FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF ARTEMISININ AND ITS
DERIVATIVES"
2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

RELATED APPLICATIONS:
This application is Complete Cognate Application of the Provisional Patent Application No. 61/MUM/2015 dated 7th January, 2015 and Provisional Patent Application No. 2684/MUM/2015 dated 15th July, 2015.
Field of the invention:
The present invention relates to a novel process for preparation of Artemisinin and its derivatives. More particularly, the invention relates to preparation of novel intermediates, Artemisinic acid of formula II and Dihydroartemisinic acid of formula Ha useful in the preparation of Artemisinin derivatives.
Background of the invention:
Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant's anti-malarial application was first described in a Chinese pharmacopeia, titled "Chinese Handbook of Prescriptions for Emergency Treatments," written at around 340 A.D.
Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.
Artemisinin and its derivatives - dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.
Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme-1.
In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane (C6Hn)2BH followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrO3/H2SO4. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.
A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene - 11,12 - epoxide) is further reduced to get amorph-

4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.
This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.
Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.
Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.
Summary of the invention:
Accordingly the present invention provides a novel route of synthesis of Artemisinin or dihydroartemisinic acid. This is been accomplished with synthesis of substantially pure Amorphadiene- 4,5- epoxide by selective oxidation of the endo double bond (4,5 position) in amorpha -4,11- diene followed by designing several novel intermediates for synthesizing artemsinic acid / dihydroartemisinic acid through the protected endo-epoxy-

Amorphadiene (Formula III). The Dihydroartemisinic acid of Formula Ha is finally converted into Artemisinin and its derivatives in substantial yields with good purity.
In one aspect, present invention provides a process for the preparation of artemisinin and/or its derivatives which comprises:
a) Epoxidation of amorpha-4,11 diene to obtain epoxide compound of formula III;
b) converting the epoxide compound of formula III to compound of formula IV;
c) oxidation of compound of formula IV to epoxy acid compound of Formula VII optionally through epoxy aldehyde of Formula V and/or epoxy alcohol of Formula VI or mixture thereof;
d) converting epoxy acid of Formula VII to Dihydroartemisinic acid of formula Ha optionally through Artemisinic acid of formula II or Epoxydihydroartemisinic acid of formula VIII and;
e) converting the Dihydroartemisinic acid of formula Ha to artemisinin and/or its derivatives.

In a preferred embodiment, in step (b), the process comprises converting Amorphadiene-4,5-epoxide of Formula -IV by reacting with an amine oxide, / hypohalites, or alkali metal phosphates in presence of suitable solvents to obtain novel intermediates of formula V and/or Formula VI that is reacted with suitable oxidizing agent in a solvent in presence of acids to obtain epoxy carboxylic acid of Formula VII.
In step (d), the process according to present invention may comprises reacting epoxy carboxylic acid of Formula VII with suitable reducing system in presence of a solvent to

obtain Epoxy dihydroartemisinic acid of Formula VIII that is deoxygenated to dihydroartemisinic acid of formula Ha; or reacting epoxy carboxylic acid of Formula VII with alkali metal or other reagents in presence of alkyl ethers of polyhydroxy alcohols and an aprotic solvent to obtain Artemisinic acid of formula II that is converted to dihydroartemisinic acid of formula Ha. In a preferred embodiment, the process is carried without isolation of intermediates of formula V, VI and/or VIII.
In the most preferred embodiment, the process comprises oxidizing Amorphadiene- 4,5-epoxide of Formula -IV directly to epoxy carboxylic acid of Formula VII using an oxidizing agent, sulfoxide and a polar aprotic solvent, optionally in presence of a base; and converting epoxy carboxylic acid of Formula VII directly to dihydroartemisinic acid of Formula Ha using excess of alkali metal.
Accordingly, in second aspect, present invention provides substantially pure Amorphadiene- 4,5- epoxide of Formula -III by selective epoxidation of endo double bond (4,5 position) in amorpha -4,11- diene.
In a third aspect, present invention provides conversion of pure Amorphadiene- 4,5-epoxide into intermediates of Formula IV - VII which can be further converted to Artemisinic acid, Dihydroartemisinic acid, Artemisinin and/or its derivatives. Intermediates of Formula -IV, V & VI are novel.

Description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows
Since, the compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all encompassed within the scope of the present invention.
The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate (4-bromobenzenesulfonate) and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
The term "halogen" means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The present invention provides a novel and economic route of synthesis of Dihydroartemisinic acid. This is been accomplished with synthesis of substantially pure Amorphadiene- 4,5- epoxide (Formula III) by selective oxidation of the endo double bond (4,5 position) in amorpha -4,11- diene followed by designing several novel intermediates for synthesizing dihydroartemisinic acid using said pure Amorphadiene- 4,5- epoxide.
Accordingly, in one aspect, the present invention provides substantially pure Amorphadiene- 4,5- epoxide of Formula -III. Substantially pure denotes that Amorphadiene- 4,5- epoxide comprises more than 75% by weight (preferably more than

85% by weight, more preferably more than 90% by weight, especially more than 98% by weight) with respect to unreacted starting material, exo epoxide and diepoxide.
Accordingly, in another aspect, present invention provides a process for the preparation of artemisinin and/or its derivatives which comprises:
a) Epoxidation of amorpha-4,11 diene to obtain epoxide compound of formula III;
b) converting the epoxide compound of formula III to compound of formula IV;
c) oxidation of compound of formula IV to epoxy acid compound of Formula VII optionally through epoxy aldehyde of Formula V and/or epoxy alcohol of Formula VI or mixture thereof;
d) converting epoxy acid of Formula VII to Dihydroartemisinic acid of formula Ha optionally through Artemisinic acid of formula II or Epoxydihydroartemisinic acid of formula VIII and;
e) converting the Dihydroartemisinic acid of formula Ha to artemisinin and/or its derivatives.

