CN101528720A - Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III - Google Patents
Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III Download PDFInfo
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- CN101528720A CN101528720A CNA2007800293778A CN200780029377A CN101528720A CN 101528720 A CN101528720 A CN 101528720A CN A2007800293778 A CNA2007800293778 A CN A2007800293778A CN 200780029377 A CN200780029377 A CN 200780029377A CN 101528720 A CN101528720 A CN 101528720A
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- silyl
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- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 68
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 66
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 60
- 229960003668 docetaxel Drugs 0.000 title claims abstract description 41
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WPPPFZJNKLMYBW-FAEUQDRCSA-N 13-acetyl-9-dihydrobaccatin iii Chemical compound O([C@@H]1[C@]2(O)C[C@@H](C(=C([C@@H](OC(C)=O)[C@H](O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]31)OC(C)=O)C2(C)C)C)OC(=O)C)C(=O)C1=CC=CC=C1 WPPPFZJNKLMYBW-FAEUQDRCSA-N 0.000 title abstract 3
- FFCWRLFQIKDRNO-UHFFFAOYSA-N 9-dihydro-13-acetyl baccatin III Natural products CC(=O)OC1C2C(O)CC(OC(=O)C)C3(CO3)C2C(OC(=O)C)C4(O)CC(OC(=O)C)C(=C(C1OC(=O)C)C4(C)C)C FFCWRLFQIKDRNO-UHFFFAOYSA-N 0.000 title abstract 3
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 title 2
- 238000000034 method Methods 0.000 claims abstract description 82
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 13
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims abstract description 11
- -1 heterocyclic radical Chemical class 0.000 claims description 121
- 229930191978 Gibberellin Natural products 0.000 claims description 82
- 235000013399 edible fruits Nutrition 0.000 claims description 82
- 239000003448 gibberellin Substances 0.000 claims description 82
- IXORZMNAPKEEDV-OBDJNFEBSA-N gibberellin A3 Chemical class C([C@@]1(O)C(=C)C[C@@]2(C1)[C@H]1C(O)=O)C[C@H]2[C@]2(C=C[C@@H]3O)[C@H]1[C@]3(C)C(=O)O2 IXORZMNAPKEEDV-OBDJNFEBSA-N 0.000 claims description 82
- 239000003375 plant hormone Substances 0.000 claims description 82
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- 230000000903 blocking effect Effects 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 9
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 8
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 8
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 8
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 238000003381 deacetylation reaction Methods 0.000 claims description 7
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 7
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 7
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 claims description 4
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- 238000010790 dilution Methods 0.000 claims description 2
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims 2
- XSYLUBKWRZCOQP-CXRLMVSZSA-N (3r,4s)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1([C@H]([C@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 XSYLUBKWRZCOQP-CXRLMVSZSA-N 0.000 claims 1
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- CZTZICYNMYGUNU-JQXSQYPDSA-N tert-butyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1=CC=CC=C1 CZTZICYNMYGUNU-JQXSQYPDSA-N 0.000 claims 1
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a novel semi-synthetic route in the preparation of docetaxel and paclitaxel. This new process involves the conversion of 9-dihydro-13-acetylbaccatinIII to docetaxel and paclitaxel by the step of converting 9-dihydro-13-acetylbaccatin III into 7-O-triethylsilyl-9,10-diketobaccatin III, and adding docetaxel and paclitaxel side chain precursors, respectively, to form a new class of taxane intermediates, such as 7-O-triethylsilyl-9,10-diketodocetaxel and 7-O-triethylsilyl-9,10-diketopaclitaxeltaxel. These new intermediates then by a series reduction, acetylation of the 10-hydroxyl position for paclitaxel and finally deprotection to yield docetaxel and paclitaxel, the most important anti-cancer drugs.
Description
Technical field
The present invention relates to a kind of precursor 10-for preparing anti-cancer medicine paclitaxel, Docetaxel and can be used as the cancer therapy drug of producing these tool popularity and take off the acetyl oar fruit Plant hormones regulators,gibberellins III and the semi-synthetic route of other taxane compounds.More particularly the present invention relates to a kind ofly take off the new semi-synthetic route of acetyl oar fruit Plant hormones regulators,gibberellins III by 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III taxol biosynthesis, Docetaxel and 10-, wherein 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is a kind of taxane compounds of separating from the green shrub T. canadensis of the length that is grown in Canadian east and Northeastern United States (Taxus Canadensis).
Background technology
Taxan is the natural yew tree that is present in of a class, for example the material in common yewtree (Taxus brevifolia), european yew (Taxus baccata) and the T. canadensis of Canadian east and Northeastern United States.9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is one of chemical substance of extracting in the needle by T. canadensis, and it is used for producing the useful intermediates 10-that is used to prepare taxol, Docetaxel and analogue thereof and takes off acetyl oar fruit Plant hormones regulators,gibberellins III.
The Taxan family of diterpenes is considered to the fabulous class cancer chemotherapeutic agents of prospect.The derivative of a lot of Taxans comprises that taxol, Docetaxel, Tyke rope (taxol) C and Cephalomannine are considered to very strong cytotoxicity, and has strong activity in vivo in leukemia and other tumour system.Taxol and many derivatives thereof in clinical trial, demonstrated to late period breast cancer and ovarian cancer be effective.In the preliminary study to other tumor types, taxol and many derivatives thereof also demonstrate its antagonistic activity likely.Recently, in the U.S. and Canada, taxol, Docetaxel have been approved for treatment breast cancer and ovarian cancer.
At present, unique available natural origin taxol is several poky yew trees (Taxus), wherein, has found the taxol of concentration very low (being less than 400ppm) in the barks of these trees or needle.Therefore, from the bark of Pacific Ocean Chinese fir (yewtree) and ground hemlock (T. canadensis), can isolate taxol, but yield very low (0.01%-0.02%), and also the process of separation and purifying is too complicated.In addition, extract very difficultly, process expends height.Because removing debarks can make tree be damaged and injure the existence of these species, it is believed that the supply that separates the supply that Taxan will be expected to make Taxan, especially taxol from the trunk of different types of Ramulus et folium taxi cuspidatae with needle becomes more sufficient.This has just caused obtaining by natural having turned to by 10-of taxol to take off the initial semi-synthetic production of acetyl oar fruit Plant hormones regulators,gibberellins III, and 10-wherein takes off acetyl oar fruit Plant hormones regulators,gibberellins III to be separated from the needle of Britain Chinese fir (european yew) and get.
Because the structural complexity of taxol and Docetaxel, for enough taxol and Docetaxels will be provided, partial synthesis is much more feasible approach.At first with the Docetaxel commercialization, it came into the market in nineteen ninety-five Aventis, and was a kind of cancer therapy drug of quick growth.This medicine is semisynthetic product, also takes off acetyl oar fruit Plant hormones regulators,gibberellins III by 10-and begins to prepare.So far, the commercial offers of Docetaxel derives from 10-basically fully and takes off acetyl oar fruit Plant hormones regulators,gibberellins III.Yet, up to the present, because the source of biomass is limited, and isolating yield low (needle of per kilogram yewtree is 50-165mg), the supply that makes 10-take off acetyl oar fruit Plant hormones regulators,gibberellins III is restricted.
Now existing people has proposed various 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III (9-DHABIII) to be converted into the method that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III.But these methods cause the yield of its finished product very low.Therefore still need a kind ofly effectively 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III to be converted into the method that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III (10-DABIII).
