Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the present invention relates to a semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds. More particularly, this invention relates to a novel semisynthetic route to synthesize paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III, a taxane compound which is isolated from Taxus Canadensis, an evergreen bush found in Eastern Canada and Northeastern United States. (b) Description of Prior Art
• taxane family of diterpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents.
• Many taxane derivatives including paclitaxel, docetaxel, taxol C and cephalomannine are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor systems.
• Paclitaxel, and a number of its derivatives have been shown to be effective against advanced breast and ovarian cancers in clinical trials. They have also exhibited promising activity against a number of other tumor types in preliminary investigations.
• Paclitaxel, docetaxel have recently been approved in the U.S. and Canada for the treatment of ovarian and breast cancers.
• paclitaxel The only available natural source of paclitaxel to date are several species of a slow growing yew trees (genus Taxus), wherein paclitaxel is found in very low concentrations (less than 400 parts per million) in the bark or needles of these trees.
• paclitaxel can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taxus Canadensis), but the yield is very low (0.01%-0.02%), and the isolation and purification process is too complicate. Furthermore the extraction is difficult, and the process is expensive.
• 10-deacetylbaccatin III 10- DAB III
• 10-DAB III has the basic diterpenoid structure of paclitaxel without the acetyl group at C-10 and side chain at the C- 13 position. Since 10-DAB III is an important staring material in paclitaxel semi-synthesis, the significance of 10-DAB III will likely increase as more clinical studies are performed using paclitaxel.
• the conversion of 10- deacetylbaccatin III into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-IO position, attachment of a C- 13 ⁇ - amido ester side chain at the C- 13 position through esterification of the C- 13 alcohol with the side chain moiety, and deprotecting C-7. Since the supply of 10- deacetylbaccatin III is limited, other sources should be pursued.
• Holton et al provided a process for the preparation of a derivative or analog of baccatin III, or 10-deacetylbaccatin III, having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10- deacetylbaccatin III was selectively reduced to the corresponding hydroxyl group.
• taxane derivatives as paclitaxel, docetaxel, cephalomannine and other taxanes structurally related to baccatin III.
• US Patent No. 5,616,740 issued on Apr 1, 1997 in the name of Abbott Laboratories, US Patent No 5,594,157, issued on Jan 14, 1997 in the name of Abbott Laboratories and US Patent No. 5,530,020 issued on Jun 25, 1996 in the name of Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which was isolated from Taxus canadensis, as well as analogs of taxol which were prepared therefrom.
• Abbott Laboratories provided deoxygenated taxol products prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which is isolated from Taxus canadensis.
• Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 3 is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 4 is a hydrogen atom, a Ci-C 20 alkyl linear or branched, Ci-C 2 O acyl group, Ci-C 20 halogenated acyl group, C 3 -Ci 2 cycloalkyl, Ci-Ci 2 heterocyclyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 6 -C] 2 aryl, C 6 -C 20 aralkyl, Ci-C 20 alkyloxy C 6 -C 20 alkylaryl, C1-C 12 heteroaryl, C 2 -C 20 alkylheterocyclyl, or C 2 -C 20 alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with
• R 6 is a Ci-C 6 alkyl, C]-Ci 2 alkyl linear or branched, C 6 -Ci 2 aryl, C 2 -C 20 alkenyl, Ci-C 20 alkoxy, C-C 20 alkyl, C 2 -C 20 alkynyl, C 6 -C 20 aralkyl, C 6 -C, 2 aryl, C 3 -C 8 cycloalkyl, Ci-C 20 aminoalkyl, C 6 -Ci 2 aminoaryl, Ci-Cu aminoheteroaryl ,Ci-C 20 hydroxyalkyl, C 6 -Ci 2 hydroxyaryl, Ci-Cj 2 hydroxyheteroaryl, Ci-C] 2 heterocyclyl, Ci-Ci 2 heteroaryl, C 2 -C 20 alkylheterocyclyl, or C 2 -C 20 alkylheteroaryl.