In a preferred embodiment, step-1 of Scheme 2, the epoxidation of amorpha-4,11 diene, selectively at endo position, is carried out using an agent in a suitable solvent. This step may optionally be conducted in presence of a suitable base and a catalyst.
In step-1, the agent includes substituted perbenzoic acids including m-chlorobenzoic acid (mCPBA), hydrogen peroxide (H2O2), Sodium Chlorite (NaClC>2), peroxydisulfate,

HCO3H, t-butyl hydroxperoxide (t-BuOOH), Sodium periodate (NaI04), dioxyrane and iodosylbenzene, oxygen etc.
In step-1, the suitable solvent for epoxidation may be selected from water, halogenated hydrocarbons such as dichloroethane and dichloromethane, halobenzene, C3-6 cyclohexanes, aromatic hydrocarbons such as toluene, xylene, C1-6 alcohols such as ethanol, methanol, isopropanol, n-butanol and t-butanol, C1-6 ketones, substituted phenol, perfluorinated alcohol solvents such as 2,2,2-trifmoroethanol and 1,1,1,3,3,3-hexafmoro-2-propanol, polar aprotic solvents, esters, nitriles and ethers or mixtures thereof. Preferred solvents include water, dichloromethane and dichloroethane.
In step-1, the suitable catalysts for epoxidation may be selected from Manganese sulphate monohydrate, Tetra-butyl ammonium bromide (TBAB), N,N'-Diisopropylcarbodiimide (DIC), acetic acid, N,N'-Dicyclohexylcarbodiimide (DCC), Ti-MMM-2, Ti(OiPr)4, (-) DET, VO(acac)2, and (bipyridyl)RuCl2-DMSO, acetic acid, formic acid, Trifluoroacetic acid, optionally substituted phenols (where substituents are selected from -F, -CI, -Br, -I, -CN, -NO2 and -OH, OMe), hydroquinone, ammonium acetate, sodium formate and ammonium formate, EDTA, metals (Ti, W, Mo, Mn, Re) or Semi metals (As, Se), Ni(acac)2, Ni(ptbbacac)2, Ni(OAc)2, Ni(OAc)2.4H20, Co(acac)2, Co(OAc)2.4H20, Mn(acac)2, Mn(OAc)2.4H20, Cu(acac)2, Fe(acac)2, Fe(acac)3, VO(acac)2, Cr(acac)3, 2-(tert-butyl)-4-methylphenol, isobutyraldehyde, 2-methylundecanal, pivaldehyde and Methyl iodide.
In step-1, the suitable base for epoxidation may be selected from NaHCCb, Urea and Na2C03.
In an alternate embodiment, the epoxidation reaction may also be carried out in an aqueous-organic solvent system in presence or absence of catalyst.
The aqueous-organic solvent system preferably forms a biphasic medium containing an aqueous phase and an organic phase, wherein at least one organic solvent is selected from water immiscible solvents. The aqueous phase comprises preferably water. Aqueous phase may also contain non-protic water miscible solvents such as dimethyl sulfoxide,

dimethyl acetamide or dimethyl formamide, in small proportions. The suitable water immiscible solvents include, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers etc. Chlorinated hydrocarbons preferably include methylene dichloride (MDC), ethylene dichloride, chloroform, carbon tetrachloride, and aromatic hydrocarbons preferably selected from toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane, n-decane etc. Esters include ethyl acetate or butyl acetate. Ethers include diisopropyl ether or diethyl ether.
After completion of reaction the epoxide of Formula III (amophadiene - 4,5-epoxide) is isolated by conventional methods. By following the process of present invention, amorphadiene-4,5-epoxide having purity >80% is obtained.
In step 2, the obtained epoxide of formula III is further reacted with suitable agents to form compounds of formula -IV wherein R is a leaving group which includes chloro, bromo, iodo, tosyl, mesyl, brosyl (4-bromobenzenesulfonate), acetoxy, trifluoroacetoxy and the like.
Among the epoxy halides of Formula—IV, epoxy bromide or chloride is preferred
V
compound.
In a preferred embodiment, in step-2 of Scheme 2, halogenated compounds of the compounds of Formula IV are prepared, wherein the halogenation is advantageously carried out in a suitable solvent using a halogenating agent in presence of acids at temperature from 0°C to reflux temperature of the solvent used.
In step-2, the halogenating agent may be selected from alkali metal hypochlorites such as Ca(OCl)2, Ca(OBr)2, NaOCl, NaOBr, LiOCl, and CeCl3; N-halo succinimides such as N-Chloro succinimide, N-Bromo succinimide and N-Iodo succinimide; N,N-dihalo-substituted hydantoins such as N,N-dichloro 5,5-dimethyl hydantoin and N,N-dibromo 5,5-dimethyl hydantoin. Vilsmeier reagent-FfcCh may also be used for halogenation.