Its precursor compound is finally depended in the preparation of D51-7059, and promptly 10-takes off the supply of acetyl oar fruit Plant hormones regulators,gibberellins III (10-DABIII), and the existing report of some in this derivative proves that it has enhanced chemotherapy vigor.10-DABIII has the basic diterpene structure of taxol, but does not have carboxyl groups in the C-10 position, does not have side chain in the C-13 position.
Because 10-DABIII is a kind of important starting raw material in taxol semi-synthetic, along with the clinical study of carrying out with taxol is more and more, the importance of 10-DABIII also may improve.One of its reason is, it seems, compares with the taxol naturally occurring, that water dissolvable is relatively poor, makes the chemotherapy preparation of the taxoid compound of the water soluble modified as cancer slightly at C-13 position side chain, may be more satisfactory.So just strengthened and come taxol biosynthesis and second or the pressing for of third generation taxoid compound as starting raw material producing 10-DABIII.Therefore, need the method for a kind of improved separation and/or synthetic 10-DABIII.
In fact, up to the present, great majority are related to the semisynthetic research of taxol and all relate to 10-and take off acetyl oar fruit Plant hormones regulators,gibberellins III.10-take off acetyl oar fruit Plant hormones regulators,gibberellins III be converted into taxol generally by the hydroxyl of protection C-7 position, connect ethanoyl in the C-10 position, by the alcohol of C-13 and the esterification of side chain integral part; connect C-13 β amino ester side chain in the C-13 position, and the deprotection of C-7 position is finished.Be restricted because 10-takes off the supply of acetyl oar fruit Plant hormones regulators,gibberellins III, must proceed the research in other source.
The Canadian patent application No.2 of the Zamir that on April 18th, 1998 announced etc., 188,190 have described a kind of semisynthetic method, this method is converted into a kind of starting raw material with naturally occurring Taxan 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III, this starting raw material is suitable on the composite structure the relevant Taxane derivative with oar fruit Plant hormones regulators,gibberellins III, as taxol, Cephalomannine and other Taxan.
The U.S. Patent No. 6,812,356 of the Findly that on November 2nd, 2004 issued provides a kind of and has produced the method that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III with 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III.
The U.S. Patent No. 6,734,304 of the Bristol-Myers Squibb company that on August 31st, 2004 issued provides new oxazolidine, and finds that it can be used as intermediate and is used for preparing the Taxan that has the C-13 side chain, for example taxol and analogue thereof.More particularly, this patent relates to and combining Yu Gai oxazolidine to form the step of Taxan.
The U.S. Patent No. 6 of the R.A.Holton that on March 23rd, 2004 issued etc., 710,191 oar fruit Plant hormones regulators,gibberellins III that a kind of C9 of preparation substituting group is provided is not ketone or 10-take off the derivative of acetyl oar fruit Plant hormones regulators,gibberellins III or the method for analogue, wherein, Tyke rope (taxol), Tyke rope analogue, oar fruit Plant hormones regulators,gibberellins III or the 10-substituting group that takes off the C9 ketone of acetyl oar fruit Plant hormones regulators,gibberellins III is reduced to corresponding oh group selectively.
The U.S. Patent No. 6,593,482 of the H.Bouchard that on July 15th, 2003 issued etc. provides a kind of method that is prepared first thiomethyl Taxan by oar fruit Plant hormones regulators,gibberellins III and beta-lactam.
The U.S. Patent No. 6,576,777 of the L.Zamir that on June 10th, 2003 issued etc. provides a kind of semisynthetic method, and this method is converted into naturally occurring Taxan the starting raw material that is suitable for taxol biosynthesis and related compound.This patent is specifically related to 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the method for the protected oar fruit of 7-Plant hormones regulators,gibberellins III; the latter can be used on the composite structure the relevant D51-7059 with oar fruit Plant hormones regulators,gibberellins III; for example, taxol, Docetaxel, Cephalomannine and other Taxan.
Other provides the patent of the method for the new taxanes of preparation to comprise the U.S. Patent No. 6 of the Aventis Pharma S.A. that on May 7th, 2002 issued, 384,701, the U.S. Patent No. 6 of the Aventis Pharma S.A. that issues December 18 calendar year 2001,331,635, U.S. Patent No. 6,232,477 with the Aventis Pharma S.A. that issues May 15 calendar year 2001.
The U.S. Patent No. 6 of the Institut National de la Research Scientific that issues April 24 calendar year 2001,222,053 provides a kind of semisynthetic method, and this method is converted into naturally occurring Taxan the starting raw material that is suitable for taxol biosynthesis and allied compound.Be specifically related to a kind of method that 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the protected oar fruit of 7-Plant hormones regulators,gibberellins III; the latter can be used as starting raw material then and comes on the composite structure the relevant D51-7059 with oar fruit Plant hormones regulators,gibberellins III; for example, taxol, Docetaxel, Cephalomannine and other Taxan.
It is a kind of by 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III oxidation is prepared the method that taxol, oar fruit Plant hormones regulators,gibberellins III and 10-take off acetyl oar fruit Plant hormones regulators,gibberellins III that the U.S. Patent No. 6,197,981 of the J.Liu that issue March 6 calendar year 2001 provides.
The U.S. Patent No. 6,175,023 of the J.Liu that issue January 16 calendar year 2001 provides a kind of and has prepared the semisynthesis of 9-dihydro Taxan as initial compounds with 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III.
The U.S. Patent No. 6,066,747 of the R.H.Holton that on May 23rd, 2000 issued etc. provides a kind of method that taxol, oar fruit Plant hormones regulators,gibberellins III and 10-take off acetyl oar fruit Plant hormones regulators,gibberellins III derivative or contain other Taxans of new C9 functional group for preparing.
The U.S. Patent No. 5 of the Abbott Laboratories that on April 1st, 1997 issued, 616,740, the U.S. Patent No. 5 of the Abbott Laboratories that issued on January 14th, 1997,594, the U.S. Patent No. 5 of the Abbott Laboratories that on June 25th, 157 and 1996 issued, 530,020 all provides the natural product 9-dihydro-prepared deoxy taxol compound of 13-acetyl oar fruit Plant hormones regulators,gibberellins III that is obtained by the T. canadensis separation respectively, and paclitaxel analogs prepared therefrom.
The U.S. Patent No. 5,440,056 of the Abbott Laboratories that issue August 8 nineteen ninety-five provides by T. canadensis separates the natural product 9-dihydro-prepared deoxy taxol product of 13-acetyl oar fruit Plant hormones regulators,gibberellins III that obtains.
The U.S. Patent No. 34 of Denis etc., 277 issue U.S. Patent No. 4 again, 924,011 provides that to take off acetyl oar fruit Plant hormones regulators,gibberellins III with 10-be starting raw material, successfully semi-synthetic first taxol, wherein used 10-take off acetyl oar fruit Plant hormones regulators,gibberellins III and can extract from the needle of yewtree and get by higher yield.
Provide a kind of precursor 10-for preparing anti-cancer medicine paclitaxel, Docetaxel and can be used as the cancer therapy drug of producing these tool popularity to take off acetyl oar fruit Plant hormones regulators,gibberellins III, and the new semisynthesis of other taxane compounds is very yearning.
Summary of the invention
Summary of the invention
According to the present invention, provide a kind of precursor 10-for preparing anti-cancer medicine paclitaxel, Docetaxel and can be used as the cancer therapy drug of producing these tool popularity to take off the acetyl oar fruit Plant hormones regulators,gibberellins III and the new semisynthesis of other taxane compounds.