• suitable protecting group for a hydroxyl group is chosen from Ci-C 25 ethers, Ci-C 25 substituted methyl ethers, C]-C 25 substituted ethyl ethers, Ci-C 25 acyl groups, Ci-C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, CpC 25 silyl ethers, Ci-C 25 esters, Ci-C 25 carbonates, and Ci-C 25 sulfonates.
• suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1- ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, /-butyl, allyl, propargyl, benzyl, /7-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, /-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, triphenyl
• Ri is triethylsilyl.
• Ri is triethylsilyl.
• R 2 is acetyl.
• R 3 is ethoxyethyl.
• R 4 is a Ci-C 6 alkyl, phenyl, r-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropy r any 1.
• R 4 is a pentyl, phenyl, r-butyloxyl, but-2-enyl, tetrahydrofuranyl, or tetrahydropyranyl.
• Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 3 is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 4 is a hydrogen atom, a C]-C 20 alkyl linear or branched, C 1 -C20 acyl group, Ci-C 20 halogenated acyl group, C 3 -Ci 2 cycloalkyl, Ci-Ci 2 heterocyclyl, C 2 -C 2 O alkenyl, C 2 -C 20 alkynyl, C 6 -C] 2 aryl, C 6 -C 20 aralkyl, C]-C 20 alkyloxy C 6 -C 20 alkylaryl, Ci-Ci 2 heteroaryl, C 2 -C 20 alkylheterocyclyl, C 2 -C 20 alkylheteroaryl, or a suitable protecting group for an amino group; and
• R 5 is a hydrogen atom or a suitable protecting group for a hydroxyl group, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, Cl, Br, I, OH, SH, NH 2 , NO 2 , CN, CF 3 , -SH, -OCH 2 Ph, -OPh, -SCH 3 , - SPh, -SCH 2 Ph, -COOH, -COOR 6 in which R 6 is a C 1 -C 6 alkyl, C 1 -C 2 alkyl linear or branched, C 6 -Ci 2 aryl C 2 -C 20 alkenyl, C 1 -C 20 alkoxy, Ci-
• the suitable protecting group for a hydroxyl group is chosen from C]-C 25 ethers, Ci-C 25 substituted methyl ethers, C 1 -C25 substituted ethyl ethers, Q-C 25 acyl groups, C 1 -C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, C 1 -C 25 silyl ethers, C 1 -C 25 esters, Ci-C 25 carbonates, and C 1 -C 25 sulfonates.
• the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxy ethyl, 1 -(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, /?-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, 7-butyldiphenylsilyl, tribenzylsily
• R- 2 is acetyl. In accordance with the present invention, in a preferred compound R- 2 is acetyl. In accordance with the present invention, in a preferred compound
• R 3 is ethoxy ethyl.
• R 4 is a C]-C 6 alkyl, phenyl, f-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropyrany 1.
• R 4 is a C]-C 6 alkyl, phenyl, f-butyloxyl, a C 2 -C 6 alkenyl, tetrahydrofuranyl, or tetrahy dropyrany 1.
• R 5 is triethylsilyl.
• Ri is a hydrogen atom or a suitable protecting group for a hydroxyl group
• R 2 is a hydrogen atom or a suitable protecting group for a hydroxyl group.
• the suitable protecting group for a hydroxyl group is chosen from C]-C 25 ethers, Ci-C 25 substituted methyl ethers, Ci-C 25 substituted ethyl ethers, Ci-C 25 acyl groups, Ci-C 25 halogenated acyl groups, Ci-C 25 substituted benzyl ethers, Cj-C 25 SiIyI ethers, C i-C 25 esters, Ci-C 25 carbonates, and Cj-C 25 sulfonates.
• the suitable protecting group for a hydroxyl group is chosen from methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, l-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, r-butyl, allyl, propargyl, benzyl, />-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, trip
• Ri is triethylsilyl.
• R 2 is acetyl.
• the oxidizing agent is chosen from tetra-n-propylammonium perruthenate, Collin's reagent, Swern reagent [(COCl) 2 , DMSO, Et 3 N], acidic pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), CrO 2 , and John's reagent.
• a process for converting 9-dihydro-13-acetylbaccatin III into a taxane derivative comprising the step of removing 10-acetyl group and oxidizing the C-9 and C-IO positions of the 9-dihydro-13-acetylbaccatin III.
• the oxidizing step is achieved by the addition of an oxidizing agent chosen from tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John's reagent.
• an oxidizing agent chosen from tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John's reagent.