In step-2, the acids may be selected from inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid and boric acid; organic acids such as formic acid, acetic acid etc. Dry ice (solid carbon dioxide) may also be used in place of acids.
In step-2, the halogenation reaction is conducted in a suitable solvent selected from water, halogenated hydrocarbons such as dichloroethane and dichloro methane, monochloro benzene aromatic hydrocarbons such as toluene, xylene, Ci-6 alcohols, polar aprotic solvents, nitriles and ethers or mixtures thereof. Preferred solvents include water, dichloromethane and dichloroethane.
After completion of reaction, the epoxy halide of Formula IV is isolated by conventional methods. The obtained epoxy halide of Formula IV is, optionally, further converted to form epoxy aldehyde of formula V & epoxy alcohol of formula VI.
In a preferred embodiment, in step-3 of Scheme 2, the obtained epoxy halide of Formula IV is reacted with an amine oxide, alkali hypohalides / hypohalites, or alkali metal phosphates in presence of suitable solvents. Dimethyl sulfoxide as a reagent also may be used instead of amine oxide. The reaction, optionally, may be conducted in presence of a base or an alkali metal halide catalyst. It is observed that during the reaction, mixture of compounds of Formula V and VI are formed. However, the major compound is found to be epoxy aldehyde of Formula V. It is further observed that when amine oxide is used in the process, it gives predominantly epoxy aldehyde of Formula V as compared to process using dimethyl sulfoxide, which gives mixture of epoxy aldehyde of Formula V & epoxy alcohol of Formula VI.
In step-3, suitable amine oxides include N-methyl morpholine-N-oxide (NMO); 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO); 1 -Dodecanamine, N,N-dimethyl-, N-oxide; 1-Tetradecanamine, N,N-dimethyl-, N-oxide; Amines, Cio-i6-alkyldimethyl, N-oxides; Amines, Ci2-i8-alkyldimethyl, N-oxides; Decanamine, N,N-dimethyl-, N-oxide; Hexadecanamine, N,N-dimethyl-, N-oxide; Octadecanamine, N,N-dimethyl-, N-oxide; Amine oxides, cocoalkyldimethyl; Amines, Cio-is-alkyldimethyl, N-oxides; Amines, C12-16-alkyldimethyl, N-oxides; Ethanol, 2,2'-iminobis-, N-coco alkyl derivs., N- Oxides; Ethanol, 2,2'-(dodecyloxidoimino)bis-; Ethanol, 2,2'-(octadecyloxidoimino)bis-; Ethanol,

2,2'-iminobis-; N-tallow alkyl derivs., N- Oxides; Ethanol, 2,2'-[(9Z)-9-octadecenyloxidoiminojbis-. However, preferred amino oxide is N-methyl morpholine-N-oxide (NMO) and 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO). The alkali metal phosphates include Na2HP04, NaH2P04, K2HPO4, KH2PO4 etc. The alkali metal halide catalysts include NaBr, KBr, Nal, KI etc.
In step-3, a wide range of solvents may be used for conducting the reduction reaction. The solvents include, but not limited to, water, alcohols, esters, aromatic hydrocarbons, nitriles and polar aprotic solvents or mixtures thereof. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, iso butanol and tertiary butanol etc. Esters include ethyl acetate, methyl acetate, n-butyl acetate or isobutyl acetate. Polar aprotic solvents include dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide or N-methylpyrrolidine. Aromatic hydrocarbons include toluene or xylene. However, preferred solvents used for the reaction are dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide or N-methylpyrrolidine.
In step-3, the base used may be selected from organic or inorganic base. More preferably, the base is selected from the group consisting of alkali metal hydroxide, alkali metal alkoxides, carbonates and bicarbonates. The organic base is selected from a group consisting of methyl amine, diethyl amine, triethyl amine, diisopropyl ethylamine.
After completion of reaction, the product, (epoxy aldehyde of Formula V containing epoxy alcohol of Formula VI in minor quantity) is isolated using conventional methods such as by extracting with suitable solvents such as methylene dichloride, ethyl acetate and the product mixture is subjected for oxidation.
In a preferred embodiment, in step-4 of Scheme 2, the product (compound of Formula V containing product Formula VI in minor quantity) is reacted with suitable oxidizing agent in a solvent in presence of acids to obtain epoxy carboxylic acid of Formula VII. The reaction, optionally, is conducted in presence of salts or scavenging agent. Usually reaction is conducted at a temperature ranging from 0°C to reflux temperature of the solvent used.

Several oxidizing agents to convert the mixture of epoxy aldehyde of Formula V containing epoxy alcohol of Formula VI in minor quantity into compound of formula VII may be used. The oxidizing agents include, but not limited to, K2Cr207, NaCr04 and (NH4)2Cr207, KMn04, NaMn04, Mn02, Cr03, NaC102, NaC104, H202, KBr03 etc.
In step-4, the oxidation reaction is carried in an inert solvent. The solvents include, but
not limited to, water, ethers, alcohols, esters, aromatic hydrocarbons, nitriles and polar
aprotic solvents or mixtures thereof. Ethers include tetrahydrofuran, diethylether,
diisopropyl ether etc. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-
butanol, iso butanol and tertiary butanol etc. Esters include ethyl acetate, methyl acetate,
n-butyl acetate or isobutyl acetate. Polar aprotic solvents include dimethyl sulfoxide, ,
dimethyl acetamide, dimethyl formamide or N-methylpyrrolidine. Aromatic hydrocarbons
include toluene or xylene. However, preferred solvents for the reaction are selected from
the group consisting of water, isopropanol, dimethyl sulfoxide, dimethyl acetamide,
dimethyl formamide or N-methylpyrrolidine. •
In step-4, the acids include Sulfuric acid, phosphoric acid or acetic acid, and the salts may be selected from alkali salts of Sulfuric acid, phosphoric acid or acetic acid such as NaH2P04, NaOAc and Na2S04. In step-4, the scavenging agent includes sulfamic acid, cyclohexene, resorcinol or hydrogen peroxide.
In the most preferred embodiment, epoxy carboxylic acid of Formula VII can be directly prepared from compound of Formula IV. According to step-6 of Scheme 2, the compound of Formula IV is oxidized to epoxy carboxylic acid of Formula VII using an oxidizing agent, sulfoxide, and a polar aprotic solvent, optionally in presence of a base at temperature ranging from 0°C to reflux temperature of the solvent used.
In step-6, the oxidizing agents include, but not limited to, K2Cr207, NaCr04 and (NH4)2Cr207, KMn04, NaMn04, Mn02, Cr03, NaC102, NaC104, H202, KBr03 etc.
In step-6, the sulfoxides may be dialkyl or diaryl sulfoxides. Dialkyl substituents may be methyl, ethyl, propyl, isopropyl, butyl or isobutyl groups, and, the diaryl sulfoxide may