Also to provide a kind of 10-of preparation to take off the semisynthetic method of acetyl oar fruit Plant hormones regulators,gibberellins III.
Also to provide a kind of and prepare the semisynthetic method that taxol, Docetaxel and 10-take off acetyl oar fruit Plant hormones regulators,gibberellins III by 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III.
Also need in addition and a kind ofly effectively 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the method that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III (DABIII).
According to the present invention, it is (I) (II) (III) or compound (IV) that structural formula is provided:
Wherein:
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
3Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
4Be the C of hydrogen atom, straight or branched
1-C
20Alkyl, C
1-C
20Acyl group, C
1-C
20Halogenated acyl group, C
3-C
12Cycloalkyl, C
1-C
12Heterocyclic radical, C
2-C
20Alkenyl, C
2-C
20Alkynyl, C
6-C
12Aryl, C
6-C
20Aralkyl, C
1-C
20Alkoxyl group, C
6-C
20Alkaryl, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl, said alkyl, cycloalkyl, heterocyclic radical, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heteroaryl, alkyl heterocyclic and miscellaneous alkyl aryl are not substituted or are replaced by at least one substituting group, and said each substituted radical is selected from F, Cl, Br, I, OH, SH, NH
2, NO
2, CN, CF
3,-SH ,-OCH
2Ph ,-OPh ,-SCH
3,-SPh ,-SCH
2Ph ,-COOH ,-COOR
6, R wherein
6Be C
1-C
6The C of alkyl, straight or branched
1-C
12Alkyl, C
6-C
12Aryl, C
2-C
20Alkenyl, C
1-C
20Alkoxyl group, C
1-C
20Alkyl, C
2-C
20Alkynyl, C
6-C
20Aralkyl, C
6-C
12Aryl, C
3-C
8Cycloalkyl, C
1-C
20Aminoalkyl, C
6-C
12Ammonia aryl, C
1-C
12Aminoheteroaryl, C
1-C
20Hydroxyalkyl, C
6-C
12Hydroxyaryl, C
1-C
12Hydroxyl heteroaryl, C
1-C
12Heterocyclic radical, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl.
According to the present invention, be applicable to that the blocking group of hydroxyl is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
According to the present invention; the blocking group that is applicable to hydroxyl is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl; t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl-methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
According to the present invention, in preferred compound, R
1It is triethylsilyl.
According to the present invention, in preferred compound, R
2It is ethanoyl.
According to the present invention, in preferred compound, R
3It is ethoxyethyl.
According to the present invention, in preferred compound, R
4Be C
1-C
6Alkyl, phenyl, tert.-butoxy, C
2-C
6Alkenyl, tetrahydrofuran base or THP trtrahydropyranyl.
According to the present invention, in preferred compound, R
4Be amyl group, phenyl, tert.-butoxy, but-2-ene base, tetrahydrofuran base or THP trtrahydropyranyl.
According to the present invention, it is (V) or compound (VI) that structural formula is provided:
Wherein:
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
3Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
4Be the C of hydrogen atom, straight or branched
1-C
20Alkyl, C
1-C
20Acyl group, C
1-C
20Halogenated acyl group, C
3-C
12Cycloalkyl, C
1-C
12Heterocyclic radical, C
2-C
20Alkenyl, C
2-C
20Alkynyl, C
6-C
12Aryl, C
6-C
20Aralkyl, C
1-C
20Alkoxyl group, C
6-C
20Alkaryl, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic, C
2-C
20Miscellaneous alkyl aryl, or be applicable to amino blocking group; And
R
5Be hydrogen atom or the blocking group that is applicable to hydroxyl; said alkyl, cycloalkyl, heterocyclic radical, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heteroaryl, alkyl heterocyclic and miscellaneous alkyl aryl are not substituted or are replaced by at least one substituting group, and each said substituted radical is selected from F, Cl, Br, I, OH, SH, NH
2, NO
2, CN, CF
3,-SH ,-OCH
2Ph ,-OPh ,-SCH
3,-SPh ,-SCH
2Ph ,-COOH ,-COOR
6,
R wherein
6Be C
1-C
6The C of alkyl, straight or branched
1-C
12Alkyl, C
6-C
12Aryl, C
2-C
20Alkenyl, C
1-C
20Alkoxyl group, C
1-C
20Alkyl, C
2-C
20Alkynyl, C
6-C
20Aralkyl, C
6-C
12Aryl, C
3-C
8Cycloalkyl, C
1-C
20Aminoalkyl, C
6-C
12Ammonia aryl, C
1-C
12Aminoheteroaryl, C
1-C
20Hydroxyalkyl, C
6-C
12Hydroxyaryl, C
1-C
12Hydroxyl heteroaryl, C
1-C
12Heterocyclic radical, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl.
According to the present invention, in preferred compound, be applicable to that the blocking group of hydroxyl is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
According to the present invention; in preferred compound; the blocking group that is applicable to hydroxyl is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl; t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl-methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl group alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
According to the present invention, in preferred compound, R
1It is triethylsilyl.
According to the present invention, in preferred compound, R
2It is ethanoyl.
According to the present invention, in preferred compound, R
3It is ethoxyethyl.
According to the present invention, in preferred compound, R
4Be C
1-C
6Alkyl, phenyl, tert.-butoxy, C
2-C
6Alkenyl, tetrahydrofuran base or THP trtrahydropyranyl.
According to the present invention, in preferred compound, R
4Be amyl group, phenyl, tert.-butoxy, but-2-ene base, tetrahydrofuran base or THP trtrahydropyranyl.
According to the present invention, in preferred compound, R
5It is triethylsilyl.
According to the present invention, provide the method for a kind of preparation structural formula for the compound of (II):
Said method comprises makes the compound reaction shown in (I) of a kind of oxygenant and structural formula:
Wherein:
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl; And R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl.
According to the present invention, be applicable to that the blocking group of hydroxyl is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
According to the present invention; the blocking group that is applicable to hydroxyl is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl; t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl-methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl group alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
According to the present invention, R
1It is triethylsilyl.
According to the present invention, R
2It is ethanoyl.
According to method of the present invention, described oxygenant was selected from ruthenic acid four n-propyl ammoniums, Collin reagent, Swern reagent [(COCl)
2, DMSO, Et
3N], tart pyridinium chlorochromate (PCC), dichromic acid pyridine (PDC), CrO
2With John reagent.
According to the present invention; provide a kind of 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the method for Taxane derivative, this method comprises acetyl group and the oxidation 9-dihydro-C-9 of 13-acetyl oar fruit Plant hormones regulators,gibberellins III and the step of C-10 position of removing the C-10 position.
According to the present invention, above-mentioned oxidation step is finished by adding oxygenant, and this oxygenant was selected from ruthenic acid four n-propyl ammoniums, Collin reagent, Swern reagent, PCC, PDC, CrO
2With John reagent.
According to the present invention, a kind of method for preparing taxol, Docetaxel and derivative thereof is provided, this method may further comprise the steps:
(a) with the hydroxyl of C-7 position among suitable blocking group protection 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III, obtain protected product;
(b) slough the C-10 position ethanoyl of protected product; And
(c) hydroxyl of the C-9 of the protected product of oxidation and C-10.