• a process for preparing paclitaxel, docetaxel and a derivative thereof comprising the steps of:
• the protecting group is chosen from benzyl, Ci-C 25 substituted benzyl, benzylformate, Ci-C 25 substituted benzylformate, tosyl, substituted tosyl, dihydropyrannyl, methoxymethyl, benzoyl, Ci-C 25 substituted benzoyl, Ci-C 25 trialkylsilyl, 2-
• the oxidizing step is achieved by the addition of an oxidizing reagent chosen from of tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John' reagent.
• an oxidizing reagent chosen from of tetra-n- propylammonium perruthenate, Collin's reagent, Swern reagent, PCC, PDC, CrO 2 and John' reagent.
• it further comprises the step of deprotecting the C- 7 position to obtain 10-deacetylbaccatin III.
• it further comprises the steps of adding a suitable side chain to the C- 13 position, reducing C-IO and selectively deprotecting to obtain a desired product.
• the deprotection is done at the C-7 and 2' positions to obtain paclitaxel and docetaxel.
• the side chain is chosen from (2R, 3S)-N-benzoyl-O-(l-ethoxyethyl)-3-phenylisoserine; (3R,
• the taxane derivative is paclitaxel or docetaxel.
• Fig. 1 illustrates taxane derivatives.
• Fig. 2 illustrates the reaction scheme 1 for preparing compound 2.
• Fig. 3 illustrates the reaction scheme 2 for preparing compound 4.
• Fig. 4 illustrates the reaction scheme 3 for preparing compounds 3 and 4.
• DETAILED DESCRIPTION OF THE INVENTION The present invention concerns 9,10-diketo taxane derivatives formed in chemical conversion from 9-dihydro-13-acetylbacatin III (9-DHAB) for the efficient production of paclitaxel and docetaxel analogs and their intermediate.
• Such conversion processes may include protection of 7-OH of the 9-DHAB, deacelaytion of C-IO position, and oxidation of C-9, and C-10 hydroxyl groups to yield a intermediate compound 7-triethylsilyl-9, 10-diketo- 13-acetylbaccatin III (6).
• a first broad aspect of the present invention provides a novel process for making paclitaxel and docetaxel by using a novel precursor, 9-dihydro- 13-acetylbaccatin III, which is abundant in Taxus canadensis, the species commonly found in Eastern Canada and Northeast United States. The isolation yield for this compound is 0.1-0.2%.
• a second broad aspect of the present invention provides a novel synthetic route in a process for the conversion of 9-dihydro-l 3-acetylbaccatin III to paclitaxel and docetaxel, the process comprising the two steps of firstly, reacting a protected paclitaxel or docetaxel side chain precursor with 7-O-triethylsilyl-9,10- diketobaccatin III (T), thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel (12), and 7-O-triethylsilyl-9, 10-diketopaclitaxel (14) containing a protected side chain.
• a third broad aspect of the present invention provides a process for the conversion of 9-dihydro-13-acetylbaccatin III to 10-deacetylbacatin III, comprising the sequential steps of converting 7-O-triethylsilyl-9,10-diketo-13- acetyllbaccatin III to 7-O-triethylsilyl-9,10-diketo-lbaccatin III, reducing said 7-0- triethylsilyl-9,10-diketobaccatin III to 7-0-triethylsilyl-lO-deacetylbaccatin III, removing the 7-0-triethylsilyl protecting group to yield 10-deacetylbaccatin III.
• a fourth broad aspect of the present invention provides a novel process for the conversion of 9-dihydro-13-acetylbaccatinIII to paclitaxel and docetaxel which comprises the sequential steps of: effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while substantially-simultaneously deacetylating the 10-acetyl group to yield a 10- hyroxy group, thereby to produce 7-0-triethylsilyl- lO-deacetyl-9-dihydro- 13- acetylbaccatin III (5); oxidizing the 9-, and 10-hydroxyl group of compound 5 to produce 13-acetyl-9,10-diketo-7-triethylsilylbaccatin III 6, removing the 13-acetyl group of 7-O-triethylsilyl-9,10-diketo-13-acetylbaccat
• the suitable protecting groups for hydroxyl groups can be any protecting group that would be used by a person skilled in the art.
• Such protecting groups can be those described in Theodora W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc., 1999, pp. 17-21, which is hereby incorporated by reference.
