Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives

• US 9,802,952 B2
• Filed: 07/14/2014
• Issued: 10/31/2017
• Est. Priority Date: 07/15/2013
• Status: Active Grant

• Current Assignee: Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften e.V. (Max-Planck-Gesellschaft zur Frderung der Wissenschaften e)
• Original Assignee: Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften e.V. (Max-Planck-Gesellschaft zur Frderung der Wissenschaften e)
• Inventors: Kopetzki, Daniel, McQuade, David Tyler, Seeberger, Peter H., Gilmore, Kerry
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/904,671
• Publication Number:
  US 20160145265A1
• Time in Patent Office: 1,205 Days
• CPC Class Codes: B01J 19/245 placed in series
• CPC Class Codes: B01J 2219/24 Stationary reactors without moving elements inside
• CPC Class Codes: C07D 493/18 Bridged systems

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 C₁-C₅ 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 C₁-C₅ 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

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 C₁-C₅ 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

3. The method according to claim 1 further comprising A) and B) before step 1):

A) providing dihydroartemisinic acid represented by the following formula

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

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 —

R¹, then the precursor compound is R¹—

X—

H or R¹-L₁;

if R is —

COR¹ and R¹ is not C₂-C₁₀ carboxylalkyl, then the precursor compound is R¹—

CO₂H, or R¹—

CO—

O—

OC—

R¹;

if R is —

COR¹ and R¹ is C₂-C₁₀ carboxylalkyl, then the precursor compound is C₃-C₁₁ cyclic anhydride of the formula

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, CaCl₂, InCl₃, Ni(bpy)Cl₂, PbF₂, PbCl₂, PbBr₂, PbI₂, RuCl₃, Ru(NO)(NO₃)₃, CoCl₂ and a mixture thereof.

8. The method according to claim 1, wherein the at least one C₁-C₅ alcohol is selected from the group consisting of CH₃OH, CH₃CH₂OH, CH₃CH₂CH₂OH, HOCH₂CH₂OH, HOCH₂CH₂CH₂OH, HC(CH₂OH)₃, HO—

C(CH₂OH)₃, and C(CH₂OH)₄.

9. The method according to claim 1, wherein the solid base is selected from a group consisting of Li₂CO₃, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃, LiOH, NaOH, KOH, Ca(OH)₂, Mg(OH)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.

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

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.

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)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, I₂, Ni salts, Ni foam, hydrogels containing Co and/or Ni nanoparticles, nanotubes containing Au nanoparticles, Pb salts, TiO₂ 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 Al₂O₃ pellets, Ru-activated carbon, CeCl₃, Ru—

CeO₂, Ru—

TiO₂, Ru-γ

Al₂O₃, Ru₆₀Co₂₀Fe₂₀, 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

13. The continuous flow reactor according to claim 11, wherein the activator is selected from a group consisting of LiF, LiCl, LiBr, LiI, CaCl₂, InCl₃, Ni(bpy)Cl₂, PbF₂, PbCl₂, PbBr₂, PbI₂, RuCl₃, Ru(NO)(NO₃)₃, CoCl₂ and a mixture thereof.

14. The continuous flow reactor according to claim 11, wherein the solid base is selected from a group consisting of Li₂CO₃, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃, LiOH, NaOH, KOH, Ca(OH)₂, Mg(OH)₂, and mixtures thereof.

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.