According to method of the present invention, used blocking group is selected from benzyl, C
1-C
25Substituted benzyl, benzyl formic acid ester group, C
1-C
25Substituted benzyl formic acid ester group, tosyl group, the tosyl group of replacement, dihydro pyranyl, methoxyl methyl, benzoyl, C
1-C
25Substituted benzoyl, C
1-C
25Trialkylsilkl, 2-(trimethyl silyl) ethoxymethyl, benzyloxycarbonyl.
According to method of the present invention, described oxidation step is finished by adding oxygenant, and this oxygenant was selected from ruthenic acid four n-propyl ammoniums, Collin reagent, Swern reagent, PCC, PDC, CrO
2With John reagent.
According to method of the present invention, also be included in the step that acetyl is taken off in the C-13 position.
According to method of the present invention, also comprise the step that the ketone of C-10 is reduced to the C-10 hydroxyl.
According to the present invention, provide a kind of method for preparing the compound of structural formula shown in 8:
This method comprises the step of reduction structural formula C-10 ketone of compound shown in 7:
According to method of the present invention, also comprise the C-7 position is carried out deprotection and obtained the step that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III.
According to method of the present invention, also be included in the C-13 position and add suitable side chain, reduction C-10 also carries out deprotection selectively to obtain required product.
According to method of the present invention, deprotection reaction carries out to obtain taxol and Docetaxel C-7 and 2 '.
According to method of the present invention, described side chain be selected from (2R, 3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine; (3R, 4S)-3-(1-ethoxy oxyethyl group)-4-(phenyl)-N-benzoyl-2-azetidinone; (2R, 3S)-N-BOC-O-(1-ethoxyethyl)-3-phenylisoserine and (3R, 4S)-3-(1-ethoxy oxyethyl group)-4-(phenyl)-N-BOC-2-azetidinone.
According to method of the present invention, described Taxane derivative is taxol or Docetaxel.
Detailed Description Of The Invention
The present invention relates to 9, the Taxane derivative of 10-diketone, this derivative are to generate in the chemical conversion process of being produced taxol and Docetaxel analogue and intermediate thereof by 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III (9-DHAB) efficiently.These conversion processes can comprise the protection of the 7-OH of 9-DHAB, the C-10 position take off acetyl, and the oxidation of C-9 and C-10 hydroxyl, generating midbody compound 7-triethylsilyl-9,10-diketone-13-acetyl oar fruit Plant hormones regulators,gibberellins III (
6).These processes also can comprise taxol and Docetaxel side chain and 9,10-diketone part (compound
7) connection, can synthesize taxol, Docetaxel and analogue thereof by this connection, and its intermediate with different C-13 side-chain structures.
First main aspect of the present invention has provided a kind of new precursor that utilizes, 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III, the novel method of preparation taxol and Docetaxel, 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III has abundant content in T. canadensis, these species are grown in the northeast of the Canadian east and the U.S. usually.Compound 9-dihydro-isolating yield of 13-acetyl oar fruit Plant hormones regulators,gibberellins III is 0.1-0.2%.
Second main aspect of the present invention is that 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is being converted in the method for taxol and Docetaxel; a kind of new synthetic route is provided; this method comprises: the first step; make through the taxol of protection or the side chain precursor and the 7-O-triethylsilyl-9 of Docetaxel, 10-diketone oar fruit Plant hormones regulators,gibberellins III (
7) connect, produce thus and contain the 7-O-triethylsilyl-9 of protecting side chain, 10-diketone Docetaxel (
12) and 7-O-triethylsilyl-9,10-diketone taxol (
14).Second step, the reduction intermediate
12With
14The ketone of C-10, generate intermediate 7-O-triethylsilyl-2 '-EE-Docetaxel (
13) and 7-O-triethylsilyl-2 '-EE-10-take off the acetyl taxol (
15); final step is a blocking group of removing 7-O-triethylsilyl-2 '-EE-Docetaxel; or; make 7-O-triethylsilyl-2 '-EE-10-take off the C-10 glycoloylization of acetyl taxol earlier; remove its blocking group then, to produce designed product Docetaxel or taxol.
The 3rd main aspect of the present invention provides and a kind of 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the method that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III; this method comprises following successive step: with 7-O-triethylsilyl-9; 10-diketone-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into 7-O-triethylsilyl-9; 10-diketone oar fruit Plant hormones regulators,gibberellins III; with this 7-O-triethylsilyl-9; 10-diketone oar fruit Plant hormones regulators,gibberellins III is reduced to 7-O-triethylsilyl-10-and takes off acetyl oar fruit Plant hormones regulators,gibberellins III, removes protecting group 7-O-triethylsilyl and takes off acetyl oar fruit Plant hormones regulators,gibberellins III to generate 10-.
The 4th main aspect of the present invention provides a kind of novel method that 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into taxol and Docetaxel; this method comprises following successive step: make the 7-hydroxyl of 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III carry out the reaction of silicoheptane alkanisation; simultaneously; basically side by side make the 10-ethanoyl take off acetyl to produce the 10-hydroxyl, generate thus 7-O-triethylsilyl-10-deacetylation-9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III (
5); Oxygenated compound
59-and 10-hydroxyl, generate 13-acetyl-9,10-diketone-7-triethyl-silicane oar fruit Plant hormones regulators,gibberellins III
6, remove 7-O-triethylsilyl-9, the 13-ethanoyl among 10-diketone-13-acetyl oar fruit Plant hormones regulators,gibberellins III, thus generate 7-O-triethylsilyl-9,10-diketone oar fruit Plant hormones regulators,gibberellins III
7Taxol or Docetaxel side chain precursor are connected with intermediate 7, generate 7-triethylsilyl-9 thus, 10-diketone-10-takes off the acetyl taxol
14Or 7-triethylsilyl-9,10-diketone Docetaxel
12, the reduction intermediate
12With
14In the 10-ketone group, generate product 7-O-triethylsilyl-2 '-EE-Docetaxel and 7-O-triethylsilyl-2 '-EE-10-thus and take off the acetyl taxol; With the C-10 glycoloylization of intermediate 14, to produce compound 18, then intermediate 12 and 18 is carried out deprotection, generate Docetaxel and taxol respectively.
The protecting group that is applicable to hydroxyl can be the used any protecting groups of those skilled in the art.
Above-mentioned protecting group can be Theodora.W.Greene etc. at Protective Groups in OrganicSynthesis, Third Edition, John Wiley﹠amp; Sons, Inc., 1999, the blocking group described in the pp.17-21, the document is hereby incorporated by.
The blocking group that is used for hydroxyl can be, for example, ether (as methyl), or the methyl ether that replaces is (as methoxyl methyl; The first thiomethyl; (xylylene silicomethane) methoxyl methyl; Benzyloxymethyl; Right-the methoxy benzyloxymethyl; Right-the nitro benzyloxymethyl; Neighbour-nitro benzyloxymethyl; (4-methoxy phenoxy) methyl; The methyl catechol methyl; Uncle's fourth oxygen methyl; 4-amylene oxygen methyl; Silicomethane oxygen methyl; 2-methoxyl group ethoxymethyl; 2,2,2-trichlorine ethoxymethyl; Two (2-chloroethoxy) methyl; 2-(trimethyl silyl) ethoxymethyl; Methoxyl methyl; THP trtrahydropyranyl; 3-bromine THP trtrahydropyranyl; Tetrahydro thiapyran base; 1-cyclohexyl methoxy hexyl; 4-methoxy THP trtrahydropyranyl; 4-methoxy tetrahydro thiapyran base; 4-methoxy tetrahydric thiapyran s, the s-dioxide; 1-[(2-chloro-4-methyl) phenyl]-4-methoxy piperidin-4-yl; 1-(2-fluorophenyl)-4-methoxy piperidin-4-yl; 1,4-diox-2-base; Tetrahydrofuran base; Tetrahydro-thienyl; 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethylammonium-4,7-methylene radical benzo furans-2-yl).
