Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives

Abstract

The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C.sub.1-C.sub.5 alcohol.

Claims

1. A method for reducing artemisinin in a continuous manner comprising: 1) providing a column containing a hydride reducing agent, at least one activator and at least one solid base or providing a first column containing at least one solid base and a second column containing a hydride reducing agent and at least one activator, 2) providing a continuous flow of a solution of artemisinin in at least one aprotic solvent containing at least one C.sub.1-C.sub.5 alcohol through the column containing the hydride reducing agent, the at least one activator and the at least one solid base or through the first column containing the at least one solid base and the second column containing the hydride reducing agent and the at least one activator, 3) thereby reducing artemisinin in a continuous manner to dihydroartemisinin of the following formula ##STR00087## wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, Superhydride® (a solution of lithium triethylborohydride), L/K/N-Selectrides (lithium/potassium/sodium tri(sec-butyl) borohdyride), LiAlH(OtBu).sub.3, RedAl, DIBAL-H, Titanocene and a mixture thereof; the at least one activator is selected from the group consisting of alkaline metal halides, alkaline earth metal halides, In salts, I.sub.2, Ni salts, Ni foam, hydrogels containing Co and/or Ni nanoparticles, nanotubes containing Au nanoparticles, Pb salts, TiO.sub.2 containing Pd or Co—Ni—P, polyaniline salts, propanephosphonic acid cyclic anhydride, protein-capped Au nanoparticles, pyridinium based dicationic ionic salts, Ru salts, Ru immobilized on Al.sub.2O.sub.3 pellets, Ru-activated carbon, CeCl.sub.3, Ru—CeO.sub.2, Ru—TiO.sub.2, Ru-γ Al.sub.2O.sub.3, Ru.sub.60Co.sub.20Fe.sub.20, Ru-promoted sulphated zirconia, titanyl acetylacetonate, Au nanoparticles, Co salts, Celite® Amberlyst 15, Amberlyst 15 with dextrose or galactose and phloroglucinol; the at least one solid base is selected from the group consisting of: metal hydroxides, metal carbonates, ammonium hydroxide, and tetraalkylammonium hydroxides; and the at least one C.sub.1-C.sub.5 alcohol is selected from the group consisting of: CH.sub.3OH, CH.sub.3CH.sub.2OH, CH.sub.3CH.sub.2CH.sub.2OH, CH.sub.3CH.sub.2CH.sub.2CH.sub.2OH, CH(CH.sub.3).sub.2CH.sub.2OH, CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, HOCH.sub.2CH(OH)CH.sub.2OH, HOCH.sub.2CH(OH)CH.sub.2CH.sub.2OH, HOCH.sub.2CH(OH)CH(OH)CH.sub.3, HOCH.sub.2CH(OH)CH(OH)CH.sub.2OH, HOCH.sub.2CH(OH)CH.sub.2CH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2CH(OH)CH.sub.2CH.sub.2OH, HOCH.sub.2CH(OH)CH(OH)CH.sub.2CH.sub.2OH, HOCH.sub.2CH(OH)CH.sub.2CH(OH)CH.sub.2OH, HOCH.sub.2CH(OH)CH(OH)CH(OH)CH.sub.2OH, HC(CH.sub.2OH).sub.3, HO—C(CH.sub.2OH).sub.3, and C(CH.sub.2OH).sub.4.

2. The method according to claim 1 comprising: 1) providing a column containing a hydride reducing agent, at least one activator and at least one solid base, 2) providing a continuous flow of a solution of artemisinin in at least one aprotic solvent containing at least one C.sub.1-C.sub.5 alcohol through the column containing the hydride reducing agent, the at least one activator and the at least one solid base, 3) thereby reducing artemisinin in a continuous manner to dihydroartemisinin of the following formula ##STR00088##

3. The method according to claim 1 further comprising A) and B) before step 1): A) providing dihydroartemisinic acid represented by the following formula ##STR00089## B) performing the following reactions i) photooxidation of dihydroartemisinic acid with singlet oxygen, ii) followed by an acid mediated cleavage, and iii) subsequent oxidation with triplet oxygen in order to obtain artemisinin of the following formula: ##STR00090##

4. The method according to claim 1 further comprising 4) after the step 3): 4) converting the dihydroartemisinin obtained from step 3) to an artemisinin derivative of the following formula ##STR00091## wherein X is O or S; R is —R.sup.1, —COR.sup.1, —CONHR.sup.1, —CSNHR.sup.1, or —SO.sub.2R.sup.1; and R.sup.1 represents a C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 halogenalkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.2-C.sub.10 alkoxyalkyl, C.sub.2-C.sub.10 carboxyalkyl, C.sub.6-C.sub.14 aryl, C.sub.7-C.sub.16 alkylaryl, C.sub.7-C.sub.16 alkoxyaryl, C.sub.7-C.sub.16 arylalkyl, C.sub.8-C.sub.16 arylalkoxyalkyl, C.sub.8-C.sub.16 alkylarylalkyl, C.sub.8-C.sub.16 alkylarylalkoxyalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.10 alkylcycloalkyl, C.sub.4-C.sub.10 alkoxyalkylcycloalkyl, C.sub.4-C.sub.12 cycloalkylalkyl, C.sub.4-C.sub.16 cycloalkylalkoxyalkyl, C.sub.1-C.sub.5 heterocyclyl, C.sub.3-C.sub.10 alkoxycarbonylalkyl, C.sub.2-C.sub.10 acyloxyalkyl, C.sub.3-C.sub.12 heterocyclylalkyl, C.sub.3-C.sub.10 alkylcarbonylaminoalkyl, C.sub.3-C.sub.10 alkoxycarbonylaminoalkyl, C.sub.1-C.sub.10 aminoalkyl, C.sub.2-C.sub.10 alkylaminoalkyl, C.sub.3-C.sub.10 dialkylaminoalkyl, C.sub.3-C.sub.10 alkylaminocarbonylalkyl, or C.sub.4-C.sub.10 dialkylaminocarbonylalkyl.

5. The method according to claim 4, wherein converting the dihydroartemisinin 4 to the artemisinin derivative of the formula (5) is performed by reacting the dihydroartemisinin 4 with a precursor compound and if R is —R.sup.1, then the precursor compound is R.sup.1—X—H or R.sup.1-L.sub.1; if R is —COR.sup.1 and R.sup.1 is not C.sub.2-C.sub.10 carboxylalkyl, then the precursor compound is R.sup.1—CO.sub.2H, or R.sup.1—CO—O—OC—R.sup.1; if R is —COR.sup.1 and R.sup.1 is C.sub.2-C.sub.10 carboxylalkyl, then the precursor compound is C.sub.3-C.sub.11 cyclic anhydride of the formula ##STR00092## or C.sub.3-C.sub.11 alkyl carboxylic acid C.sub.1-C.sub.4 alkyl ester; if R is —CONHR.sup.1, then the precursor compound is R.sup.1—N═C═O; if R is —CSNHR.sup.1, then the precursor compound is R.sup.1—N═C═S; if R is —SO.sub.2R.sup.1, then the precursor compound is R.sup.1SO.sub.3H, R.sup.1SO.sub.2Cl, or R.sup.1SO.sub.2—O—SO.sub.2R.sup.1; wherein R.sup.1 has the same meaning as defined in claim 4; L.sub.1 is a leaving group selected from the group consisting of —F, —Cl, —Br, —I, —OSO.sub.2Me, —OSO.sub.3Me, —OSO.sub.2CF.sub.3, —OSO.sub.2CF.sub.2CF.sub.3, and —OSO.sub.2(p-Tol).