be diphenyl sulfoxide, di(ptolyl) sulfoxide, di(m-tolyl) sulfoxide, phenyl o-tolyl sulfoxide, phenyl p-tolyl sulfoxide, o, m-ditolyl sulfoxide and m,p-ditolyl sulfoxide.
In step-6, the polar aprotic solvents include dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide or N-methylpyrrolidine.
In step-6, the base used may be selected from organic or inorganic base. The base is selected from the group consisting of alkali metal hydroxide, alkali metal alkoxides, carbonates and bicarbonates.
After completion of the oxidation, the epoxy carboxylic acid of Formula VII is isolated from the reaction mass by conventional methods.
In one preferred embodiment, according to step-5 of Scheme 2, the epoxy carboxylic acid of Formula VII is deoxygenated to Artemisinic acid of Formula II using alkali metal or other reagents in presence of alkyl ethers of polyhydroxy alcohols and an aprotic solvent at <0°C to reflux temperature of the solvent.
In another preferred embodiment, according to step-5a of Scheme 2, the epoxy carboxylic acid of Formula VII is further reacted with suitable reducing system in presence of a solvent to obtain Epoxy dihydroartemisinic acid of Formula VIII. Usually the reaction is conducted at a temperature ranging from 0°C to reflux temperature of the solvent used.
In step-5a, many reducing agents to convert the epoxy acid of Formula VII into Epoxy dihydroartemisinic acid of Formula VIII may be used. The reducing agents include, but not limited to Hydrazine hydrate, Hydrogen peroxide, TsNHNH2 and hydrogen gas pressure etc. The catalysts include, but not limited to Wilkinson's catalyst (tris(triphenylphosphene) rhodium chloride), KOOC-N=N-COOK, 10% Pd on carbon, Cu(II), 5% iridium carbonate, (R)-Xyl-PhanePhos-RuCl2-(DMF)2, nanopalladium catalyst etc.
In step-5a, the solvent include, but not limited to Ci-6 alcohol such as ethanol, methanol, isopropanol, n-butanol and t-butanol, aromatic hydrocarbons such as toluene or xylene,

aprotic solvents, glycol and acetic acid. The aprotic solvent can be a solvent which does not have an active hydrogen atom which reacts with the alkali metal, and it is preferable to use a solvent dried before use. Examples of the aprotic solvent which can suitably be used are N,N-Dimethylformamide, hydrocarbons such as benzene, toluene and xylene, biphenyl, mesitylene, cyclohexane and ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane and dibutyl ether.
In a further preferred embodiment as shown in step-7 of Scheme 2, Epoxy dihydroartemisinic acid of Formula VIII is deoxygenated to dihydroartemisinic acid of Formula Ha using alkali metal or other reagents in presence of alkyl ethers of polyhydroxy alcohols and an aprotic solvent at a temperature ranging from 0°C to reflux temperature of the solvent.
In the most preferred embodiment, dihydroartemisinic acid of Formula Ha can be directly prepared from Epoxy carboxylic acid of Formula VII without preparing Epoxy dihydroartemisinic acid of Formula VIII. According to step-8 of Scheme 2, the Epoxy carboxylic acid of Formula VII is converted to dihydroartemisinic acid of Formula Ha using excess of alkali metal or other reagents in presence of alkyl ethers of polyhydroxy alcohols and an aprotic solvent at a temperature ranging from 0°C to reflux temperature of the solvent.
In steps 5, 7 or 8, the alkali metal is metallic sodium, metallic potassium or metallic lithium and preferred one is metallic Lithium.
In steps 5, 7 or 8, other reagents used in this de-oxygenation reaction include CrC12,
Cr(OAc)2, Cr(C104)2- H2NCH2CH2NH2, Zn-Nal-NaOAc, Triphenylphosphene, nBu3P,
m-ClC6H4CHO, (EtO)3P, Triphenylphosphene Dihalide, Cp2TiCl2/Zn, Cp2TiCl2/Mg,
TMSCl/Zn, Ph3PSe/CF3COOH, KSeCN/MeOH-H20,(EtO)2POTeM, Methyl
triphenylphosphonium iodide(MTPI)/BF3.Et20, Trimethylsilyliodide,
nBuLi/Bis(dimethylamino)phosphorus acid, Lithiumdiphenylphosphide,
Octacarbonyldicobalt, Lithium halide/trifluoroacetic anhydride, Potassium n-butyl xanthate, Triphenylphosphene diodide and triphenylphosphene hydriodide, Diphosphorus tetraiodide, Fe(CO)5, Ph3P-I2, Sml2 or Ybl2, FeCl3-nBuLi, TiCl3-LiAlH4, Ti, V, Cr, Co,