• the protecting groups for hydroxyl groups can be, for example, ethers (such as methyl), or substituted methyl ethers (such as methoxymethyl; methylthiomethyl; (phenyldimethylsilyl)methoxymethyl; benzyloxymethyl; p- methoxybenzyloxymethyl; p-nitrobenzyloxymethyl; o-nitrobenzyloxymethyl; (4- methoxyphenoxy)methyl; guaiacolmethyl; /-butoxymethyl; 4-pentenyloxymethyl; siloxymethyl; 2-methoxyethoxymethyl; 2,2,2-trichloroethoxymethyl; bis(2- chloroethoxy)methyl; 2-(trimethylsilyl)ethoxymethyl; menthoxymethyl; tetrahydropyranyl; 3-bromotetrahydropyranyl; tetrahydrothiopyranyl; 1- methoxycyclohexyl; 4-methoxy tetrahydropyranyl; 4- methoxytetrahydr
• the protecting groups for hydroxyl groups can be, for example, substituted ethyl ethers (such as 1 -ethoxy ethyl; l-(2-chloroethoxy)ethyl; l-[2- (trimethylsilyl)ethoxy]ethyl; 1 -methyl- 1 -methoxyethyl; 1 -methyl- 1 - benzyloxyethyl; 1 -methyl- l-benzyloxy-2-fluoroethyl; 1 -methyl- 1-phenoxy ethyl; 2,2,2-trichloroethyl; 1 , 1 -dianisyl-2,2,2-trichloroethyl; 1,1,1 , 3,3,3 -hexafluoro-2- phenylisopropyl; 2-trimethylsilylethyl; 2-(benzylthio)ethyl; 2-(phenylselenyl)ethyl; /-buty
• Step A To a solution of 95% of ethanol, 45 mg of the compound 6 was added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6ml) was added, then the solution was stirred for 8 hours at room temperature, after that the reaction was quenched by brine and extracted with dichloromethane and organic phase was collected and concentrated to dryness in vacuum. The residue was purified through silica gel column.
• the product from step A was dissolved in 10 ml of THF, 5 mg of LiAlH 4 was then slowly added with stirring. After stirring for 2 hours at room temperature, the reaction was quenched by adding of 1% HCl (0.5 ml) and brine, the product was extracted with CH 2 Cl 2 .
• Step B 7-TES-lO-deacetylbaccatin III was dissolved in a mixture of acetonitrile and acetone (3:1), the solution then was stirred at room temperature for a few minutes before 5 ml of sodium hypochloride (NaOCl) was added dropwise. The mixture was reacted at room temperature for 2 hours and then quenched with brine and extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and the residue was re-crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white powder (shown as compound 2).
• NaOCl sodium hypochloride
• Step B 35 mg of 7-TES-9, 10-diketobaccatin III was placed in a 25 ml round bottom flask, and 3 mole equivalents of protected docetaxel side chain precursor, (2R,3S)-N-boc-O-(l-ethoxyethyl)-3-phenylisoserine or (3R,4S)-3-(l- ethoxyethyl)-4-(phenyl)-N-boc-2-azetidinone, were dissolved in 20 ml of tetrahydrofuran (THF) at -45 0 C, then 6 mole equivalents of LiHMDS and 1 mole equivalent of CeCl 3 were added slowly.
• THF tetrahydrofuran
• Step B The residue was re-dissolved in THF, and sodium hypochloride (NaOCl) was added dropwise. The mixture was stirred for 2 hours at room temperature then work-up as above. The residue was purified through flash column chromatography. Docetaxel was obtained as white needles (see compound 4 on Fig. 4). 7-triethylsilyl-2'-EE-10-deacetylpaclitaxeI (compound JJQ can be made through the same manner as for making intermediate compound 13 by using a paclitaxel side chain attached to 13-C position.
• 7-triethyl-2'-EE-paclitaxel 1.5g of 7-triethylsilyl-2'-EE-10- deacetylpaclitaxel (18) was dissolved in THF (20 ml), the solution was poured into a 50 ml round-bottom flask equipped with a magnetic stirrer, then 5 ml of DMAP was added and the mixture was cooled to 0 0 C, and 5 ml of acetyl chloride was added and the mixture was stirred for 10 hours at 0 0 C, then the temperature was slowly raised to room temperature and kept for another hour. After the reaction was completed, the reaction was quenched by adding 50 ml of brine.
• paclitaxel can be obtained as white powder.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Epoxy Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=38831365

Family Applications (1)

Country Status (2)

Family Cites Families (12)

• 2007
  • 2007-06-12 EP EP07719967A patent/EP2029563A4/de not_active Withdrawn
  • 2007-06-12 WO PCT/CA2007/001051 patent/WO2007143839A1/en not_active Ceased

Also Published As

Similar Documents

Legal Events