6. The method according to claim 1, wherein the molar ratio of artemisinin to hydride reducing agent is in the range of 1.0:1.0 to 1.0:2.0.

7. The method according to claim 1, wherein the activator is selected from a group consisting of LiF, LiCl, LiBr, LiI, CaCl.sub.2, InCl.sub.3, Ni(bpy)Cl.sub.2, PbF.sub.2, PbCl.sub.2, PbBr.sub.2, PbI.sub.2, RuCl.sub.3, Ru(NO)(NO.sub.3).sub.3, CoCl.sub.2 and a mixture thereof.

8. The method according to claim 1, wherein the at least one C.sub.1-C.sub.5 alcohol is selected from the group consisting of CH.sub.3OH, CH.sub.3CH.sub.2OH, CH.sub.3CH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2OH, HOCH.sub.2CH.sub.2CH.sub.2OH, HC(CH.sub.2OH).sub.3, HO—C(CH.sub.2OH).sub.3, and C(CH.sub.2OH).sub.4.

9. The method according to claim 1, wherein the solid base is selected from a group consisting of Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, CaCO.sub.3, MgCO.sub.3, LiOH, NaOH, KOH, Ca(OH).sub.2, Mg(OH).sub.2, and mixtures thereof.

10. The method according to claim 1, wherein the solid base and/or the activator and the hydride reducing agent are mixed with a filler material.

11. A continuous flow reactor configured and adapted to the continuous production and reduction of artemisinin comprising: a photochemical reactor configured and adapted to performing the photooxidation of dihydroartemisinic acid with singlet oxygen in a continuous manner, a reactor configured and adapted to performing an acid mediated cleavage of the photooxidation product and the subsequent oxidation with triplet oxygen in order to obtain artemisinin, a column containing a hydride reducing agent, at least one activator and at least one solid base or a first column containing at least one solid base and a second column containing a hydride reducing agent and at least one activator, said columns are configured and adapted to reduce artemisinin to dihydroartemisinin; wherein the hydride reducing agent is selected from the group consisting of: sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, Superhydride® (a solution of lithium triethylborohydride), L/K/N-Selectrides (lithium/potassium/sodium tri(sec-butyl) borohdyride), LiAlH(OtBu).sub.3, RedAl, DIBAL-H, Titanocene and a mixture thereof; the at least one activator is selected from the group consisting of: alkaline metal halides, alkaline earth metal halides, In salts, I.sub.2, Ni salts, Ni foam, hydrogels containing Co and/or Ni nanoparticles, nanotubes containing Au nanoparticles, Pb salts, TiO.sub.2 containing Pd or Co—Ni—P, polyaniline salts, propanephosphonic acid cyclic anhydride, protein-capped Au nanoparticles, pyridinium based dicationic ionic salts, Ru salts, Ru immobilized on Al.sub.2O.sub.3 pellets, Ru-activated carbon, CeCl.sub.3, Ru—CeO.sub.2, Ru—TiO.sub.2, Ru-γ Al.sub.2O.sub.3, Ru.sub.60Co.sub.20Fe.sub.20, Ru-promoted sulphated zirconia, titanyl acetylacetonate, Au nanoparticles, Co salts, Celite® Amberlyst 15, Amberlyst 15 with dextrose or galactose and phloroglucinol; and the at least one solid base is selected from the group consisting of: metal hydroxides, metal carbonates, ammonium hydroxide, and tetraalkylammonium hydroxides.

12. The continuous flow reactor according to claim 11 further comprising: a reactor configured and adapted to converting dihydroartemisinin to the artemisinin derivative of the following formula ##STR00093## wherein X is O or S; R is —R.sup.1, —COR.sup.1, —CONHR.sup.1, —CSNHR.sup.1, or —SO.sub.2R.sup.1; and R.sup.1 represents a C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 halogenalkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.2-C.sub.10 alkoxyalkyl, C.sub.2-C.sub.10 carboxyalkyl, C.sub.6-C.sub.14 aryl, C.sub.7-C.sub.16 alkylaryl, C.sub.7-C.sub.16 alkoxyaryl, C.sub.7-C.sub.16 arylalkyl, C.sub.8-C.sub.16 arylalkoxyalkyl, C.sub.8-C.sub.16 alkylarylalkyl, C.sub.8-C.sub.16 alkylarylalkoxyalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.4-C.sub.10 alkylcycloalkyl, C.sub.4-C.sub.10 alkoxyalkylcycloalkyl, C.sub.4-C.sub.12 cycloalkylalkyl, C.sub.4-C.sub.16 cycloalkylalkoxyalkyl, C.sub.1-C.sub.5 heterocyclyl, C.sub.3-C.sub.10 alkoxycarbonylalkyl, C.sub.2-C.sub.10 acyloxyalkyl, C.sub.3-C.sub.12 heterocyclylalkyl, C.sub.3-C.sub.10 alkylcarbonylaminoalkyl, C.sub.3-C.sub.10 alkoxycarbonylaminoalkyl, C.sub.1-C.sub.10 aminoalkyl, C.sub.2-C.sub.10 alkylaminoalkyl, C.sub.3-C.sub.10 dialkylaminoalkyl, C.sub.3-C.sub.10 alkylaminocarbonylalkyl, or C.sub.4-C.sub.10 dialkylaminocarbonylalkyl.

13. The continuous flow reactor according to claim 11, wherein the activator is selected from a group consisting of LiF, LiCl, LiBr, LiI, CaCl.sub.2, InCl.sub.3, Ni(bpy)Cl.sub.2, PbF.sub.2, PbCl.sub.2, PbBr.sub.2, PbI.sub.2, RuCl.sub.3, Ru(NO)(NO.sub.3).sub.3, CoCl.sub.2 and a mixture thereof.

14. The continuous flow reactor according to claim 11, wherein the solid base is selected from a group consisting of Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, CaCO.sub.3, MgCO.sub.3, LiOH, NaOH, KOH, Ca(OH).sub.2, Mg(OH).sub.2, and mixtures thereof.

15. The method according to claim 2 further comprising the following steps A) and B) before step 1): A) providing dihydroartemisinic acid represented by the following formula ##STR00094## B) performing the following reactions i) photooxidation of dihydroartemisinic acid with singlet oxygen, ii) followed by an acid mediated cleavage, and iii) subsequent oxidation with triplet oxygen and obtaining artemisinin of the following formula: ##STR00095##

16. The method according to claim 1, wherein the activator is Li salts.

17. The method according to claim 1, wherein the metal hydroxides are alkaline metal hydroxides or alkaline earth metal hydroxides.

18. The continuous flow reactor according to claim 11, wherein the activator is Li salts.

19. The continuous flow reactor according to claim 11, wherein the metal hydroxides are alkaline metal hydroxides or alkaline earth metal hydroxides.

Description

DESCRIPTION OF FIGURES

(1) FIG. 1A: Schematic drawing of the photochemical reactor (7) for performing the photooxidation of dihydroartemisinic acid with singlet oxygen.