The blocking group that is used for hydroxyl can be that for example, the ethyl ether of replacement is (as the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 1-[2-(trimethyl silyl) oxyethyl group] ethyl; 1-methyl isophthalic acid-methoxyethyl; 1-methyl isophthalic acid-benzyloxy ethyl; 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl; 1-methyl isophthalic acid-benzene oxygen ethyl; 2,2,2-three chloroethyls; 1,1-two anisyls-2,2,2-three chloroethyls; 1,1,1,3,3,3-hexafluoro-2-benzene sec.-propyl; 2-trimethyl silyl ethyl; 2-(benzylthio-) ethyl; 2-(benzene selenyl) ethyl; The tertiary butyl; Allyl group; Propargyl; Rubigan; P-methoxyphenyl; P-nitrophenyl; 2, the 4-dinitrophenyl; 2,3,5,6-tetrafluoro-4-(trifluoromethyl) phenyl; Benzyl), the dibenzyl ether of replacement is (as right-methoxybenzyl; 3, the 4-veratryl; Adjacent nitrobenzyl; To nitrobenzyl; To halogeno-benzyl; 2, the 6-dichloro benzyl; To the cyano group benzyl; To phenylbenzyl; 2, the 6-difluorobenzyl; To the amido benzyl; To the azido-benzyl; 4-azido--3-benzyl chloride base; The 2-trifluoromethyl benzyl; To (methyl sulfinyl) benzyl; 2-and 4-picolyl; 3-methyl-2-picolyl n-oxygen support; 2-quinoline methyl; 1-pyrenyl methyl; Diphenyl-methyl; Right, to ' the dinitrobenzene diphenyl-methyl; 5-dibenzo suberyl; Trityl; α-naphthalene diphenyl-methyl; The p-methoxyphenyl diphenyl-methyl; Two-(p-methoxyphenyl) phenmethyls; Three (p-methoxyphenyl) methyl; 4-(4 '-bromobenzene formyl methoxyl group) phenyl diphenyl-methyl; 4,4 ', 4 " three (4,5-dichlorobenzene diformazan imide phenyl) methyl; 4,4 ', 4 " three (acetyl propoxy phenyl) methyl; 4,4 ', 4 " three (benzoyl oxygen phenyl) methyl; 4,4 '-dimethoxy-3 " [just (imidazoles methyl)] trityl; 4,4 '-dimethoxy-3 " [just (imidazole ethyl) formamyl] trityl; 1, two (4-methoxyphenyl)-the 1 '-pyrene methyl of 1-; 4-(17-four benzoyls [a, c, g, i] fluorene methyl)-4,4 '-dimethoxytrityl; The 9-anthryl; 9-(9-phenyl) xanthenyl; 9-(9-phenyl-10-oxo) anthryl; 1,3-dibenzoyl disulfide penta ring-2-base; Benzisothiazole s, s-dioxy support (benzisothiazoyl s, s-dioxido)), silicomethane ether is (as trimethyl silyl; Triethylsilyl; The triisopropyl silyl; Diformazan sec.-propyl silyl; Diethyl sec.-propyl silyl; Dimethyl thexyl silyl; T-butyldimethylsilyl; T-butyldiphenylsilyl; The tribenzyl silyl; Three p-Xylol silyls; The triphenyl silyl; The diphenyl-methyl silyl; Di-t-butyl methyl-silicane base; Three (trimethyl silyl) silyl; Silyl; (2-hydroxy styrenes) dimetylsilyl; (2-hydroxy styrenes) di-isopropyl silyl; Tertiary butyl methoxyphenyl silyl; Uncle's fourth oxygen diphenylmethyl silylation), ester is (as manthanoate; Benzoyl formiate; Acetic ester; Chloracetate; The dichloro acetic acid ester; Trichloroacetic esters; Trifluoro-acetate; The methoxyimino acetic acid ester; Triphen methoxyimino acetic acid ester; The phenoxy acetic acid ester; The p-chlorophenoxyacetic acid ester; Phenylacetate; Right-P-phenylacetate diphenyl acetic acid ester; Nicotinate; The 3-Phenpropionate; The 4-pentenoate; 4-oxopentanoie acid ester (levulinate); 4, two (4-methoxyphenyl) hydroxy methyl phenyloxies of 4-(ethene dithio) valerate 5-[3-] levulinate; Pivalate; 1-Buddha's warrior attendant acid esters; Crotonate; 4-methoxyl group crotonate; Benzoic ether; To phenylbenzoate; Mesitylene carboxylic acid ester (dish acid esters)), carbonic ether is (as the methyl carbonyl; The methoxyl methyl carbonyl; 9-fluorene methyl carbonyl; The ethyl carbonyl; 2,2,2-three chloroethyl carbonyls; 1,1-dimethyl-2,2,2-three chloroethyl carbonyls; 2-(trimethyl silyl) ethyl carbonyl; 2-(benzene sulfonyl) ethyl carbonyl; 2-(triphen phosphorus) ethyl carbonyl; The isobutyl-carbonyl; Vinyl carbonyl; The allyl group carbonyl; The p-nitrophenyl carbonyl; Benzyloxycarbonyl group; To the methoxybenzyl carbonyl; 3,4-veratryl carbonyl; Adjacent nitrobenzyl carbonyl; To the nitrobenzyl carbonyl), by β elimination reaction splitted carbonic ether (as 2-dansyl ethyl; 2-(4-oil of mirbane) ethyl; 2-(2, the 4-dinitrobenzene) ethyl 2-cyano group-1-styroyl; Thiocarbonic acid SOH s-benzyl ester; 4-oxyethyl group-1-naphthyl; The dithiocarbonic acid methyl esters), and mixed ester (as 2,6-two chloro-4-methylenedioxy phenoxy yl acetates; 2,6-two chloro-4-(1,1,3, the 3-tetramethylbutyl) phenylium ester; 2,4 pairs of (1, the 1-dimethylpropyl) phenylium esters; The chlorodiphenyl yl acetate; Isobutyrate; One succinate; (e)-2-methyl-2-butene ester (cautious announcement acid esters); Adjacent (methoxycarbonyl) benzoic ether; Right-the P-benzoic ether; The α-Nai Jiasuan ester; Nitric ether; N, n, n ', n '-tetramethyl diamino alkyl phosphate; 2-chloro-benzoic acid ester; The 4-bromo-benzoate; 4-nitrobenzoyl acid esters; 3, ' 5 '-dimethoxy st-yrax; The n-phenylcarbamate; Boric acid ester; The methyl-sulfide phosphino-; 2,4-dinitrobenzene-sulfinic acid ester), and sulphonate is (as sulfuric ester; The allyl sulphonate; Methanesulfonates; The benzyl sulphonate; Tosylate; 2-[(4-oil of mirbane) ethyl] sulphonate).
Description of drawings
Fig. 1 illustrates the derivative of taxol with figure.
Fig. 2 prepares compound with the figure explanation
2Reaction process.
Fig. 3 prepares compound with the figure explanation
4Reaction process.
