoxide of Formula (II) is prepared according to a process comprising the step of epoxidizing amorpha-4,11-diene of Formula (IV):
  • each of X 1 -X 12 is independently H, halo or linear or branched alkyl; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is independently halo or linear or branched alkyl with the proviso that at least one of X 1 Ot 12 is not H.
  • the amorphadiene- 11 -S, 12-epoxide of Formula (II) can be prepared by a microorganism.
  • artemisinic-11-5,12-epoxide (artemisinic epoxide) is prepared from amorpha-4,11-diene by using a protein engineered- cytochrome P450 BM3 (CYP 102) as a catalyst.
  • CYP 102 protein engineered- cytochrome P450 BM3
  • Such a biosynthesis method is described in Dietrich, et al., "Production of Artemisinic- 11, 12 -Epoxide by Engineered Cytochrome P450 Bm3," SBE's International Conference on Biomolecular Engineering, which is incorporated herein by reference.
  • artemisinin can be prepared by the following process comprising the steps of:
  • artemisinin can be prepared by the following process comprising the steps of:
  • TDCPPH 2 The compound 5,10, 15,20-Tetrakis-2,6-dichlorophenylporphyrin (TDCPPH 2 ) was prepared according to the procedures of Lindsey and Wagner, J. Org. Chem., 1989, 54, 828-836, which is incorporated herein by reference.
  • the reaction mixture was stirred at ambient temperature (23 0 C) for about one hour before the solution was heated and refluxed.
  • 1.84 g (7.5 mmol) of chloranil was added at once to the reaction mixture.
  • the reaction mixture was allowed to cool to ambient temperature.
  • 0.460 mL (0.334 g, 3.3 mmol) of triethylamine was added to the reaction mixture, and the solvent was removed under reduced pressure, giving the crude product.
  • the crude product was scraped onto a filter funnel and washed with methanol until the washes were pale green in color. The supernatant was vacuum dried on the filter funnel to give 2.08 g of porphyrin in the form of black microcrystalline solid.
  • the NMR spectrum of the black microcrystalline solid was similar to that reported in the literature.
  • TMPH 2 The compound 5,10, 15,20-Tetrakismesitylporphyrin (TMPH 2 ) was prepared according to similar procedures for preparing TDCPPH 2 as described above, except that 1.48 mL (1.48 g, 10.0 mmol) of mesitaldehyde, 0.694 mL (0.67 Ig, 10.0 mmol) of pyrrole and 0.420 mL (0.468 g, 3.30 mmol) of boron trifluoride etherate (BF 3 ⁇ t 2 0) were used. The resulting product was 2.09 g of TMPH 2 in the form of black solid. The NMR spectrum of the black solid was similar to that reported in the literature.
  • TDCPPMnCl was prepared according to a similar procedure for preparing TPFPPMnCl as described above, except that 0.250 g (0.280 mmol) of TDCPPH 2 and 0.267 g (1.35 mmol) of manganese chloride tetrahydrate (MnCl 2 ⁇ H 2 O) were mixed and heated in 50 mL of DMF. The resulting product was 0.043 g of TDCPPMnCl (15% yield) in the form of dark green microcrystalline powder.
  • TDCPPMnCl was prepared according to a similar procedure for preparing TPFPPMnCl as described above, except that 0.250 g (0.280 mmol) of TDCPPH 2 and 0.267 g (1.35 mmol) of manganese chloride tetrahydrate (MnCl 2 ⁇ H 2 O) were mixed and heated in 50 mL of DMF. The resulting product was 0.043 g of TDCPPMnCl (15% yield) in the form of dark green microcrystalline powder.
  • TMPMNCl was prepared according to a similar procedure for preparing TPFPPMnCl as described above, except that 1.00 g (1.27 mmol) of TMPH2, 1.01 g (5.10 mmol) of MnCl 2 .4H 2 O, and 150 mL of DMF were used to produce 0.73 (65%) of TMPMNCl as a finely divided black powder.
  • H 2 O 2 30% hydrogen peroxide
  • NH 4 HCO 3 ammonium bicarbonate
  • 11,12-epoxide was prepared according to similar steps as described in Method 1, except that. 0.100 mg of amorphadiene was reacted with TPFPPMnCl (instead of TDCPPMnCl) and hydrogen peroxide (H 2 O 2 ) in acetonitrile.