Ni, (Ti-C6H6)2Ti, Mg(Hg)-MgBr2, Zn-Cu, NbCl5-NaAlH4, (n-CsHs^MoCh-NaCHg), (n-C5H5)2WCl2-Na(Hg), (n-C5H5)2 TiCb-Na(Hg), (r|-C5H5)2 ZrCl2-Na(Hg), (ri-C5H5)2 MOO-Na(Hg), (Ti-C5H5)2WO-Na(Hg).
In steps 5, 7 or 8, the alkyl ethers of polyhydroxy alcohols are selected from the group consisting of dimethoxyethane (DME, ethylene glycol dimethyl ether), ethylene glycol diethyl ether, diethylene glycol dimethyl ether, Methylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether and propylene glycol dimethyl ether etc. However, it is particularly preferable to use dimethoxyethane.
In steps 5, 7 or 8, the aprotic solvent can be a solvent which does not have an active hydrogen atom which reacts with the alkali metal, and it is preferable to use a solvent dried before use. Examples of the aprotic solvent which can suitably be used are aromatic hydrocarbons such as benzene, toluene and xylene, biphenyl, mesitylene and ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane and dibutyl ether.
After completion of reaction, artemisinic acid of Formula II or dihydroartemisinic acid of Formula Ha is isolated by conventional & standard work up methods known in the literature. Then artemisinic acid / dihydroartemisinic acid thus obtained by the above procedures are converted into artemisinin and its derivatives such as dihydroartemisinin, artemether, arteether, and artesunate by the procedures known in the literature.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples
Brief manufacturing process for preparation of artemisinic acid:
STEP-1
Epoxidation of amorpha-4,11 diene

Amorphadiene (100 g) and formic acid (6.8 g) were charged into the 4-neck round bottom flask at 25°C. Reaction mass was warmed up to 30°C. H2O2 (70 ml) (50% aqueous solution) was added drop wise to the reaction mass at 30-34°C over a period of 12 hours and reaction mass maintained for 15.5 hours. A 2nd lot of H2O2 (7 ml)(50% aqueous solution) was added at 30-34°C over a period of 1 hour and the reaction mass maintained for 18.5 hours. The reaction mass was cooled to 5-10*C followed by addition of water. pH of reaction mass was adjusted to 7-8 using 5% NaOH solution and MDC (700 ml) was charged. Aqueous layer was back extracted with MDC (300 ml) and the combined organic layer was washed with 10% sodium metabisulfite solution (2x 500 ml) at 25°C. Further organic layer was washed with water (1000 ml) and brine solution (500 ml). Solvent was distilled out under vacuum at 40-45°C.Crude mass (Purity: 80-85%) of epoxide of formula III was degassed at 50°C for 2-3 hours. Weight: 88.46 gm Yield:82%
STEP-2
Preparation of compound of formula IV (R = CI)
The epoxide of formula III (85 g), dichloromethane (MDC, 850ml) and water (170 ml) were charged into the 4-neck round bottom flask at 25°C and the reaction mass was cooled up to 0°C. Calcium hypochlorite (33.91 g) was charged to the reaction mass followed by drop wise addition of 4% aqueous HC1 (140 ml) over a period of 1 hour at -2°C to 2°C. Further reaction mass was maintained for 2 hours at 0-2°C. Calcium hypochlorite (2nd lot, 3.4 g) was charged slowly to the reaction mass at 0-2°C within 15 minutes. The reaction mass pH was adjusted with dilute 4% aqueous HC1 (14 ml), stirred 15 minutes at 0-2°C till completion of reaction. Reaction mass was diluted with water (850 ml) at 0-2°C, warmed up to 20-25°C and stirred for one hour. Aqueous layer was back extracted with MDC (2 X 255 ml) at 20-25°C. Combined organic layer was washed with water (2 x 850 ml) at 25°C. Further, the organic layer was washed with brine solution (850 ml). Solvent was distilled out under vacuum at 40°C. Crude mass (purity: 60-68%) of compound of formula IV (R = CI) was degassed under vacuum at 45-50°C. Weight: 88.44 gm Yield:90%

STEP-3
Preparation of epoxy aldehyde of formula V
NMO (50% aqueous solution) (187.9 g) and toluene (680 ml) was charged to the 4-neck
round bottom flask at 26°C. Then water (92 ml) was removed by azeotropic reflux of
toluene at 110°C. Toluene (544 ml) was distilled out at 110°C. Further solution of
compound of formula IV (R = CI) (68 g) in DMSO (136 ml) was charged to the reaction
mass at 26°C and the reaction mass was maintained for 9 hours at 35°C till completion.
The reaction mass was cooled 20°C. Water (680 ml) and toluene (680 ml) were charged to
the reaction mass; pH adjusted to 5-6 with HC1 solution (16% in water) and stirred for 30
minutes. Layers were separated out and aqueous layer was back extracted with toluene (2
X 204 ml). Organic layer was washed with water (680 ml) and saturated brine solution
(840 ml). The solvent was distilled out under vacuum at 50°C and the crude mass (purity:
50-55%) of an epoxy aldehyde compound of formula V (A = CHO) was degassed at 50-
55°C.
Weight: 57.5 gm
Yield:92%
Preparation of epoxy alcohol of formula VI
A compound of formula IV (R = CI) (100 g), DMSO (1000 ml), NaOAc (64.38 gm) were charged into the 4-neck round bottom flask at 25°C. The reaction mass was warmed up to 90-95°C and maintained for 10 hours till completion. The reaction mass was cooled to 25-30°C. The reaction mass was charged with water (1000 ml) at 25-30°C and extracted with MDC (1000 ml). MDC layer was washed with water (1000 ml) and then with saturated NaCl solution (500 ml). MDC layer was distilled out under vacuum at 40-45°C and the crude mass (purity: 47%) was degassed at 50°C for 2-3 hours. The crude product was purified by column chromatography using 100-200 mesh silica gel and mobile phase (2% ethyl acetate in hexane) to obtain an epoxy acetate compound of formula IV (R = OAc) (purity: 90-99%).
The epoxy acetate of formula IV (R = OAc) (100 g), water (1000 ml) and KOH (40.31 gm) were charged into the 4-neck round bottom flask at 25°C and reaction mass stirred for 1 hour. The reaction mass cooled to 10-15°C and pH 4 was adjusted with HC1 solution. The reaction mass extracted with MDC (1000 ml) and the MDC layer was washed with water (1000 ml) then with saturated NaCl solution (500 ml). The MDC layer was distilled