(2) FIG. 1B: Schematic drawing of synthesis of artemisinin (3) in continuous manner via the photochemical reactor (7) and the reactor (8) for performing an acid mediated cleavage of the photooxidation product and the subsequent oxidation with triplet oxygen

(3) FIG. 1C: Schematic drawing of the LED box assembly (20) for performing the photooxidation of dihydroartemisinic acid with singlet oxygen

(4) FIG. 1D: Schematic drawing of synthesis of artemisinin (3) in continuous manner via the photochemical reactor (7) and the reactor (8)

(5) FIG. 1E: Schematic drawing of synthesis of artemisinin (3) in continuous manner via the LED reactor (20).

(6) FIG. 2: Schematic drawing of the column (9) (Omni-Fit® 6.6 mm ID) for reduction of crude artemisinin output from photochemical reactor.

(7) FIG. 3: System pressure observed during reduction of crude artemisinin as a function of cosolvent and solid additives in the Celite®/NaBH.sub.4 column (9). All reactions run at 0.2 ml/min in THF with 2.6 ml of the 0.5 M crude solution. 9 equiv. (with respect to Artemisinin) of MeOH/EtOH used with a ratio of additives 1:1:1:0.7 (w/w) of NaBH.sub.4:Celite:Li.sub.2CO.sub.3:LiCl.

(8) FIG. 4: Schematic drawing of the combination of the first column (10A) filled with at least one solid base and the second column (10B) filled with a mixture of hydride reducing agent and at least one activator.

(9) FIG. 5: Schematic drawing of the reactor (12) connected with a 6-channel mixer. The mixer (13) is arranged between the column for reducing artemisinin to dihydroartemisinin and the reactor (12) for converting dihydroartemisinin to the artemisinin derivates. The direction arrows represent the flow direction.

(10) FIG. 6: Schematic drawing of the continuous flow reactor for the synthesis of artemisinin derivatives. A solution of dihydroartemisininic acid and trifluoroacetic acid (TFA) in toluene is combined via a simple T-mixer with oxygen gas. The gas-liquid mixture is irradiated with 420 nm light while maintaining the solution at −20° C., followed by 10 minutes at room temperature under visible light. The crude output of the photoreactor (artemisinin) is then passed through a composite NaBH.sub.4 packed-bed. The resulting mixture is washed with water and the organic phase containing dihydroartemisinin is combined with either (A) HCl/trimethylorthoformate(TMOF)/CH.sub.3OH, (B) HCl/triethylorthoformate(TEOF)/CH.sub.3CH.sub.2OH or (C) succinic anhydride/triethyl amine/methylene chloride and allowed to react for X minutes. The output is the active pharmaceutical ingredients artemether (A), artemotil (B) or artesunate C).

EXAMPLES

(11) Methods:

(12) .sup.1H NMR spectra were recorded on a Varian 400-MR spectrometer (at 400 MHz) at ambient temperature. The proton signal of residual non-deuterated solvent (δ 7.26 ppm for CHCl.sub.3) was used as an internal reference for .sup.1H spectra. Data are reported as follows: chemical shift in parts per million (δ, ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, m=multiplet and br=broad), coupling constant reported in Hertz (Hz) and integration. .sup.13C spectra were recorded on a Varian 400-MR spectrometer (at 101 MHz) at ambient temperature. Chemical shifts are reported in parts per million (δ, ppm). The carbon signal of deuterated solvent (δ 77.16 ppm for CDCl.sub.3) was used as an internal reference for .sup.13C spectra.

(13) Infrared (IR) spectra were recorded as thin films on a Perkin-Elmer 1600 FTIR spectrophotometer. Melting points were recorded using an Electrothermal IA 9300 melting point apparatus and are uncorrected. Optical rotations (OR) were measured with a Schmidt & Haensch Unipol L 1000 at a concentration (c) expressed in g/100 mL. High-resolution mass spectra (HRMS) were recorded with an Agilent 6210 ESI-TOF mass spectrometer at the Freie Universität Berlin, Mass Spectrometry Core Facility. The measured [M+H.sup.+] masses, if available, are indicated in the experimental part.

(14) Analytical thin layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates pre-coated with a 0.25 mm thickness of silica gel. The TLC plates were visualized with UV light and by staining with an aqueous solution of potassium permanganate (KMnO.sub.4) or a mixture of iodine and silica. Column chromatography was performed using Kieselgel 60 (230-400 mesh) silica gel with a typical 50-100:1 weight ratio of silica gel to crude product.

Example 1: Reaction Conditions for the Synthesis of Artemisinin (3) in Continuous Flow (FIG. 1B)

(15) ##STR00041##

(16) A solution of dihydroartemisinic acid (2.95 g, 12.5 mmol) and tetraphenylporphyrin (15 mg, 0.02 mmol) in dichloromethane (total volume of the solution: 25 mL, volumetric flask) and a solution of trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (18.1 mL) were prepared and given into their respective feed. The Hg lamp was turned on 30 min prior to the beginning of the experiment and the second portion of the photochemical reactor was heated at 60° C. The photochemical reactor (7) was flushed with pure dichloromethane (2.5 mL/min), dichloromethane (0.5 mL/min) and oxygen (7.5 mL/min, 11.5 bar) for 10 min. The reagents were then injected via their respective feed at a flow rate of 2.5 mL/min and the oxygen flow was readjusted to 7.5 mL/min (11.5 bar). Both streams joined in the first mixer. From there they entered the photochemical reactor (7). The TFA solution was injected at the exit of the photochemical reactor into a second mixer at a flow rate of 0.5 mL/min and the resulting mixture was pushed into the thermal reactor (8). The crude material containing the produced artemisinin was collected in a flask containing a saturated aqueous solution of NaHCO.sub.3. The resulting biphasic mixture was stirred at room temperature until the green color disappeared. Phases were separated and the aqueous phase was extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification over silica gel (5%-20% EtOAc, in cyclohexane) afforded artemisinin (1.36 g, 39%) as a off-white solid. Further purification by recrystallization in cyclohexane afforded white needles. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.86 (s, 1H), 3.40 (dq, J=7.3, 5.4 Hz, 1H), 2.47-2.39 (m, 1H), 2.08-1.98 (m, 2H), 1.91-1.86 (m, 1H), 1.81-1.74 (m, 2H), 1.51-1.34 (m, 3H), 1.45 (s, 3H), 1.21 (d, J=7.3 Hz, 3H), 1.11-1.04 (m, 2H), 1.00 (d, J=6.0 Hz, 3H). The .sup.1H NMR spectrum of the obtained artemisinin (6) is shown in FIG. 3. Mp=153-154° C. [α].sub.D.sup.20+66.3° (c 0.97, CHCl.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.2, 105.5, 93.9, 79.6, 50.2, 45.1, 37.7, 36.1, 33.8, 33.0, 25.4, 25.0, 23.6, 19.9, 12.7. IR (film) ν 2960, 2933, 2860, 1731, 1112, 991 cm.sup.−1. HRMS calcd for C.sub.15H.sub.22O.sub.5 (M+) 282.1467, found 282.1463. MS (EI) m/z 282 (1) [M.sup.+], 250 (5), 192 (70), 150 (40), 55 (63), 43 (100).