  • the percentages of the various components of the reaction mixture by GC-MS analysis were as follows: amorphadiene (13.8%); 4,5-epoxide 1 (1.54%); 4,5-epoxide 2 (8.58%); 11,12-epoxide (21.61%, desired epimer); 11,12-epoxide (8.31%, wrong epimer); bis-epoxide 1 (16.77%); and bis-epoxide 2 (6.88%).
  • Dihydroartemisinic-1 l-i?-alcohol was prepared according to the following procedures. To a 25 mL round-bottomed flask equipped with a magnetic stirrer and rubber septum pierced with a syringe needle were added 27 mg (0.12 mmol) of amorphadiene- 11 - 5,12-epoxide, 5.0 mL of anhydrous ether and 0.60 mL of a solution of boron trifluoride etherate (BF 3 Et 2 O) in ether (prepared by adding 0.30 mL of BF 3 Et 2 O to 2.0 mL of ether).
  • boron trifluoride etherate BF 3 Et 2 O
  • IHA Dihydroartemisinic-1 l-i?-alcohol
  • the cooling bath was recharged with dry-ice and allowed to come to ambient temperature. After 16 hours, the mixture was tested by TLC (silica gel, 20% EtOAc/hexane), which revealed that starting material was still be present. The mixture was again cooled to -78 ° C, and an additional 1.47 mL of 9-BBN solution was then added. The cooling bath was again allowed to come to ambient temperature. After 18 hours, the mixture was tested by TLC, which indicated that only a small amount of starting material remained. The mixture was then cooled to 0 C by ice bath.
  • Dihydroartemisinic aldehyde was prepared according to the procedure described in Krysan, D. J.; Haight, A. R.; Menzia, J. A.; Welch, N., Tetrahedron, 1994, 50 (21), 6163-6171, which is incorporated herein by reference.
  • the layers were separated and the organic phase was washed with 10 mL of citric acid solution, 10 mL of saturated NaHCO 3 solution and 10 mL of saturated NaCl solution, dried magnesium sulphate (MgSO 4 ) and the solvent removed under reduced pressure to afford 0.447 g of pale yellow oil.
  • the oil was passed through a plug (5 X 1 cm) of silica gel with 20% EtOAc/hexane 0.377 g (76.4%) of the product, dihydroartemisinic aldehyde, as a colorless oil.
  • the GC/MS and NMR spectra of the product was similar to an authentic sample.
  • dihydroartemisinic aldehyde was prepared according to the following procedure. To a 250 mL round-bottomed three-necked flask equipped with a mechanical stirrer and two stoppers were added 40 mL of 0.2N NaOH solution, 1.22 g (4.51 mmol) OfK 2 S 2 O 8 and 250 mg of tetrabutylammonium bromide (TBAB). The mixture was stirred vigorously at 325 rpm to form a solution.
  • TBAB tetrabutylammonium bromide
  • DHAA dihydroartemisinic acid
  • toluene 50 mL
  • This amount corresponded to 5.0 g (21 mmol) of DHAA.
  • the mixture was stirred and when solution had been achieved 1.7 mL, 2.8 g (23 mmol, 110 mol%) of thionyl chloride were added via syringe.
  • the mixture was heated to a gentle reflux and after 1.5 h a small sample was treated with methyl-t-butylsilyltrifluoro-acetamide to derivatize any unreacted DHAA.
  • the reaction mixture was diluted with 100 mL of CH 2 Cl 2 , transferred to a separatory funnel and washed with 50 mL of water.
  • the aqueous phase was back extracted with 100 mL Of CH 2 Cl 2 and the combined organics were washed twice with 50 mL portions Of H 2 O.
  • the organics were dried over magnesium sulphate (MgSO 4 ), vacuum filtered, and concentrated in vacuo to about 10 mL of crude product.
  • the crude product was analyzed by HPLC which indicated that 82% (by area) of the crude product was the hydroperoxide intermediate (retention time of 8.717 min.) and a possible isomer at 12.480 minutes with 2% by area.
  • Dihydroartemisinic acid was prepared by the following asymmetric hydrogenation of artemisinic acid with a noble metal catalyst.