Fig. 4 prepares compound with the figure explanation
3With
4Reaction process.
Embodiment
By following embodiment, will be more readily understood the present invention, these embodiment are of the present invention in order to illustrate, and unrestricted this scope of invention.
In the 10ml acetonitrile, add 102mg 9-dihydro-13-acetyl Baccatine III (compound as shown in fig. 1
1) and the positive Si Ding of 73mg iodate Ji , mixture was stirred 5 minutes, maintain-10 ℃ of of of of of of dissolve fully until 9-dihydro-13-acetyl Baccatine III.Make mixture, after-10 ℃ of of of of of of of following of drip chlorotriethyl silane then.This mixture was poured the 26mg sodium methylate in this round-bottomed flask into restir 5-10 minutes.Mixture continued restir after 1 hour under the same temperature, 0 ℃ of of of of 0 ℃ of of of of of of of of of of of of and of .Then temperature of kept of its temperature is risen to about, 1 hour under is risen to room temperature and mixture was continued to stir, 2 hours again.Make behind the reaction all standing with ethyl acetate extracting three times with salt solution dilution.Merge organic phase, be evaporated to drying in a vacuum.Residue produces white solid (85mg, 85%) 7-O-triethylsilyl-10-deacetylation-9-dihydro-13-acetyl oar fruit Plant hormones regulators, gibberellins III (compound as shown in Figure 2 with preliminary TLC purifying5).
73mg 7-TES-10 is taken off in acetyl-9-dihydro-13-acetyl Baccatine III (compound 5 as shown in Figure 2) and 35mg 4-methylmorpholine-N-dioxide (NMO) adding round-bottomed flask, and add 10ml acetonitrile/acetone (3:1) mixture.After in mixture, adding molecular sieve then and stirring 5 minutes, add 10mg and cross ruthenic acid four Zheng Bing Ji (TPAP), and, 40 ℃ of of of of of of this mixture of subsequently its temperature is risen to stir about, 6 hours at room temperature.Mixture maintains under this temperature and spends the night, and finishes until reaction.In case reaction is finished, be about to this mixture and pour short silicagel column into.With 50ml methylene dichloride (CH2Cl
2) this post of wash-out, obtain CH
2Cl
2Fraction is concentrated into this fraction dried again.Residue produces the 65mg white solid with preliminary TLC purifying, is accredited as 7-TES-9,10-diketone-13-acetyl Baccatine III, compound as shown in Figure 2
6
Steps A: with the 45mg compound
6Add in 95% the ethanolic soln, after being stirred to solid and dissolving fully, add the monohydrate (0.6ml) of hydrazine, at room temperature with solution stirring 8 hours, after this, make the reaction all standing then with salt solution, use the methylene dichloride extracting then, collect organic phase and be evaporated to dried in a vacuum.Residue is by the silicagel column purifying.The product of steps A gained is dissolved among the 10mlTHF, under agitation slowly adds 5mg LiAlH then
4After at room temperature stirring 2 hours, add 1%HCl (0.5ml) and salt solution and make the reaction all standing, reaction product CH
2Cl
2Extracting.Organic phase is concentrated in a vacuum dried, obtains final product.Product 7-TES-10-deacetylation baccatin III is a compound as shown in Figure 2
8, be the crystal of little Huang.
Step B: 7-TES-10-deacetylation baccatin III is dissolved in the mixture of acetonitrile/acetone (3: 1), the solution of gained is at room temperature stirred several minutes after, be added dropwise to the 5ml clorox.After mixture at room temperature reacts 2 hours, make the reaction all standing, and use the ethyl acetate extracting with salt solution.With ethyl acetate be concentrated into mutually do after, make residue recrystallization in acetonitrile, the 10-deacetylation baccatin III that produces white powder is (as compound
2Shown in).
Embodiment 4 preparation 7-TES-9,10-diketone Docetaxel (12)
Steps A: with the 40mg compound
6In the ethanolic soln of adding 95%, after stirring several minutes to solid dissolves fully, add the monohydrate of 1ml hydrazine.The gained mixture is at room temperature stirred after 8 hours with ethyl acetate (50ml) dilution, pour saturated NH then into
4In the Cl solution (40ml).Isolate organic phase and it is concentrated.Residue obtains 30mg7-TES-9 with preliminary TLC purifying, and 10-diketone-Baccatine III (is seen the compound among Fig. 4
7).
Step B:35mg7-TES-9; 10-diketone-Baccatine III is put into the 25ml round-bottomed flask; 3 mol equivalents are through the Docetaxel side chain precursor (2R of protection; 3S)-N-boc-0-(1-ethoxyethyl group)-3-phenylisoserine or (3R; 4S)-3-(1-ethoxyethyl group)-4-(phenyl)-N-boc-2-azetidinone is dissolved in 20ml-45 ℃ the tetrahydrofuran (THF), slowly adds normal LiHMDS of 6 mol and the normal CeCl of 1 mol then
3The mixture of gained stirs 30 minutes post-heating to room temperature at-45 ℃.The process of reaction is monitored by TLC, until finishing.In case reaction is finished, and promptly uses methylene dichloride (50ml) with this mixture diluted, pours saturated NH then into
4In the Cl solution (40ml).Organic Layer is separated and concentrates.Residue obtains 7-TES-9 with preliminary TLC purifying, and 10-diketone Docetaxel (is seen the compound among Fig. 4
12).
Steps A: 7-triethylsilyl-2 '-EE-Docetaxel (
13): with compound
12(1.0g) be dissolved among the THF (30ml), gained solution is poured the 50ml round-bottomed flask that magnetic stirring apparatus is housed into, adds the CeCl of 0.4M then
3.7H
2O be dissolved in THF/MeOH (2/1, solution 3ml).The mixture that obtains was at room temperature stirred 5 minutes.Under agitation slowly add then NaBH4 (45mg, 1.2mmol).Mixture is restir 10 minutes or after react completely at room temperature, adds 5%HCl (2ml) and makes reaction all standing, product
13CH with 50ml
2Cl
2With saturated NH
4The mixture of Cl (3: 1) extracting.Isolate organic Layer, vapourisation under reduced pressure as for, the not purified next step that promptly is used for of residue (is seen the compound among Fig. 4
13).
Step B: residue is dissolved among the THF again, drips clorox (NaOCl) solution.Mixture at room temperature stirred 2 hours, finished by the above step subsequently.Residue is analysed purifying by flash distillation post Layer.The Docetaxel that obtains white needles (is seen the compound among Fig. 4
4).
Use is connected to the paclitaxel lateral chain of 13-C position, just can be according to the preparation midbody compound
13Same mode is made 7-triethylsilyl-2 '-EE-10-and is taken off acetyl taxol (compound
18).
7-triethylsilyl-2 '-EE-taxol (
15): with 1.5g 7-triethylsilyl-2 '-EE-10-take off the acetyl taxol (
18) be dissolved among the THF (20ml), gained solution is poured the 50ml round-bottomed flask that magnetic stirring apparatus is housed into, add 5ml DMAP then, and this mixture is cooled to 0 ℃, after adding the 5ml Acetyl Chloride 98Min., mixture stirred 10 hours down at 0 ℃, then its temperature was slowly risen to room temperature, and kept 1 hour in room temperature again.After reaction is finished, add 50ml salt solution and make the reaction all standing.With ethyl acetate with this aqueous solution extracting 2 times.The organic phase that merges is washed to DMAP with saturated copper sulfate solution and is removed fully, washs with saturated sodium chloride solution then, washes with water again.At last, organic phase is dry on anhydrous sodium sulphate, be concentrated into dried then in a vacuum.Residue is analysed purifying by silicagel column Layer, generation 7-triethylsilyl-2 '-EE-taxol (
15).