Example 2: Flow Reactor Setup for the Synthesis of Artemisinin According to Example 1

(17) The flow reactor setup (FIG. 1D) for the synthesis of artemisinin (3) consists of a feed F1 for a solution of dihydroartemisinic acid (2), an automated two inlet switch valve 14a for regulating the composition of the feed for the solution of dihydroartemisinic acid (2), allowing for rapid switching from pure solvent to the solution containing the dissolved dihydroartemisinic acid, a first HPLC pump 15a (Vapourtec, R2C+ unit) downstream to switch valve 14a, pumping the dihydroartemisinic acid (2) solution with a throughput of 2.5 mL/min to the first ETFE T-mixer 28 (IDEX Health and Science, P-632) for mixing the dihydroartemisinic acid (2) solution and the oxygen, a first check-valve 16 (IDEX Health and Science, inline check-valve CV-3010) between the first HPLC pump 15a and the mixer 28, a mass flow controller 18b (Influx, SV1B5-AI05, allowing control of the oxygen flow rate from 5-90 cm.sup.3/min) connected to a manometer 18a fixed on an oxygen tank 17 (Air Liquide, O.sub.2 99.995% pure), thus generating a steady oxygen flow of 7.5 mL/min, another check valve 18c (IDEX Health and Science, inline check-valve CV-3010) between the mass flow controller 18b and the first mixer 28, multiple loops of FEP tubing 22 (20 mL, IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in) wrapped tightly around a Pyrex filter 31 (inner diameter 4.5 cm and wall thickness 0.2 cm) which surrounds the quartz immersion well 32 cooled by a thermostat 33 (Huber, Unistat 360), a medium pressure Hg lamp 11 (Ace Glass, UV 450 immersion lamp, 5 in arc, radial lead, 7825-34), a power supply 34 for photochemical lamp 11 (Ace Glass, 7830), a second ETFE T-mixer 13 IDEX Health and Science, P-632), a first PTFE reactor 12a (11 mL, Omnifit, outside diameter (OD) 1/16 in and inside diameter (ID) 0.8 mm), a second PTFE reactor at room temperature 12b (5 mL, Vapourtec), a third heated (60° C.) PTFE reactor 12c (10 mL, Vapourtec, R4 unit) and a collection flask 30 for collecting the synthesized artemisinic acid. A feed F2 for the TFA solution is regulated via an automated two inlet switch valve 14b for regulating the composition of the feed for the TFA solution, allowing for rapid switching from pure solvent to the TFA solution. A second HPLC pump 15b (Vapourtec, R2C+ unit) pumps TFA with a throughput of 0.5 mL/min to into the second mixer 28 disposed at the outlet of the tubing 22 of the photochemical reactor. There the TFA is reacted with the products of the photochemical reactor process. A back-pressure regulator 19b of 2.2 bar (Vapourtec) was installed in order to increase the internal pressure of the system. FEP tubing was selected for its high transmittance and stability in the UV-vis light range, its flexibility and its high chemical resistance. The 2 mm thick Pyrex filter was essential to absorb wavelengths below 300 nm, to prevent degradation of the tubing, and to avoid any undesired side reactions involving short wavelength light. The temperature in the tube during the reaction is estimated to range from 25 to 30° C., based on temperature measurements taken between the cooling jacket and the tube. For safety reasons, the lamp was placed inside an aluminum box for blocking UV irradiation. Two fans were installed for additional cooling.

Example 3: Synthesis of Hydroperoxide (2a-c) in Continuous Flow Using the Box Assembly

(18) The flow reactor setup (FIG. 1C) for the synthesis of hydroperoxide (3) consists of a feed F1 for a solution of dihydroartemisinic acid (2), a pumping unit analogously to example 2 (consisting of an automated two inlet switch valve 14a for regulating the composition of the feed for the solution of dihydroartemisinic acid (2), allowing for rapid switching from pure solvent to the solution containing the dissolved dihydroartemisinic acid, a HPLC pump 15a (Vapourtec, R2C+ unit) downstream to switch valve 14a), pumping the dihydroartemisinic acid (2) solution with a throughput of 1.25 mL/min to a ETFE T-mixer 28 (IDEX Health and Science, P-632) for mixing the dihydroartemisinic acid (2) solution and the oxygen, a mass flow controller 18b (Influx, SV1B5-AI05, allowing control of the oxygen flow rate from 5-90 cm.sup.3/min) connected to a manometer 18a fixed on an oxygen tank 17 (Air Liquide, O.sub.2 99.995% pure), thus generating a steady oxygen flow of 5 mL/min, a check valve 18c (IDEX Health and Science, inline check-valve CV-3010) between the mass flow controller 18b and the mixer 28, a photochemical reactor comprising the mixer and a tubing inlet 29, consisting of multiple loops of FEP tubing 22 (3.8 mL, IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in) wrapped tightly around a transparent body 21 (polycarbonate plate, size 9.0×14.0 cm.sup.2) which is irradiated by an arrangement of 60 High Power LEDs 24 combined in an LED module 23 emitting at 420 nm (OSA Opto Lights, 72 W electrical power, cooled by a fan, emission area 2.5×2.5 cm.sup.2) or at 660 nm (OSA Opto Lights, 46 W electrical power, cooled by a fan, emission area 2.5×2.5 cm.sup.2), electronics for supplying a constant current to the LED module (OSA Opto Lights), a power supply (Manson HCS-3202) and a back-pressure regulator of 6.9 bar (IDEX Health and Science) installed after the tubing outlet 26 in order to increase the internal pressure of the system. Because the LED module does not emit UV-radiation which would lead to undesired side reactions, additional filters are not necessary. The wrapped FEP tubing 22 was irradiated directly by the LED module 23, which was installed in a distance of 3 cm in front of the transparent body 21. For maximum efficiency, the tubing was irradiated in a box covered with reflective material 27 (aluminium foil). No additional cooling system for the photochemical reactor was installed. When using the LED module emitting at 420 nm, the feed F3 was a solution of dihydroartemisinic acid at a concentration of 0.5 mol/L and the photosensitizer tetraphenylporphyrin at a concentration of 1 mmol/L in dichloromethane (2.95 g dihydroartemisinic acid and 15 mg tetraphenylporphyrin, total volume 25 mL, volumetric flask), whereas the photosensitizer was methylene blue instead of tetraphenylporphyrin at a concentration of 1 mmol/L when using the LED module emitting at 660 nm (2.95 g dihydroartemisinic acid and 8 mg methylene blue, total volume 25 mL, volumetric flask). The feed was introduced at a flow rate of 1.25 mL/min and the oxygen flow adjusted to 5 mL/min, resulting in a nearly complete conversion of 99% yielding 72% of the desired hydroperoxide (3) with a selectivity of 73% (LED module emitting at 420 nm). When increasing the flow rate, a higher productivity is achieved, however at the expense of the high conversion, as shown in Table 1:

(19) TABLE-US-00001 TABLE 1 flow rate yield feed F3 flow rate conversion hydro- mL/ mmol/ min mmol/ peroxide min min mmol.sup.−1 min 2a selectivity 5 2.5 0.4 51.4% 1.29 36.7% 71.3% 2.5 1.25 0.8 82.9% 1.04 59.2% 71.4% 1.75 0.875 1.143 90.3% 0.79 66.7% 73.9% 1.25 0.625 1.6 99.3% 0.62 72.7% 73.2%

(20) For obtaining artemisinin, the product stream leaving the photochemical reactor at the tubing outlet 26 can be mixed with a solution of trifluoroacetic acid at a concentration of 1.875 mol/L in dichloromethane (1.9 mL trifluoroacetic acid in 18.1 mL dichloromethane) and reacted in a thermal reactor, analogously as described in example 5, injecting the trifluoroacetic acid solution at a flow rate of 0.25 mL/min. Alternatively trifluoroacetic acid can already be added to the feed solution F3 at a concentration of 0.375 mol/L.