  • a IL reactor model No. 4525 obtainable Parr Instrument Company, Moline, IL
  • a glass liner a glass liner
  • a mechanical stirrer a cooling system
  • a nitrogen inlet and a thermocouple were added 400 mL of toluene, 202.7 mg of Wilkinson's catalyst, i.e., tris(triphenylphosphine) rhodium chloride in aprotic solvents, and 100.8 g of artemisinic acid under house vacuum at about 25 °C, and about 300-700 psi of hydrogen pressure was applied.
  • the mixture was heated to about 80 0 C and was agitated at about 70-80 0 C for about 20 hours.
  • the mixture was cooled to about 20 -25 °C.
  • the catalyst was filtered out, and the remaining mixture was concentrated by vacuum distillation until the volume of the mixture was about 140 mL.
  • the crude product had a purity of about 82%. Good diastereoselectivity (>10:l) was observed. The yield was higher than 83%.
  • the crude product was used without purification in the next step.
  • Dihydroartemisinic acid methyl ester of formula (XIII) was prepared also according to the following method. To a 0.125 L reactor was equipped with a magnetic stirrer, nitrogen inlet and thermometer and was purged with nitrogen were added 50 mL of anhydrous toluene and 8.5g of 59% dihydroartemisinic acid. The mixture was stirred for 15 minutes at 2 0 C. Then, 1.7 mL of thionyl chloride was added. The mixture was agitated at 75 0 C for 90 minutes. Then, excess thinly chloride and toluene were removed by distillation.
  • Dihydroartemisinic acid methyl ester was also prepared using dimethyl carbonate and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) according to the procedure described in Shieh, W.-C; Dell, S.; Repic, O., "Nucleophilic Catalysis with 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) for the Esterification of Carboxylic Acids with Dimethyl Carbonate," J. Org. Chem. 2002, 67, 2188-2191. The yield was higher than 80%.
  • DBU dimethyl carbonate
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • Dihydroartemisinic acid methyl ester was also prepared by using dicyclohexylcarbodiimide (DCC) or dimethylaminopropylethylcarbodiimide (EDC) as the activating agent, 4-dimethylaminopyridine as the catalyst, and methanol as the nucleophile. The yield was about 92%.
  • Dihydroartemisinic acid methyl ester of formula (XIII) was also prepared by a two-step process, wherein the carboxylic acid was reacted with oxalyl chloride or thionyl chloride in the presence of a catalytic amount of dimethylformamide (DMF), yield an acid chloride. The acid chloride was then converted to methyl ester by reacting with an alcohol in the presence of a base to trap the freed hydrochloride.
  • DMF dimethylformamide
  • Ethyl, isopropyl, cyclohexy, or benzyl esters of dihydroartemisinic acid were also prepared for the purpose of synthesizing artemisinin.
  • the allylic hydroperoxide of formula (XIV) was prepared according to the following procedure. To a 25 mL flask were added 0.139 g of sodium molybdate dehydrate, 0.347 g of the dihydroartemisinic acid methyl ester of formula (XIII), and 3.47 mL of 1,2- butanediol. The mixture was agitated at about 20-25 0 C. Then, 2.2 mL of 50% hydrogen peroxide was added to the mixture over 4 hours by adding 0.1 mL of 50% hydrogen peroxide first, followed with addition of the same at 0.44 mL/hr, while ensuring that the internal temperature was kept below 30 0 C .
  • the mixture was agitated at about 20-25 °C for about 90 minutes until the color of the mixture changed from brown to light brown. Then, 8.0 mL of dichloromethane was added over 5 minutes at about 20-25 °C, followed with addition of 4.0 mL of water over 5 minutes at about 20-25 0 C. The mixture was agitated for 10 minutes and was allowed to settle for 10 minutes. The aqueous phase (top layer) of the mixture was removed. The organic phase was concentrated via vacuum distillation at 25°C to about 5 mL. The concentrated organic phase was used in the next step without purification.
  • the allylic hydroperoxide of formula (XIV) was also prepared according to the following procedure. To a cylindrical reactor with overhead stirring was added the dihydroartemisinic acid methyl ester of formula (XIII) (1.9789 g, 7.9036 mmol) and sodium molybdate (0.792 g) in 1 ,2-butanediol (19.8 mL). The mixture was stirred for 10 minutes. Then 50% hydrogen peroxide was added drop-wise at a rate of 1.67 mL/hr until a total of 5.86 mL (94.8 mmol) was delivered. After 2.92 mL of hydrogen peroxide had been delivered, the reaction started to turn from a yellow color to brown.