The same manner with the preparation Docetaxel makes
15Behind the deprotection, obtain the taxol of white powder.
Though invention has been described to have combined its specific embodiment, but should be realized that, this invention can be done further to revise, and, present patent application is intended to cover any change body of the present invention, purposes or adaptation, in general, these change body, purposes or adaptation are followed principle of the present invention, comprise again and depart from content disclosed in this invention, known or conventional working specification in the technical field of the invention for example, with the content that goes for essential characteristic mentioned above, and the following appended interior content of claim scope.
Claims (40)
1, a kind of structural formula is (I), (II), (III) or compound (IV):
Wherein:
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
3Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
4Be the C of hydrogen atom, straight or branched
1-C
20Alkyl, C
1-C
20Acyl group, C
1-C
20Halogenated acyl group, C
3-C
12Cycloalkyl, C
1-C
12Heterocyclic radical, C
2-C
20Alkenyl, C
2-C
20Alkynyl, C
6-C
12Aryl, C
6-C
20Aralkyl, C
1-C
20Alkoxyl group, C
6-C
20Alkaryl, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl,
Said alkyl, cycloalkyl, heterocyclic radical, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heteroaryl, alkyl heterocyclic and miscellaneous alkyl aryl are not substituted or are replaced by at least one substituting group, and said each substituted radical is selected from F, Cl, Br, I, OH, SH, NH
2, NO
2, CN, CF
3,-SH ,-OCH
2Ph ,-OPh ,-SCH
3,-SPh ,-SCH
2Ph ,-COOH ,-COOR
6R wherein
6Be C
1-C
6The C of alkyl, straight or branched
1-C
12Alkyl, C
6-C
12Aryl, C
2-C
20Alkenyl, C
1-C
20Alkoxyl group, C
1-C
20Alkyl, C
2-C
20Alkynyl, C
6-C
20Aralkyl, C
6-C
12Aryl, C
3-C
8Cycloalkyl, C
1-C
20Aminoalkyl, C
6-C
12Ammonia aryl, C
1-C
12Aminoheteroaryl, C
1-C
20Hydroxyalkyl, C
6-C
12Hydroxyaryl, C
1-C
12Hydroxyl heteroaryl, C
1-C
12Heterocyclic radical, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl.
2, the described compound of claim 1, the wherein said blocking group of hydroxyl that is applicable to is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
3; the described compound of claim 1; the wherein said blocking group of hydroxyl that is applicable to is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl (dimethylthexylsilyl); t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl-methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
4, the described compound of claim 1, R wherein
1It is triethylsilyl.
5, the described compound of claim 1, R wherein
2It is ethanoyl.
6, the described compound of claim 1, R wherein
3It is ethoxyethyl.
7, the described compound of claim 1, R wherein
4Be C
1-C
6Alkyl, phenyl, tert.-butoxy, C
2-C
6Alkenyl, tetrahydrofuran base or THP trtrahydropyranyl.
8, the described compound of claim 1, R wherein
4Be amyl group, phenyl, tert.-butoxy, but-2-ene base, tetrahydrofuran base or THP trtrahydropyranyl.
9, a kind of structural formula is (V) or compound (VI):
Wherein
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
3Be hydrogen atom or the blocking group that is applicable to hydroxyl;
R
4Be the C of hydrogen atom, straight or branched
1-C
20Alkyl, C
1-C
20Acyl group, C
1-C
20Halogenated acyl group, C
3-C
12Cycloalkyl, C
1-C
12Heterocyclic radical, C
2-C
20Alkenyl, C
2-C
20Alkynyl, C
6-C
12Aryl, C
6-C
20Aralkyl, C
1-C
20Alkoxyl group, C
6-C
20Alkaryl, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic, C
2-C
20Miscellaneous alkyl aryl; And
R
5Be hydrogen atom or the blocking group that is applicable to hydroxyl; said alkyl, cycloalkyl, heterocyclic radical, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heteroaryl, alkyl heterocyclic and miscellaneous alkyl aryl are not substituted or are replaced by at least one substituting group, and each said substituted radical is selected from F, Cl, Br, I, OH, SH, NH
2, NO
2, CN, CF
3,-SH ,-OCH
2Ph ,-OPh ,-SCH
3,-SPh ,-SCH
2Ph ,-COOH ,-COOR
6, R wherein
6Be C
1-C
6The C of alkyl, straight or branched
1-C
12Alkyl, C
6-C
12Aryl, C
2-C
20Alkenyl, C
1-C
20Alkoxyl group, C
1-C
20Alkyl, C
2-C
20Alkynyl, C
6-C
20Aralkyl, C
6-C
12Aryl, C
3-C
8Cycloalkyl, C
1-C
20Aminoalkyl, C
6-C
12Ammonia aryl, C
1-C
12Aminoheteroaryl, C
1-C
20Hydroxyalkyl, C
6-C
12Hydroxyaryl, C
1-C
12Hydroxyl heteroaryl, C
1-C
12Heterocyclic radical, C
1-C
12Heteroaryl, C
2-C
20Alkyl heterocyclic or C
2-C
20Miscellaneous alkyl aryl.
10, the described compound of claim 9, the wherein said blocking group of hydroxyl that is applicable to is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
11; the described compound of claim 9; the wherein said blocking group of hydroxyl that is applicable to is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl; t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl-methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
12, the described compound of claim 9, R wherein
1It is triethylsilyl.
13, the described compound of claim 9, R wherein
2It is ethanoyl.
14, the described compound of claim 9, R wherein
3It is ethoxyethyl.
15, the described compound of claim 9, R wherein
4Be C
1-C
6Alkyl, phenyl, tert.-butoxy, C
2-C
6Alkenyl, tetrahydrofuran base or THP trtrahydropyranyl.
16, the described compound of claim 9, R wherein
4Be amyl group, phenyl, tert.-butoxy, but-2-ene base, tetrahydrofuran base or THP trtrahydropyranyl.
17, the described compound of claim 9, R wherein
5It is triethylsilyl.
18, a kind of preparation structural formula method that is the compound of (II):
Said method comprises that making oxygenant and structural formula is the compound reaction of (I):
Wherein
R
1Be hydrogen atom or the blocking group that is applicable to hydroxyl; And
R
2Be hydrogen atom or the blocking group that is applicable to hydroxyl.
19, the described method of claim 18, the wherein said blocking group of hydroxyl that is applicable to is selected from C
1-C
25Ether, C
1-C
25Substituent methyl ether, C
1-C
25Replacement ethyl ether, C
1-C
25Carboxyl groups, C
1-C
25Halo carboxyl groups, C
1-C
25Substituted benzyl ether, C
1-C
25Silicomethane ether, C
1-C
25Ester, C
1-C
25Carbonic ether and C
1-C
25Sulphonate.