Example 4: Synthesis of Artemisinin (3) in Continuous Flow Using the Cooled Box Assembly (FIG. 1E)

(21) The flow reactor setup for the synthesis of artemisinin consists of a feed for a mixture of dihydroartemisinic acid, trifluoroacetic acid and the photosensitizer dicyanoanthracene, a pumping unit analogously to example 2 (consisting of an automated two inlet switch valve 14a for regulating the composition of the feed for the solution of dihydroartemisinic acid, allowing for rapid switching from pure solvent to the feed solution containing the dissolved dihydroartemisinic acid, an HPLC pump 15a (Vapourtec, R2C+ unit) downstream to switch valve), pumping the dihydroartemisinic acid solution with a throughput of 1.25 mL/min to an ETFE T-mixer 28 (IDEX Health and Science, P-632) for mixing the feed solution and oxygen, a mass flow controller 18b (Influx, SV1B5-AI05, allowing control of the oxygen flow rate from 5-90 cm.sup.3/min) connected to a manometer 18a fixed on an oxygen tank (Air Liquide, O.sub.2 99.995% pure), thus generating a steady oxygen flow of 5 mL/min, a check valve 18c (IDEX Health and Science, inline check-valve CV-3010) between the mass flow controller and the mixer, a photochemical reactor 20 comprising the mixer and a tubing inlet, consisting of multiple loops of FEP tubing (7 mL, IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in) wrapped tightly around a transparent body (glass plate, size 9.0×14.0 cm.sup.2) which is irradiated by an arrangement of 60 High Power LEDs combined in an LED module emitting at 420 nm (OSA Opto Lights, 72 W electrical power, cooled by a fan, emission area 2.5×2.5 cm.sup.2), electronics for supplying a constant current to the LED module (OSA Opto Lights) and a power supply (Manson HCS-3202). The wrapped FEP tubing was irradiated directly by the LED module, which was installed in a distance of 3 cm in front of the transparent body. For maximum efficiency, the tubing was irradiated in a tray made of stainless steel to reflect throughpassing light onto the photochemical reactor, which was immersed in this tray, filled with an ethylene glycol:water bath (3:2 v/v) cooled to −20° C. with the help of an immersion cooler (Huber, TC100E-F-NR). After leaving the photochemical reactor the solution was passed through a reactor with 10 ml volume (inner diameter 0.03 inch, FEP tubing), kept at 10° C. by immersion in a water bath and then 30 mL (inner diameter 0.06 inch, FEP tubing), kept at room temperature. A back-pressure regulator of 8 bar (Vapourtec) was installed after the tubing outlet in order to increase the internal pressure of the system.

(22) The feed was a solution of dihydroartemisinic acid at a concentration of 0.5 mol/L, trifluoroacetic acid at a concentration of 0.25 mol/L and the photosensitizer dicyanoanthracene at a concentration of 2.5 mmol/L in toluene (29.5 g dihydroartemisinic acid, 7.13 g trifluoroacetic acid and 143 mg dicyanoanthracene, total volume 250 mL, volumetric flask). The feed was introduced at a flow rate of 1.25 mL/min and the oxygen flow adjusted to 5 mL/min.

(23) The solution exiting the reactor was collected and washed twice with sat. NaHCO.sub.3 to quench the acid and then washed with water and brine. The organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure, then acetonitrile was added and evaporated to remove most toluene and dried under high vacuum overnight, yielding 30.509 g crude containing 22.945 g artemisinin according to NMR analysis. Thus a yield of 65% was achieved at a conversion of 97%.

(24) The crude was solubilized in 60 mL acetonitrile, activated carbon added and the solution refluxed shortly. After cooling down, the carbon was filtrated off with a PTFE syringe filter (0.45 μm) and the solvent was removed, yielding 29.735 g of a nearly white solid, as most dicyanoanthracene is removed by this procedure.

(25) The solid was recrystallized from 150 mL cyclohexane:ethanol (9:1 v/v), which yielded off-white needles. These were filtrated, washed three times with 100 mL cyclohexane each and dried under high vacuum (16.515 g, pure artemisinin according to NMR analysis, 47% isolated yield, recovery of recrystallization 72%).

(26) The dried mother liquor (13.288 g) was recrystallized from 50 mL cyclohexane. This yielded slightly yellow crystals, which were washed with cyclohexane and dried under high vacuum (3.597 g, consisting of artemisinin with 96% purity (3.446 g), isolated yield 10%, total combined isolated yield including first recrystallization 57% (87% recovery)).

(27) Both artemisinin batches were combined and recrystallized from 150 mL cyclohexane:ethanol (9:1 v/v), yielding purely white needles, which were filtrated off and washed twice with cyclohexane (16.079 g of pure artemisinin, 46% isolated yield based on initial dihydroartemisinic acid).

Example 5: Optimization of Composition of Filling Materials

(28) (According to FIG. 3)

(29) When the crude solution of Artemisinin was pumped through a 1:1 mixture (w/w) of NaBH.sub.4 and Celite, the process was unstable and clogged, but prior to clogging the effluent from the column contained almost pure DHA. Column clogging is quantified by measuring the back pressure as a function of time. As shown in FIG. 3, the column back-pressure is strongly dependent on column composition and solvent additives. As depicted, the column back-pressure rises quickly when crude artemisinin is pumped through the simple sodium borohydride/celite column (FIG. 3, blue line). We thus examined the additives which may facilitate the reduction. LiCl has been shown to accelerate NaBH.sub.4 reductions via in situ formation of LiBH.sub.4, however, clogging remained a problem (FIG. 3, cyan line). We hypothesized that the instability observed was the result of the TFA from the previous reaction, though no improvement was observed upon the addition of Li.sub.2CO.sub.3. Rewardingly, upon combining these two additives, mixing NaBH.sub.4, Celite, Li.sub.2CO.sub.3, and LiCl in a 1:1:1:0.7 ratio (w/w), the clogging issue was eliminated (FIG. 3 red and black lines), providing complete and clean reduction of crude artemisinin. In addition to the column composition, an alcohol cosolvent was also found to be essential, ethanol providing the best results (FIG. 3, red line).

Example 6: Optimization of Reduction of Carbonyl Group by Sodium Borohydride and Activator. (FIG. 2)

(30) A column packed with a 1:1 (w/w) mixture of celite and NaBH.sub.4 gave inconsistent reductions of benzaldehyde in flow using THF as solvent. Leaching and precipitation of unidentified salts caused fluctuations in both pressure and conversion. While leaching was eliminated using SiO.sub.2 plugs to terminate the column, benzaldehyde reductions still resulted in incomplete conversion.

(31) Conversion was then measured as a function of cosolvent (MeOH) with 0.7 equiv. of LiCl (with respect to NaBH.sub.4) added to the column mixture. The reduction to benzyl alcohol is dependent on methanol concentration, and a maximum conversion is achieved using 9-9.5 equivalents MeOH with respect to benzaldehyde.