  • the temperature throughout the reaction ranged from about 21.6 0 C to about 35.8 °C.
  • the yellow reaction mixture was diluted with CH 2 Cl 2 and washed with water.
  • the aqueous phase was extracted twice with CH 2 Cl 2 , and the combined organics were washed twice with water.
  • the organic phase was dried over MgSO 4 , filtered through a glass frit, and concentrated in vacuo to 10 mL.
  • HPLC analysis showed an area percent ratio for formula (XIV)/possible isomer/formula PCIII) Of 89/0/0.
  • the allylic hydroperoxide of formula (XTV) can also be prepared by the photochemical production of singlet oxygen from triplet oxygen.
  • the generated singlet oxygen gives predominantly the desired hydroperoxide which undergoes Hock rearrangement and ring closures to artemisinin.
  • the singlet oxygen was also produced by non photochemical methods, for example, by using bleach to oxidize hydrogen peroxide and using sodium and lithium molybdate salts for effective catalyzation of hydrogen peroxide to singlet oxygen and water. The reaction was carried following the procedure described in Aubry J.M. Search for singlet oxygen in the decomposition of hydrogen peroxide by mineral compounds in aqueous solutions. J. Am. Chem. Soc. 1985, 707, 5844-5849 and numerous subsequent papers from his group, and is incorporated herein by reference.
  • a microemulsion system comprising 0.50 mL of methylene chloride, 53.3 mg of sodium dodecyl sulfate (SDS, a surfactant), 85.6 mg of deuterium oxide, 92.6 mg of deuteroethanol and 10.6 mg of sodium molybdate dehydrate were used to give 43% yield of artemisinin over Scheme 10 (above) and Scheme 1 1 (described below).
  • SDS sodium dodecyl sulfate
  • deuterium oxide 92.6 mg of deuteroethanol
  • 10.6 mg of sodium molybdate dehydrate were used to give 43% yield of artemisinin over Scheme 10 (above) and Scheme 1 1 (described below).
  • SDS sodium dodecyl sulfate
  • NS no substrate (DHAA ester).
  • Suitable solvents in Scheme 10 include 2-methoxyethanol 29%; 1 ,2-butanediol%; 1,2-propanediol 19%; ethylene glycol 4%.
  • Scheme 12 depicts a redox mechanism involving radical cation intermediates in which the enol intermediate (XVIII) reacts with triplet oxygen to form a diradical of formula (XIX) followed by a hydrogen atom shift to give the ⁇ -hydroperoxyaldehyde of formula (XX).
  • Artemisinin of formula (XV) was prepared according to the last step of Scheme 11 by the following procedure. To a round bottom flask equipped with a magnetic stir bar was added copper/DOWEX 50WX-200 (0.23 g) and oxalic acid (0.048 g, 0.53 mmol, 27 mol %) in CH 2 Cl 2 (5 mL). After the mixture was stirred for 10 minutes, air (filtered through a Drierite column) was bubbled into the mixture for 20 minutes at room temperature using a gas dispersion tube.
  • the product was isolated by silica gel chromatography using 20% ethyl acetate/hexanes as eluent. The yield of the product was 144.65 mg.
  • the product can be isolated according to the following steps: dilute the mixture with 7.3 mL n- heptane, remove dichloromethane by distillation, cool the mixture to 25 0 C and agitate the mixture for 8 hours and filter the mixture.
  • the wet cake obtained from the filtration was dissolved in 5.5 mL of «-heptane and heated to dissolve. The solution was cooled to 25 °C and agitated for 6 hours before the was filtered and dried.
  • the weight of the product was 0.12 g.
  • the yield was 32 %.
  • the molar yield was 30.6%, and the purity was 95 % by HPLC.
  • ⁇ Denotes that the starting material was derived from yeast fermentation.
  • the mixture was filtered and concentrated in vacuo to give 175 mg brown oil.
  • the mixture was purification by silica gel chromatography (10% ethyl acetate/hexanes to 20% ethyl acetate step gradient). The product had a yield of 50.2%.