20; the described method of claim 18; the wherein said blocking group of hydroxyl that is applicable to is selected from methyl; methoxyl methyl; Bian oxygen methyl; THP trtrahydropyranyl; tetrahydrofuran base; 2-(trimethyl silyl) ethoxymethyl alkyl dioxin; the 1-ethoxyethyl; 1-(2-chloroethoxy) ethyl; 2; 2; 2-three chloroethyls; the tertiary butyl; allyl group; propargyl; benzyl; to methoxybenzyl; diphenyl-methyl; trityl; trimethyl silyl; triethylsilyl; the triisopropyl silyl; diformazan sec.-propyl silyl; diethyl sec.-propyl silyl; dimethyl thexyl silyl; t-butyldimethylsilyl; tertiary butyl hexichol silyl; the tribenzyl silyl; the triphenyl silyl; the diphenyl methyl silyl; the benzyl manthanoate; the methyl carbonyl; the ethyl carbonyl; the methoxyl methyl carbonyl; the trichlorine ethoxy carbonyl; benzyloxycarbonyl group; benzyloxycarbonyl; the allyl alkylsulfonyl; methylsulfonyl, and p-toluenesulfonyl.
21, the described method of claim 18, wherein R
1It is triethylsilyl.
22, the described method of claim 18, wherein R
2It is ethanoyl.
23, the described method of claim 18, wherein said oxygenant were selected from ruthenic acid four n-propyl ammoniums, Collin reagent, PCC, PDC, CrO
2, activatory dimethyl sulfoxide (DMSO) (Swern reagent) and John reagent.
24, a kind of 9-dihydro-13-acetyl oar fruit Plant hormones regulators,gibberellins III is converted into the method for Taxane derivative, this method comprises removes the 9-dihydro-10-ethanoyl of 13-acetyl oar fruit Plant hormones regulators,gibberellins III and the step of oxidation C-9 and C-10 position.
25, the described method of claim 24, oxidation step is wherein finished by adding oxygenant, and this oxygenant was selected from ruthenic acid four n-propyl ammoniums, Collin reagent, PCC, PDC, CrO
2, activatory dimethyl sulfoxide (DMSO) (Swern reagent) and John reagent.
26, a kind of method for preparing taxol, Docetaxel and derivative thereof may further comprise the steps:
(a) with the C-7 position hydroxyl of the blocking group protection 9-dihydro that is fit to-13-acetyl oar fruit Plant hormones regulators,gibberellins III, obtain protected product;
(b) the 10-ethanoyl to protected product carries out deacetylation;
(c) C-9 of the protected product of oxidation and C-10 hydroxyl.
27, the described method of claim 26, wherein said blocking group is selected from benzyl, C
1-C
25Substituted benzyl, benzyl formic acid ester group, C
1-C
25Substituted benzyl formic acid ester group, tosyl group, the tosyl group of replacement, dihydro pyranyl, methoxyl methyl, benzoyl, C
1-C
25Substituted benzoyl, C
1-C
25Trimethyl silyl, 2-(trimethyl silyl) ethoxymethyl, benzyloxycarbonyl, triethylsilyl, triisopropyl silyl, diformazan sec.-propyl silyl, tertiary butyl hexichol silyl.
28, the described method of claim 26, oxidation step is wherein finished by adding oxygenant, and this oxygenant was selected from ruthenic acid four n-propyl ammoniums, Collin reagent, PDC, PCC, CrO
2,, the activatory dimethyl sulfoxide (DMSO).
29, the described method of claim 26, this method also comprises the step of C-13 position deacetylation.
30, the described method of claim 29, deacetylation step is wherein finished by adding highly basic, and this highly basic is selected from n-Butyl Lithium, CH
3Li, NaBH
4, red aluminium and hydrazine monohydrate.
31, the described method of claim 29, this method also comprises the step that the ketone of C-10 position is reduced to the C-10 hydroxyl.
32, the described method of claim 31, the step of C-10 ketone of wherein reducing is finished by adding reductive agent, and this reductive agent is selected from Pd/C, NaBH
4/ CeCl
3, LiAlH
4, and BINAP and (S)-alkyl propylene diamine (diam)-BINAP.
33, a kind ofly prepare the method that structural formula is 8 compound:
This method comprises with structural formula being the C-10 ketone step of reducing of 7 compound:
。
34, the described method of claim 33, the step of C-10 ketone of wherein reducing is finished by adding reductive agent, and this reductive agent is selected from Pd/C, NaBH
4/ CeCl
3, LiAlH
4, and BINAP and (S)-alkyl propylene diamine (diam)-BINAP.
35, the described method of claim 34, this method also comprise carries out deprotection and obtains the step that 10-takes off acetyl oar fruit Plant hormones regulators,gibberellins III the C-7 position.
36, the described method of claim 29, this method also are included in the C-13 position and add suitable side chain, reduction C-10 and carry out deprotection selectively to obtain the step of required product.
37, the described method of claim 36, deprotection wherein carries out C-7 and 2 ', to obtain taxol and Docetaxel.
38, the described method of claim 37, deprotection is wherein finished by adding deprotection agent, and this deprotection agent is selected from HCl, HF and the NaOCl of dilution.
39, the described method of claim 36, side chain wherein be selected from (2R, 3S)-N-benzoyl-O-(1-ethoxyethyl group)-3-phenylisoserine; (3R, 4S)-3-(1-ethoxy ethoxy)-4-(phenyl)-N-benzoyl-2-azetidinone; (2R, 3S)-N-boc-O-(1-ethoxyethyl group)-3-phenylisoserine and (3R, 4S)-3-(1-ethoxy ethoxy)-4-(phenyl)-N-boc-2-azetidinone.
40, the described method of claim 24, wherein said Taxane derivative is taxol or Docetaxel.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002549951A CA2549951A1 (en) | 2006-06-12 | 2006-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| CA2,549,951 | 2006-06-12 | ||
| US11/425,034 | 2006-06-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101528720A true CN101528720A (en) | 2009-09-09 |
Family
ID=38829282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800293778A Pending CN101528720A (en) | 2006-06-12 | 2007-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101528720A (en) |
| CA (1) | CA2549951A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964316A (en) * | 2012-11-14 | 2013-03-13 | 湖北一半天制药有限公司 | Radical protection method for synthesis of docetaxel |
| CN104592173A (en) * | 2014-12-31 | 2015-05-06 | 宁波绿之健药业有限公司 | Preparation method for synthesizing 10-DAB (10-deacetyl baccatin) III from 9-DHB (13-acetyl-9-dihydrobaccatin) III |
| CN114656427A (en) * | 2022-03-31 | 2022-06-24 | 上海健佑生物科技有限公司 | Taxol anticancer drug and synthesis method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2008288651A1 (en) * | 2007-08-22 | 2009-02-26 | 6570763 Canada Inc. | Process for converting 9-dihydro-13-acetylbaccatin III into docetaxel or paclitaxel |
-
2006
- 2006-06-12 CA CA002549951A patent/CA2549951A1/en not_active Abandoned
-
2007
- 2007-06-12 CN CNA2007800293778A patent/CN101528720A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964316A (en) * | 2012-11-14 | 2013-03-13 | 湖北一半天制药有限公司 | Radical protection method for synthesis of docetaxel |
| CN104592173A (en) * | 2014-12-31 | 2015-05-06 | 宁波绿之健药业有限公司 | Preparation method for synthesizing 10-DAB (10-deacetyl baccatin) III from 9-DHB (13-acetyl-9-dihydrobaccatin) III |
| CN114656427A (en) * | 2022-03-31 | 2022-06-24 | 上海健佑生物科技有限公司 | Taxol anticancer drug and synthesis method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2549951A1 (en) | 2007-12-12 |
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Application publication date: 20090909 |