out under vacuum at 40-45°C and the crude mass (purity: 40%) of an epoxy alcohol of formula VI (A = CH2OH) was degassed at 50°C for 2-3 hours. Weight: 27.87 gm Yield: 30%
STEP-4
Preparation of epoxy acid of formula VII from epoxy aldehyde
In the 4-neck round bottom flask, an epoxy aldehyde of formula V (A = CHO) (90 g) and isopropyl alcohol (IPA, 450 ml) was charged at 30°C and reaction cooled to 0-5°C. Parallel addition of NaClC>2 solution (41.7 g NaC102 + 360 ml water) and sulfamic acid solution (9.9 g sulfamic acid + 180 ml water) was done by maintaining pH 4.71 within 80 minutes. Further pH of reaction mass was adjusted to 3.73 by sulfamic acid solution (2 g sulfamic acid + 30 ml tap water) and reaction mass was maintained for 1 hour till completion. Water (360 ml) and ethyl acetate (900 ml) were added to the reaction mass at 5°C and reaction mass stirred for 20 minutes. Layers were separated out. Aqueous layer was back extracted with ethyl acetate (2 X 180 ml). Combined organic layer was washed with water (450 ml) and saturated NaCl solution (450 ml) and then solvent distilled out under vacuum at 50°C. Crude mass (purity: 50-55%) was degassed at 55°C under vacuum for 2-3 hours. The crude product (91 g) was dissolved in ethyl acetate (1820 ml). NaHCC"3 (8% solution in water) (910 ml) was charged to the reaction mass, stirred for one hour at 20°C and layers separated out. Again NaHCCb (8% solution in water) (910 ml) was charged to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaHC03 solution wash was adjusted to 4.0 with diluted HC1 (16%) solution in water) at 5-lO°C under stirring. Ethyl acetate (910 ml) was charged to aqueous acidic mass, stirred for 30 minutes and layers were separated out. Aqueous layer was extracted with ethyl acetate (2 X 273 ml). The combined organic layer was washed with water (910 ml) and saturated brine solution (455 ml). Solvent was distilled out under vacuum. Purified mass was degassed under vacuum at 50-55°C to obtain an epoxy acid of formula VII (purity: 84-94%). Weight: 28.85 gm Yield: 30%
Preparation of epoxy acid of formula VII from epoxy alcohol

An epoxy alcohol of formula VI (R = CH2OH) (100 g) and acetone (1000 ml) were charged into the 4-neck round bottom flask and cooled to 0-5°C. Previously prepared Jones reagent (Cr03 (126.93 g) + H2SO4 (124.5 g)) was added over 2 hours and the reaction mass was stirred for 2 hours at 0-5°C. After the reaction was completed, ether was added to reaction mass for precipitate out chromeous salt then reaction mass filtered. The filtrate was distilled out and purified by addition of 5% aqueous NaOH solution. The aqueous layer was acidified and extracted with ethyl acetate. Ethyl acetate layer was washed with water (1000 ml) then with saturated NaCl solution (500 ml). Ethyl acetate layer was distilled out under vacuum at 40-45°C and the crude mass (purity: 60%) was degassed at 50°C for 2-3 hours. The crude product was purified by column chromatography using 100-200 mesh silica gel and mobile phase (2% ethyl acetate in hexane) to obtain epoxy acid of formula VII (purity: 90-99%). Weight: 10.5 gm Yield: 10%
STEP -5
Preparation of artemisinic acid from compound of formula VII
THF (900 ml), Cp2TiCl2 (99.44 gm), Mg-metal (9.71 gm) were charged into the 4-neck round bottom flask at 25°C and stirred for 1 hour. Reaction mass cooled to -65°C. Drop wise added epoxy acid of formula VII (100 gm) diluted in THF (100 ml) and stirred for 1 hour. The reaction mass was charged with water (1000 ml) at 25-30°C and filtered. The filtrate was extracted with ethyl acetate. Ethyl acetate layer washed with water (1000 ml) and then with saturated NaCl solution (500 ml). Ethyl acetate layer was distilled out under vacuum at 40-45°C.Crude mass (purity: 70-80%) was degassed at 50°C for 2-3 hours. The crude product was purified by column chromatography using 100-200 mesh silica gel and mobile phase (2% ethyl acetate in hexane) to obtain Artemisinic acid of formula II (purity: 90-99%). Weight: 9.28 gm Yield: 10%
STEP -5a
Preparation of Epoxydihydroartemisinic acid of formula VIII from Epoxy carboxylic acid of formula VII