  • Artemisinin of formula (XV) can also be prepared according to Scheme 13 shown below.
  • the first step is the reduction of the 11,12 double bond to give dihydroartemisinic acid, which can exist in two stereoisomer forms, of which only one (the R,R isomer) has the correct stereochemistry found in artemisinin.
  • the next step is the esterification of the carboxylic acid functionality.
  • the third step involves the an "ene-type" reaction of singlet oxygen with the

Abstract

La présente invention porte sur des procédés de préparation d'artémisinine et de ses précurseurs comprenant l'amorphadiène, l'époxyde d'amorphadiène, l'alcool dihydroartémisinique et l'acide dihydroartémisinique. De façon spécifique, l'artémisinine est préparée par des procédés synthétiques à multiples étapes à partir d'amorphadiène, d'époxyde d'amorphadiène, d'alcool dihydroartémisinique ou d'acide dihydroartémisinique. L'invention porte également sur des procédés de préparation d'amorphadiène, d'époxyde d'amorphadiène, d'alcool dihydroartémisinique et d'acide dihydroartémisinique.
PCT/US2008/011662 2007-12-30 2008-10-10 Procédé de préparation d'artémisinine et de ses précurseurs WO2009088404A1 (fr)

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WO2011030223A3 (fr) * 2009-09-11 2011-05-19 Sanofi-Aventis Procédé de production d'intermédiaires d'artémisinine
CN102617415A (zh) * 2012-02-20 2012-08-01 常熟理工学院 一种利用氧气氧化有机硫化物的反应方法
CN102718773A (zh) * 2012-06-05 2012-10-10 上海交通大学 一种由青蒿酸制备青蒿素的方法
EP2565197A1 (fr) 2011-08-29 2013-03-06 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé et dispositif pour la synthèse d'artémisinine
WO2013030247A1 (fr) 2011-08-29 2013-03-07 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé et dispositif pour la synthèse d'artémisinine
CN103087074A (zh) * 2012-12-14 2013-05-08 湖南科源生物制品有限公司 一种青蒿素的半合成方法
CN103172645A (zh) * 2012-06-05 2013-06-26 上海交通大学 一种青蒿素的高效合成方法
CN103193790A (zh) * 2012-06-05 2013-07-10 上海交通大学 抗疟疾类药物青蒿素的高效制备方法
CN103224501A (zh) * 2012-06-05 2013-07-31 上海交通大学 抗疟疾类药物青蒿素的制备方法
US8507697B2 (en) 2009-09-01 2013-08-13 Sanofi Photochemical process for producing artemisinin
EP2660234A1 (fr) * 2012-05-02 2013-11-06 Sanofi Procédé de production dýintermédiaires d'artémisinine
WO2014090208A2 (fr) 2012-12-14 2014-06-19 Forschungszentrum Jülich GmbH Procédé d'identification d'une cellule présentant, comparativement à son type sauvage, une concentration intracellulaire augmentée d'un métabolite déterminé, la modification de la cellule s'effectuant par recombinaison, un procédé pour produire une cellule de production d'un métabolite déterminé, génétiquement modifiée comparativement à son type sauvage, ladite cellule étant à production optimisée, un procédé pour produire ledit métabolite ainsi que des acides nucléiques requis à cet effet
WO2016110864A1 (fr) * 2015-01-05 2016-07-14 Mantri Ashish Ompakash Procédé de purification d'artémisinine et d'autres constituants issus d'artemisia annua avec un rendement élevé et une pureté élevée
CN112538010A (zh) * 2019-09-20 2021-03-23 凯特立斯（深圳）科技有限公司 一种青蒿素类化合物合成关键中间体的制备方法
WO2021052225A1 (fr) * 2019-09-18 2021-03-25 浙江海正药业股份有限公司 Procédé de semi-synthèse chimique pour l'artémisinine

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US8507697B2 (en) 2009-09-01 2013-08-13 Sanofi Photochemical process for producing artemisinin
WO2011030223A3 (fr) * 2009-09-11 2011-05-19 Sanofi-Aventis Procédé de production d'intermédiaires d'artémisinine
CN102612507A (zh) * 2009-09-11 2012-07-25 赛诺菲 制备青蒿素中间体的方法