(32) TABLE-US-00002 TABLE 2 In-Flow Reduction of Aldehydes and Ketones to the Respective alcohols..sup.a Entry R.sub.1 R.sub.2 Yield 1 C.sub.6H.sub.5 H 99% 2 4-CNC.sub.6H.sub.4 H 99% 3 (E)-C.sub.6H.sub.5CHCH H 94% 4 CH.sub.3(CH.sub.2).sub.4 H 74% 5 Ph Ph 83% 6 CH(Ph).sub.2 CH.sub.3 74% 7 —CH.sub.2(CH.sub.2).sub.3CH.sub.2— 89% .sup.aColumn prepared using (1:1:0.76 w/w) Celite:NaBH.sub.4:LiCl. Concentration aldehyde/ketone was 0.66M (THF) with 9.5 equiv. MeOH added, run at 0.5 mL/min.

Example 7-1. Reduction of Artemisinin (3) to Dihydroartemisinin (4) by Using the Inventive Continuous Flow Reactor with Two Columns

(33) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was first passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3 and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top.) at a flow rate of 0.2 mL/min using THF as eluent. The resultant solution was then passed through a second, 2.5 mL column (prepared by grinding 650 mg Celite, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top.) using THF as eluent and collected over water. Extraction with methylene chloride yielded the desired dihydroartemisinin.

Example 7-2. Reduction of Artemisinin (3) to Dihydroartemisinin (4) by Using the Inventive Continuous Flow Reactor with One Column

(34) ##STR00043##

(35) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top.) at a flow rate of 0.2 mL/min using THF as eluent and collected over water. Extraction with methylene chloride yielded the desired dihydroartemisinin.

(36) .sup.1H NMR (CDCl.sub.3): 5.60 (s, 1H), 5.28 (t, J=4 Hz, 1H), 2.62 (m, 1H), 2.48 (dd, J=<4, 4 Hz, 1H), 2.38 (td, J=4, 8 Hz, 1H), 2.05 (m, 1H), 1.85 (m, 3H), 1.65 (m, 1H), 1.53 (m, 3H), 1.36 (m, 2H), 1.25 (m, 2H), 0.97 (s, 3H), 0.95 (s, 3H).

Example 7-3. Synthesis of Artemether (5-1) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(37) ##STR00044##

(38) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(39) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution A (2 mL methanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemether 5-1 as white solid.

(40) .sup.1H NMR (CDCl.sub.3): 5.38 (s, 1H), 4.68 (d, J=4 Hz, 1H), 3.42 (s, 3H), 2.63 (m, 1H), 2.37 (ddd, J=16, 12, 4 Hz, 1H), 2.02 (ddd, J=16, 4, 4 Hz, 1H), 1.88 (m, 1H), 1.76 (m, 2H), 1.64 (m, 1H), 1.49 (m, 2H), 1.44 (s, 3H), 1.34 (m, 1H), 1.24 (m, 1H), 0.96 (d, J=8 Hz, 3H), 0.92 (m, 1H), 0.9 (d, J=8 Hz, 3H).

Example 7-4. Synthesis of Arteether (5-2) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(41) ##STR00045##

(42) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(43) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL ethanol, 1 mL triethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure arteether 5-2 as white solid.

(44) .sup.1H NMR (CDCl.sub.3): 5.40 (s, 1H), 4.79 (d, J=<4 Hz, 1H), 3.86 (dq, J=12, 8, 8 Hz, 1H), 3.47 (dq, J=8, 8, 4 Hz, 1H), 2.59 (m, 1H), 2.34 (ddd, J=12, 12, 4 Hz, 1H), 2.01 (ddd, J=16, 4, 4 Hz, 1H), 1.80 (m, 3H), 1.61 (ddd, J=12, 8, 4 Hz, 1H), 1.45 (m, 2H), 1.41 (s, 3H), 1.31 (m, 1H), 1.22 (dd, J=12, 8 Hz, 1H), 1.16 (t, J=8 Hz, 3H), 0.93 (d, J=8 Hz, 3H), 0.90 (m, 1H), 0.88 (d, J=8 Hz, 3H).

Example 7-5. Synthesis of Artesunate (5-3) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(45) ##STR00046##

(46) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(47) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution C (1.3 g succinic anhydride, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artesunate 5-3 as white solid.

(48) .sup.1H NMR (CDCl.sub.3): 5.80 (d, J=8 Hz, 1H), 5.44 (s, 1H), 2.71 (m, 4H), 2.56 (m, 1H), 2.37 (td, J=16, 4 Hz, 1H), 2.04 (dt, J=16, 4 Hz, 1H), 1.87 (m, 1H), 1.75 (m, 2H), 1.62 (dt, J=12, 4 Hz, 1H), 1.43 (s, 3H), 1.49-1.27 (m, 4H), 1.02 (m, 1H), 0.96 (d, J=8 Hz, 3H), 0.85 (d, J=8 Hz, 3H).

Example 7-6. Synthesis of Artelinic Acid (5-4) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column

(49) ##STR00047##

(50) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(51) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution D (396 mg 4-(hydroxymethyl)benzoic acid was dissolved in 2 mL THF with 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artelinic acid 5-4 as white solid.

(52) mass spec: C.sub.23H.sub.30O.sub.7; 419.1982 [M+H.sup.+].

Example 7-7. Synthesis of Artemether (5-1) from Dihydroartemisinic Acid (2)

(53) ##STR00048##

(54) The initial stages of the transformation were performed according to Example 4, however, the stream exiting BPR 19B (FIG. 1D+E), as opposed to entering collection flask 30, was fed into a mixer, where it was mixed with a EtOH (6 equiv. with respect to DHAA)/THF solution. The resulting solution was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(55) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution A (2 mL methanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemether 5-1 as white solid.

(56) .sup.1H NMR (CDCl.sub.3): 5.38 (s, 1H), 4.68 (d, J=4 Hz, 1H), 3.42 (s, 3H), 2.63 (m, 1H), 2.37 (ddd, J=16, 12, 4 Hz, 1H), 2.02 (ddd, J=16, 4, 4 Hz, 1H), 1.88 (m, 1H), 1.76 (m, 2H), 1.64 (m, 1H), 1.49 (m, 2H), 1.44 (s, 3H), 1.34 (m, 1H), 1.24 (m, 1H), 0.96 (d, J=8 Hz, 3H), 0.92 (m, 1H), 0.9 (d, J=8 Hz, 3H). mass spec: C.sub.16H.sub.26O.sub.5; 299.1769 [M+H.sup.+].

Example 7-8. Synthesis of Arteether (5-2) from Dihydroartemisinic Acid (2)

(57) ##STR00049##

(58) The initial stages of the transformation were performed according to Example 4, however, the stream exiting BPR 19B (FIG. 1D+E), as opposed to entering collection flask 30, was fed into a mixer, where it was mixed with a EtOH (6 equiv. with respect to DHAA)/THF solution. The resulting solution was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(59) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL ethanol, 1 mL triethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure arteether 5-2 as white solid.