The epoxy acid of formula VII (90 g) and IP A (360 ml) were charged into the 4-neck round bottom flask at 26°C. Hydrazine hydrate (65% in aqueous solution) (35.95 g) and hydrogen peroxide (50% in aqueous solution) (22.93 ml) were simultaneously added at 30-32°C over a period of 3.25 hours. The reaction mass was maintained for at 30-32°C till completion. The reaction mass was cooled up to 5-10°C and water (900 ml) added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with diluted HC1 (240 ml) (8% solution in water) at 10°C. Ethyl acetate (630 ml) was added, the mass stirred for 15 minutes at 15-20°C and layers were separated. The aqueous layer was back extracted with ethyl acetate (2 X 180 ml) and the combined organic layer was washed with 10% sodium metabisulfite solution (450 ml), water (450 ml) and saturated brine solution (450 ml). The solvent was distilled out under vacuum at 45°C and crude mass (purity: 50-55%) degassed at 50-55°C. The crude product (85 g) was dissolved in ethyl acetate (1700 ml). NaOH (10% solution in water) (850 ml) was charged to the reaction mass and stirred one hour at 20°C and layers separated. Again NaOH (10% solution in water) (850ml) was charged to the organic layer, stirred for 30 minutes and layers separated. The pH of combined NaOH solution wash was adjusted to 4.0 with diluted HC1 (16% solution in water) at 5-10°C. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred for 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 255 ml) and the combined organic layer was washed with water (850 ml) and saturated brine (425 ml). The solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain epoxy dihydroartemisinic acid of formula VIII (purity: 84-94%). Weight: 27.2 gm Yield: 30%
STEP -6
Preparation of compound of formula VII from compound of formula IV DMSO (1000 ml), compound of formula IV (R = CI) (100 gm), and Na2HP04 (867.7 gm) were charged into the 4-neck round bottom flask at 25°C and reaction mass was heated to 100-105°C and maintained for 8 hours. The reaction mass cooled to 10-15°C and charged with DMSO (2000 ml). NaClOi (345 gm) diluted in H20 (1000 ml) was added and reaction mass stirred for 4 hours. After completion, the reaction mass was cooled up to 5-10°C and pH was adjusted to 3 with 20% Ortho phosphoric acid. The reaction mass was

extracted with MDC (1000 ml) and MDC layer washed with H20 (1000 ml) and then with saturated brine (500 ml). The solvent was distilled out under vacuum at 40-45°C and the crude mass (purity: 35-40%) was degassed at 65-70°C. The crude product (100 g) was dissolved in ethyl acetate (1000 ml) followed by addition of 10% aqueous NaOH (1000 ml) with stirring for one hour at 20°C. The layers were separated out and organic layer was again treated with 10% aqueous NaOH (500ml) with stirring. The layers were separated out and the pH of combined NaOH solution wash, was adjusted to 4.0 with dilute 16% aqueous HC1 at 5-10°C under stirring. Ethyl acetate (1000 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 500 ml) and the combined organic layer was washed with water (1000 ml) and saturated brine (500 ml). The organic layer was dried over sodium chloride, solvent distilled out under vacuum and purified mass was degassed under vacuum at 50-55°C to obtain an epoxy acid of formula VII (purity: 90-99%). Weight: 9.82 gm Yield: 10%
Preparation of Artemisinin
a) Dihydroartemisinic acid: Method 1 (STEP 7):
Preparation of Dihydroartemisinic acid of formula Ha from Epoxydihydroartemisinic acid of Formula-VIII:
Epoxy dihydroartemisinic acid of formula VIII (5 g), biphenyl (0.46 g), Lithium metal (0.82 g) and 1, 2-Dimethoxyethane (20 ml) were charged into the reaction mass under nitrogen gas atmosphere. The reaction mass was heated to 50-53°C and maintained for 10 hours till completion. The reaction mass was cooled up to 0-5°C and water was added drop wise over a time of one hour. The reaction mass was stirred for two hours at 20-25°C. Toluene (35 ml) was added with stirring over 30 minutes, layers separated and aqueous layer was washed with toluene (35 ml). The combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15°C and pH adjusted 3.5 to 4 with dil HC1 (16% solution in water) solution. MDC (50 ml) was added and stirred 30 minutes at 20-25°C. The layers are separated and aqueous layer extracted with MDC (25 ml). The combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml).

Solvent was distilled out under vacuum at 40-45°C and the crude mass (purity: 70-80%) was degassing at 65-70°C. To the crude product (5 g) dissolved in ethyl acetate (200 ml) was added NaOH (10% solution in water) (100 ml) and reaction mass stirred for one hour at 20°C. The layers were separated out. Again added NaOH (10% solution in water) (100ml) to the organic layer, stirred for 30 minutes and layers were separated out. The pH of combined NaOH solution wash was adjusted to 4.0 with diluted HC1 (16% solution in water) at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred for 30 minutes and layers were separated out. Aqueous layer was back extracted with ethyl acetate (2 X 30 ml). The combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid of formula Ha (purity: 90-95%). Weight: 1.87 gm Yield: 40%
Method 2 (STEP 8):
Preparation of Dihydroartemisinic acid of formula Ha from Epoxy carboxylic acid of formula VII:
Epoxy acid of formula VII (5 g), biphenyl (3.4g), Lithium metal (1.4 g) and 1, 2-Dimethoxyethane (20 ml) were charged into the reaction mass under nitrogen gas atmosphere. The reaction mass was heated to 80-85°C and maintained for 10 hours till completion. The reaction mass was cooled up to 0-5°C, water was added drop wise over one hour and mixture stirred for two hours at 20-25°C. Toluene (35 ml) was charged and stirred for 30 minutes, layers separated and aqueous layer washed with toluene (35 ml). The combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The charged aqueous layer was cooled to 10-15°C and pH adjusted to 3.5-4 with dilute HC1 (16% solution in water) solution. MDC (50 ml) was charged with stirring for 30 minutes at 20-25°C and layers were separated. The aqueous layer extracted with MDC (25 ml). The combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). Solvent was distilled out under vacuum at 40-45°C. The crude mass (70-80%) was degassed at 65-70°C. The crude product (8 g) was dissolved in ethyl acetate (200 ml). NaOH (10% solution in water) (100 ml) was charged to the reaction mass, stirred one hour at 20°C and layers separated out.