EA021061B1 (ru) * 2009-09-11 2015-03-31 Санофи Способ производства промежуточных продуктов артемизинина
US8334392B2 (en) 2009-09-11 2012-12-18 Sanofi Process for the production of artemisinin intermediates
JP2013504557A (ja) * 2009-09-11 2013-02-07 サノフイ アルテミシニン中間体の製造方法
AU2010293907B2 (en) * 2009-09-11 2016-03-03 Huvepharma Italia S.R.L Process for the production of artemisinin intermediates
US9409142B2 (en) 2011-08-29 2016-08-09 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Method and device for the synthesis of artemisinin
WO2013030247A1 (fr) 2011-08-29 2013-03-07 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé et dispositif pour la synthèse d'artémisinine
EP2565197A1 (fr) 2011-08-29 2013-03-06 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Procédé et dispositif pour la synthèse d'artémisinine
CN102617415A (zh) * 2012-02-20 2012-08-01 常熟理工学院 一种利用氧气氧化有机硫化物的反应方法
WO2013164367A1 (fr) * 2012-05-02 2013-11-07 Sanofi Procédé pour la production d'intermédiaires de l'artémisinine
EP2660234A1 (fr) * 2012-05-02 2013-11-06 Sanofi Procédé de production dýintermédiaires d'artémisinine
CN102718773B (zh) * 2012-06-05 2013-05-08 上海交通大学 一种由青蒿酸制备青蒿素的方法
CN103193790B (zh) * 2012-06-05 2015-04-22 上海交通大学 抗疟疾类药物青蒿素的高效制备方法
CN103193791A (zh) * 2012-06-05 2013-07-10 上海交通大学 一种药用青蒿素的高效合成方法
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CN103172645A (zh) * 2012-06-05 2013-06-26 上海交通大学 一种青蒿素的高效合成方法
WO2013181913A1 (fr) * 2012-06-05 2013-12-12 上海交通大学 Procédé pour la préparation d'artémisinine à partir d'acide artémisinique
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CN103172645B (zh) * 2012-06-05 2015-05-20 上海交通大学 一种青蒿素的高效合成方法
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CN103193791B (zh) * 2012-06-05 2015-12-09 上海交通大学 一种药用青蒿素的合成方法
DE102012024435A1 (de) 2012-12-14 2014-07-10 Forschungszentrum Jülich GmbH Verfahren zur Identifizierung einer Zelle mit gegenüber ihrem Wildtyp erhöhten intrazellulären Konzentration eines bestimmten Metaboliten, wobei die Veränderung der Zelle durch Rekombi-neering erreicht wird, sowie ein Verfahren zur Herstellung einer gegenüber ihrem Wildtyp genetisch veränderten Produktionszelle mit optimierter Produktion eines bestimmten Metaboliten, ein Verfahren zur Herstellung dieses Metaboliten, sowie dafür geeignete Nukleinsäuren
CN103087074A (zh) * 2012-12-14 2013-05-08 湖南科源生物制品有限公司 一种青蒿素的半合成方法
WO2014090208A2 (fr) 2012-12-14 2014-06-19 Forschungszentrum Jülich GmbH Procédé d'identification d'une cellule présentant, comparativement à son type sauvage, une concentration intracellulaire augmentée d'un métabolite déterminé, la modification de la cellule s'effectuant par recombinaison, un procédé pour produire une cellule de production d'un métabolite déterminé, génétiquement modifiée comparativement à son type sauvage, ladite cellule étant à production optimisée, un procédé pour produire ledit métabolite ainsi que des acides nucléiques requis à cet effet
WO2016110864A1 (fr) * 2015-01-05 2016-07-14 Mantri Ashish Ompakash Procédé de purification d'artémisinine et d'autres constituants issus d'artemisia annua avec un rendement élevé et une pureté élevée
WO2021052225A1 (fr) * 2019-09-18 2021-03-25 浙江海正药业股份有限公司 Procédé de semi-synthèse chimique pour l'artémisinine
CN112538010A (zh) * 2019-09-20 2021-03-23 凯特立斯（深圳）科技有限公司 一种青蒿素类化合物合成关键中间体的制备方法
CN112538010B (zh) * 2019-09-20 2023-08-11 凯特立斯（深圳）科技有限公司 一种青蒿素类化合物合成关键中间体的制备方法

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