(60) .sup.1H NMR (CDCl.sub.3): 5.40 (s, 1H), 4.79 (d, J=<4 Hz, 1H), 3.86 (dq, J=12, 8, 8 Hz, 1H), 3.47 (dq, J=8, 8, 4 Hz, 1H), 2.59 (m, 1H), 2.34 (ddd, J=12, 12, 4 Hz, 1H), 2.01 (ddd, J=16, 4, 4 Hz, 1H), 1.80 (m, 3H), 1.61 (ddd, J=12, 8, 4 Hz, 1H), 1.45 (m, 2H), 1.41 (s, 3H), 1.31 (m, 1H), 1.22 (dd, J=12, 8 Hz, 1H), 1.16 (t, J=8 Hz, 3H), 0.93 (d, J=8 Hz, 3H), 0.90 (m, 1H), 0.88 (d, J=8 Hz, 3H). mass spec: C.sub.17H.sub.28O.sub.5; 313.1925 [M+H.sup.+].

Example 7-9. Synthesis of Artesunate (5-3) from Dihydroartemisinic Acid (2)

(61) ##STR00050##

(62) The initial stages of the transformation were performed according to Example 4, however, the stream exiting BPR 19B (FIG. 1D+E), as opposed to entering collection flask 30, was fed into a mixer, where it was mixed with a EtOH (6 equiv. with respect to DHAA)/THF solution. The resulting solution was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(63) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution C (1.3 g succinic anhydride, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artesunate 5-3 as white solid.

(64) .sup.1H NMR (CDCl.sub.3): 5.80 (d, J=8 Hz, 1H), 5.44 (s, 1H), 2.71 (m, 4H), 2.56 (m, 1H), 2.37 (td, J=16, 4 Hz, 1H), 2.04 (dt, J=16, 4 Hz, 1H), 1.87 (m, 1H), 1.75 (m, 2H), 1.62 (dt, J=12, 4 Hz, 1H), 1.43 (s, 3H), 1.49-1.27 (m, 4H), 1.02 (m, 1H), 0.96 (d, J=8 Hz, 3H), 0.85 (d, J=8 Hz, 3H). mass spec: C.sub.19H.sub.28O.sub.8; 385.1777 [M+H.sup.+].

Example 7-10. Synthesis of Artelinic Acid (5d) from Dihydroartemisinic Acid (2)

(65) ##STR00051##

(66) The initial stages of the transformation were performed according to Example 4, however, the stream exiting BPR 19B (FIG. 1D+E), as opposed to entering collection flask 30, was fed into a mixer, where it was mixed with a EtOH (6 equiv. with respect to DHAA)/THF solution. The resulting solution was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(67) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (396 mg 4-(hydroxymethyl)benzoic acid was dissolved in 2 mL THF with 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artelinic acid 5-4 as white solid.

(68) mass spec: C.sub.23H.sub.30O.sub.7; 419.1971 [M+H.sup.+].

Example 7-11. Synthesis of Artemisinin Ester Derivate (5-5) from Artemisinin (3)

(69) ##STR00052##

(70) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(71) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.27 mL butyryl chloride, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-5 as white solid. mass spec: C.sub.19H.sub.30O.sub.6; 355.2038 [M+H.sup.+].

Example 7-12. Synthesis of Artemisinin Ester Derivate (5-6) from Artemisinin (3)

(72) ##STR00053##

(73) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(74) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (368 mg isonicotinoyl chloride, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-6 as white solid.

(75) mass spec: C.sub.21H.sub.27NO.sub.6; 390.1818 [M+H.sup.+].

Example 7-13. Synthesis of Artemisinin Sulfonate Derivative (5-7) from Artemisinin (3)

(76) ##STR00054##

(77) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(78) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (496 mg p-tolylsulfonyl chloride, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-7 as white solid.

(79) mass spec: C.sub.22H.sub.30O.sub.7S; 439.1685 [M+H.sup.+].

Example 7-14. Synthesis of Artemisinin Carbamate Derivative (5-8) from Artemisinin (3)

(80) ##STR00055##

(81) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(82) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.321 mL benzyl isocyanate, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-8 as white solid.

(83) mass spec: C.sub.22H.sub.29NO.sub.6; 404.1978 [M+H.sup.+].

Example 7-15. Synthesis of Artemisinin Thiocarbamate Derivative (5-9) from Artemisinin (3)

(84) ##STR00056##

(85) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(86) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.344 mL benzyl isothiocyanate, 1.8 mL triethylamine in 7 mL dichloromethane) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NH.sub.4Cl. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-9 as white solid.

(87) mass spec: C.sub.22H.sub.29NO.sub.5S; 420.1733 [M+H.sup.+].

Example 7-16. Synthesis of Artemisinin Ether Derivative (5-10) from Artemisinin (3)

(88) ##STR00057##

(89) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(90) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.363 mL 2-cyclohexylethanol, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-10 as white solid. mass spec: C.sub.23H.sub.38O.sub.5; 395.2704 [M+H.sup.+].

Example 7-17. Synthesis of Artemisinin Ether Derivative (5-11) from Artemisinin (3)

(91) ##STR00058##

(92) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(93) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.145 mL, ethylene glycol, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-11 as white solid.

(94) mass spec: C.sub.17H.sub.28O.sub.6; 329.1896 [M+H.sup.+].

Example 7-18. Synthesis of Artemisinin Ether Derivative (5-12) from Artemisinin (3)

(95) ##STR00059##

(96) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(97) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (198 mg glycolic acid, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-12 as white solid.

(98) mass spec: C.sub.17H.sub.26O.sub.7; 343.1663 [M+H.sup.+].

Example 7-19. Synthesis of Artemisinin Ether Derivative (5-13) from Artemisinin (3)

(99) ##STR00060##

(100) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(101) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (0.177 mL allyl alcohol, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-13 as white solid.

(102) mass spec: C.sub.18H.sub.28O.sub.5; 325.1922 [M+H.sup.+].

Example 7-20. Synthesis of Artemisinin Ether Derivative (5-14) from Artemisinin (3)

(103) ##STR00061##

(104) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(105) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution (0.151 mL propargyl alcohol, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-14 as white solid.

(106) mass spec: C.sub.18H.sub.26O.sub.5; 323.1767 [M+H.sup.+].

Example 7-21. Synthesis of Artemisinin Thioether Derivative (5-15) from Artemisinin (3)

(107) ##STR00062##

(108) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(109) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (0.192 mL ethanethiol, 0.45 mL conc. HCl in 2 mL THF) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure Artemisinin derivative 5-15 as white solid.

(110) mass spec: C.sub.17H.sub.28O.sub.4S; 329.1701 [M+H.sup.+].

Example 7-22. Synthesis of Artemisinin Derivative (5-16) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(111) ##STR00063##

(112) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(113) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 1-octanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-16 as white solid.

(114) mass spec: C.sub.23H.sub.40O.sub.5; 397.2861 [M+H.sup.+].

Example 7-23. Synthesis of Artemisinin Derivative (5-17) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(115) ##STR00064##

(116) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(117) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 2,2,2-trifluoroethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-17 as white solid. mass spec: C.sub.17H.sub.25F.sub.3O.sub.5; 367.1637 [M+H.sup.+].

Example 7-24. Synthesis of Artemisinin Derivative (5-18) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(118) ##STR00065##

(119) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(120) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 1,3-propanediol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-18 as white solid.

(121) mass spec: C.sub.18H.sub.30O.sub.6; 343.2017 [M+H.sup.+].