Again NaOH (10% solution in water) (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The combined NaOH solution wash was adjusted to pH 4.0 with diluted HC1 (16% solution in water) at 5-10°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml). The combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The solvent was distilled out under vacuum. Purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (60:40 isomeric ratio, purity: 90-95%). Weight: 1.4 gm Yield: 30%
Method 3 (From Artemisinic acid):
Artemisinic acid (84.15 g) and IPA (337 ml) were charged into the 4-neck round bottom flask at 26°C. 65% aqueous Hydrazine hydrate (35.95 g) and 50% aqueous hydrogen peroxide (22.93 ml) were simultaneously added at 30-32°C over a period of 3.25 hours. The reaction mass was maintained for 3 hours at 30-32°C till completion. The reaction mass was cooled up to 5-10°C and water (900 ml) added to the reaction mass. The reaction mass pH was adjusted to 3.8 with diluted HC1 (240 ml) (8% solution in water) at 10°C. Ethyl acetate (630 ml) was added to the reaction mass at 10°C and stirred 15 minutes at 15-20°C. Layers were separated and aqueous layer was back extracted with ethyl acetate (2 X 180 ml). The combined organic layer was washed with 10% sodium metabisulfite solution (450 ml), water (450 ml) and saturated brine solution (450 ml). The solvent was distilled out under vacuum at 45°C. The crude mass (purity: 85%) was degassed at 50-55°C. Weight: 73.8 gm Yield: 87%
Method 4 (From compound of formula IV (R = CI)):
In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30°C followed by heating and maintaining the temperature for 40 hours at 80°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

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

and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55°C to obtain Dihydroartemisinic acid (Purity: 90-95%).
b) Methyl ester of Dihydroartemisinic acid:
To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass. Weight: 41.88 gm Yield = 98%
c) Artemisinin:
Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm Yield= 70.7%
Purification of Artemisinin:
Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution
was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was
isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.
Weight: 4 gm
Yield: 40%

We Claim,
1. A process for preparation of artemesinin or its intermediate Dihydroartemisinic acid of formula Ha comprising the steps of:
a) epoxidation of amorpha-4,11 diene to obtain epoxide compound of formula III,
b) converting the epoxide compound of formula III to obtain compound of formula IV, wherein R is a leaving group;
c) oxidation of compound of formula IV to obtain epoxy acid of Formula VII; and
d) converting epoxy acid of Formula VII to obtain Dihydroartemisinic acid of formula Ha via reduction and deoxygenation reactions.
2. The process according to claim 1, wherein the step 1-c comprising oxidation of compounds of formula IV to epoxy acid of formula VII proceed through epoxy alcohol of Formula VI and/or epoxy aldehyde of Formula V.
3. The process according to claim 2, wherein the step 1-c comprising reacting compounds of formula IV with an alkali metal phosphates or amine oxide to obtain epoxy aldehyde of Formula V; followed by oxidizing epoxy aldehyde of Formula V to epoxy acid of Formula VII with an oxidizing agent in presence of inert solvent.

4. The process according to claim 2, wherein the step 1-c comprising converting the compounds of formula IV to an epoxy alcohol of Formula VI via acetate derivative; followed by oxidizing the epoxy alcohol of Formula VI to Epoxy acid of Formula VII using an oxidizing agent.
5. The process according to claim 3, wherein the alkali metal phosphate is Na2HP04 and K2HPO4 and amine oxide is N-methyl morpholine-N-oxide and 2,2,6,6-tetramethyl-l-piperidinyloxy.
6. The process according to claim 3, wherein the oxidizing agent is selected from the
group consisting of NaClCh, KMn04 and hydrogen peroxide, and the inert solvent is
water and isopropyl alcohol.
7. The process according to claim 4, wherein the oxidizing agent is Jones reagent or 2,2,6,6-tetramethyl-1 -piperidinyloxy (TEMPO).
8. The process according to claim 2, wherein the intermediates of Formula V and VI are not isolated.
9. The process according to claim 1, wherein the step 1-d comprising converting epoxy acid of Formula VII to Dihydroartemisinic acid of formula Ha through formation of Epoxy dihydroartemisinic acid of Formula VIII or Artemisinic acid of Formula II.
10. The process according to claim 14, wherein the intermediates of Formula VIII and formula II are not isolated.

11. The process according to claim 1, wherein, the process comprising converting the compound of formula IV directly into Dihydroartemisinic acid of formula Ha without isolation of any intermediates.
12. The process according to claim 1, wherein the Dihydroartemisinic acid of formula Ha is further converted to Artemisinin and/or its derivatives.
13. The process according to claim 1, wherein the process of step-a is carried out using an epoxidizing agent in a solvent.
14. The process according to claim 1, wherein the process of step-a is carried in presence of a catalyst.
15. The process according to claim 13, wherein the epoxidizing agent used in step-a is selected from the group consisting of substituted perbenzoic acids, hydrogen peroxide, t-butyl hydroxperoxide, Sodium periodate or sodium chlorite.
16. The process according to claim 14, the catalyst is selected from the group consisting of acetic acid, formic acid, tetra-butyl ammonium bromide and 4-chlorophenol.
17. The process according to claim 15, wherein the substituted perbenzoic acids is m-chlorobenzoic acid.
18. The process according to claim 1, wherein the process of step-b is carried out using a halogenating agent in a solvent.

19. Intermediate compounds: a) formula IV, b) an epoxy aldehyde of Formula V and c) an epoxy alcohol of Formula VI.
wherein, R is a leaving group.