Example 7-25. Synthesis of Artemisinin Derivative (5-19) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(122) ##STR00066##

(123) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(124) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 3-methoxy-1-propanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-19 as white solid.

(125) mass spec: C.sub.19H.sub.32O.sub.6; 357.2185 [M+H.sup.+].

Example 7-26. Synthesis of Artemisinin Derivative (5-20) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(126) ##STR00067##

(127) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(128) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (500 mg glycolic acid, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-20 as white solid.

(129) mass spec: C.sub.17H.sub.26O.sub.7; 343.1661 [M+H.sup.+].

Example 7-27. Synthesis of Artemisinin Derivative (5-21) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(130) ##STR00068##

(131) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water. The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (1 mL ethyl glycolate, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-21 as white solid. mass spec: C.sub.19H.sub.30O.sub.7; 371.19915 [M+H.sup.+].

Example 7-28. Synthesis of Artemisinin Derivative (5-22) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(132) ##STR00069##

(133) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(134) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (500 mg N-(2-hydroxyethyl)propanamide, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-22 as white solid. mass spec: C.sub.20H.sub.33NO.sub.6; 384.2287 [M+H.sup.+].

Example 7-29. Synthesis of Artemisinin Derivative (5-23) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(135) ##STR00070##

(136) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(137) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (100 mg 2-hydroxy-N-methylacetamide, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-23 as white solid.

(138) mass spec: C.sub.18H.sub.29NO.sub.6; 356.1977 [M+H.sup.+].

Example 7-30. Synthesis of Artemisinin Derivative (5-24) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(139) ##STR00071##

(140) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(141) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (100 mg ethyl N-(2-hydroxyethyl)-carbamate, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-24 as white solid.

(142) mass spec: C.sub.20H.sub.33NO.sub.7; 400.2264 [M+H.sup.+].

Example 7-31. Synthesis of Artemisinin Derivative (5-25) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(143) ##STR00072##

(144) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(145) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 ml 3-dimethylamino-1-propanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-25 as white solid.

(146) mass spec: C.sub.20H.sub.35NO.sub.5; 370.2496 [M+H.sup.+].

Example 7-32. Synthesis of Artemisinin Derivative (5-26) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(147) ##STR00073##

(148) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(149) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 2-(tert-butylamino)ethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-26 as white solid. mass spec: C.sub.21H.sub.37NO.sub.5; 384.2656 [M+H.sup.+].

Example 7-33. Synthesis of Artemisinin Derivative (5-27) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(150) ##STR00074##

(151) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(152) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (100 mg 3-hydroxy-N,N-dimethylpropanamide, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-27 as white solid. mass spec: C.sub.20H.sub.33NO.sub.6; 384.2288 [M+H.sup.+].

Example 7-34. Synthesis of Artemisinin Derivative (5-28) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(153) ##STR00075##

(154) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(155) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL phenol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-28 as white solid.

(156) mass spec: C.sub.21H.sub.28O.sub.5; 361.1926 [M+H+].

Example 7-35. Synthesis of Artemisinin Derivative (5-29) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(157) ##STR00076##

(158) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(159) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 4-penten-1-ol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-29 as white solid.

(160) mass spec: C.sub.20H.sub.32O.sub.5; 353.2243 [M+H.sup.+].

Example 7-36. Synthesis of Artemisinin Derivative (5-30) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(161) ##STR00077##

(162) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(163) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL cyclohexanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-30 as white solid.

(164) mass spec: C.sub.21H.sub.34O.sub.5; 367.2392 [M+H.sup.+].

Example 7-37. Synthesis of Artemisinin Derivative (5-31) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(165) ##STR00078##

(166) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(167) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 2-methylcyclopentanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-31 as white solid.

(168) mass spec: C.sub.21H.sub.34O.sub.5; 367.2387 [M+H.sup.+].

Example 7-38. Synthesis of Artemisinin Derivative (5-32) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(169) ##STR00079##

(170) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(171) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (1 mL 2-methoxycyclohexanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-32 as white solid.

(172) mass spec: C.sub.22H.sub.36O.sub.6; 397.2495 [M+H.sup.+].

Example 7-39. Synthesis of Artemisinin Derivative (5-33) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(173) ##STR00080##

(174) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(175) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL cyclohexanemethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-33 as white solid. mass spec: C.sub.22H.sub.36O.sub.5; 381.2544 [M+H.sup.+].

Example 7-40. Synthesis of Artemisinin Derivative (5-34) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(176) ##STR00081##

(177) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(178) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 2-(cyclohexyloxy)ethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-34 as white solid.

(179) mass spec: C.sub.23H.sub.38O.sub.6; 411.2645 [M+H.sup.+].

Example 7-27. Synthesis of Artemisinin Derivative (5-35) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(180) ##STR00082##

(181) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(182) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL tert-butylphenol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-35 as white solid.

(183) mass spec: C.sub.25H.sub.36O.sub.5; 417.2540 [M+H.sup.+].

Example 7-41. Synthesis of Artemisinin Derivative (5-36) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(184) ##STR00083##

(185) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(186) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 4-ethoxyphenol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-36 as white solid.

(187) mass spec: C.sub.23H.sub.32O.sub.6; 405.2182 [M+H.sup.+].

Example 7-42. Synthesis of Artemisinin Derivative (5-37) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(188) ##STR00084##

(189) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(190) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (100 mg 4-fluorobenzyl alcohol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-37 as white solid. mass spec: C.sub.22H.sub.29FO.sub.5; 393.1985 [M+H.sup.+].

Example 7-43. Synthesis of Artemisinin Derivative (5-38) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(191) ##STR00085##

(192) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(193) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2 mL 2-phenoxyethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-38 as white solid.

(194) mass spec: C.sub.23H.sub.32O.sub.6; 405.2177 [M+H.sup.+].

Example 7-44. Synthesis of Artemisinin Derivative (5-39) from Artemisinin (3) by Using the Inventive Continuous Flow Reactor with One Column (FIG. 6)

(195) ##STR00086##

(196) To the crude solution of Artemisinin (2.7 mL), prepared as described in Example 4, was added 0.37 mL of ethanol. This was passed through a 2.2 mL column (prepared by mixing 650 mg Celite and 650 mg Li.sub.2CO.sub.3, 650 mg NaBH.sub.4, and 520 mg LiCl together and packing into a 6.6 mm×150 mm Omnifit column with a 1 cm cotton plug at the outlet end. The material was packed by tapping on the bench top) at a flow rate of 0.2 mL/min using THF as eluent and collected over water.

(197) The organic phase pumped at a flow rate of 0.5 mL/min. Reagent solution B (2-furylmethanol, 1 mL trimethylorthoformate, 0.45 mL conc. HCl) was mixed in at a flow rate of 0.5 mL/min and the mixture introduced into reactor 12, consisting of 20 mL tubing (IDEX Health & Science, fluorinated ethylene polymer 1520, natural color, outside diameter (OD) 1/16 in and inside diameter (ID) 0.030 in). After exiting the reactor the solution was collected over saturated aqueous NaHCO.sub.3. The organic phase was dried down yielding an off-white solid. Purification was achieved by column chromatography over silica gel (5%-20% EtOAc, in cyclohexane) providing pure artemisinin derivative 5-39 as white solid.

(198) mass spec: C.sub.20H.sub.28O.sub.6; 365.1879 [M+H.sup.+].