WO2002012220A2 - Process for preparing discodermolide and analogues thereof - Google Patents
Process for preparing discodermolide and analogues thereof Download PDFInfo
- Publication number
- WO2002012220A2 WO2002012220A2 PCT/EP2001/009068 EP0109068W WO0212220A2 WO 2002012220 A2 WO2002012220 A2 WO 2002012220A2 EP 0109068 W EP0109068 W EP 0109068W WO 0212220 A2 WO0212220 A2 WO 0212220A2
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- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- compound
- hydroxyl protecting
- acid labile
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 6
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 title abstract description 21
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- -1 ketone compound Chemical class 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 239000003495 polar organic solvent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 238000007273 lactonization reaction Methods 0.000 claims description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 2
- 150000000185 1,3-diols Chemical class 0.000 claims 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 102000004243 Tubulin Human genes 0.000 description 7
- 108090000704 Tubulin Proteins 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- 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 description 7
- 102000029749 Microtubule Human genes 0.000 description 6
- 108091022875 Microtubule Proteins 0.000 description 6
- 210000004688 microtubule Anatomy 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229960005499 (+)-discodermolide Drugs 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C(**)C(C)C(N(*)O*)=O)C(C*)=O Chemical compound CC(C(**)C(C)C(N(*)O*)=O)C(C*)=O 0.000 description 1
- RFJYFQBYOLOEPX-UHFFFAOYSA-N CCN(C(C(C)C(C(C)C(C)=O)O)=O)OCC Chemical compound CCN(C(C(C)C(C(C)C(C)=O)O)=O)OCC RFJYFQBYOLOEPX-UHFFFAOYSA-N 0.000 description 1
- 241001290275 Discodermia dissoluta Species 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000036815 beta tubulin Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- PSEHHVRCDVOTID-YYNWCRCSSA-N chloro-bis[(1r,3s,4r,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@@H]([C@H]1C)B(Cl)[C@H]2C[C@@H]3C[C@@H](C3(C)C)[C@@H]2C)[C@H]2C(C)(C)[C@@H]1C2 PSEHHVRCDVOTID-YYNWCRCSSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 150000003881 polyketide derivatives Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to a process for preparing discodermolide and analogues thereof, to novel compounds utilized in the process and to novel compounds prepared by the process.
- (+)-Discodermolide is a novel polyketide natural product that was isolated from extracts of the marine sponge Discodermolide dissoluta by researchers at the Harbor Branch Oceanographic Institution (HBOI) (Gunasekera SP, Gunasekera M, Longley RE, Schulte GK. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta. [published erratum appears in J. Org. Chem. 1991;56:1346]. J. Org. Chem. 1990;55:4912-15.).
- HBOI Harbor Branch Oceanographic Institution
- Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. In fact, of the handful of compounds known to induce polymerization of purified tubulin, discodermolide is the most potent. However, microtubules, a major structural component in cells, are not simple equlibrium polymers of tubulin. They exist as regulated GTP-driven dynamic assemblies of heterodimers of ⁇ and ⁇ tubulin.
- the dynamics are relatively slow in interphase cells, upon entering mitosis, the rate of growing and shortening increases 20 to 100-fold — the average microtubule turns over half the tubulin subunits every ten seconds.
- This change in rate allows the cytoskeletal microtubule network to dismantle and a bipolar spindle-shaped array of microtubules to assemble.
- the spindle attaches to chromosomes and moves them apart.
- the response to complete suppression of microtubule dynamics in cells is death.
- mitotic cells are more sensitive and the tolerance threshold appears to be cell-type specific.
- Molecules like paclitaxel that bind with high affinity to microtubules disrupt the dynamics process in tumor cells with lethal results even when the ratio of bound drug to tubulin is very low.
- Discodermolide binds to tubulin competitively with paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders.
- discodermolide or structurally related analogues are hindered by the lack of a reliable natural source of the compound or a feasible synthetic route.
- Naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. Accordingly, there is an ever-growing need for improved syntheses which enable the preparation of commercially acceptable quantities of discodermolide and structurally related analogues.
- the present invention relates to a more practical synthesis of discodermolide and analogues thereof.
- the instant invention relates to novel compounds useful in the preparation of discodermolide and analogues thereof.
- the instant invention relates to novel compounds which are prepared by the process of the instant invention.
- the essence of the instant invention is the discovery of a more practical synthesis for discodermolide and analogues thereof. More particularly, it has been discovered that discodermolide and analogues thereof can be prepared by a three-step reaction as follows: STEP1
- Ri is (C ⁇ ) alkyl, benzyl or an acid labile hydroxyl protecting group
- R 2 is (C]. 6 ) alkyl or benzyl
- R 3 is hydrogen, (C . 6 ) alkyl, benzyl, C(O)(CM 2 ) alkyl, C(O)Ph, 0(0)0(0 ⁇ 2 ) alkyl, C(O)OPh, C(O)NH(C ⁇ - ⁇ 2 ) alkyl, C(O)NHPh or an acid labile hydroxyl protecting group
- R 3 " is an acid labile hydroxyl protecting group
- R 4 is hydrogen or methyl
- X is O, NH, NCH 3 , S or CH 2 , with the proviso that when X is O and R 3 is an acid labile hydroxyl protecting group in the compound of formula I, the "-X-R 3 " moiety in the compound of formula V is -OH.
- Step 1 involves the coupling of a ketone compound of formula I with an aldehyde compound of formula II via an aldol reaction to obtain a ⁇ - hydroxyketone compound of formula III.
- the coupling is conveniently carried out with between 1 and 20, preferably between 5 and 15, equivalents of the ketone compound of formula I relative to the aldehyde compound of formula II.
- the coupling is conducted in the presence of: 1) a dialkylboron halide or triflate, preferably a chiral boron chloride or triflate, more preferably ⁇ -chlorodiisopinocamphenylborane; 2) a base, preferably an amine, more preferably triethylamine; and 3) a polar organic solvent, preferably an ether, more preferably diethyl ether, at a temperature of between - 100 9 C and 20 9 C, preferably between -78 9 C and -20 9 C, for a period of between 2 and 72 hours, preferably for 16 hours.
- a dialkylboron halide or triflate preferably a chiral boron chloride or triflate, more preferably ⁇ -chlorodiisopinocamphenylborane
- a base preferably an amine, more preferably triethylamine
- 3) a polar organic solvent preferably an ether, more preferably
- Step 2 concerns the reduction of the ⁇ -hydroxy ketone compound of formula III and, more particularly, the ketone group common to such compounds, to obtain a 1 ,3-diol compound of formula IV.
- the reduction is conducted in the presence of: 1) a ketone reducing agent, preferably a borohydride such as tetramethylammonium triacetoxyborohydride; 2) a polar organic solvent, preferably acetonitrile; and 3) a protic solvent, preferably a carboxylic acid, such as acetic acid, at a temperature of between 78 9 C and 20 9 C, preferably between -40 9 C and -10 9 C, for a period of between 2 and 72 hours, preferably for 16 hours.
- a ketone reducing agent preferably a borohydride such as tetramethylammonium triacetoxyborohydride
- a polar organic solvent preferably acetonitrile
- a protic solvent preferably a carboxylic acid, such as
- Step 3 it involves the lactonization and deprotection of the acid labile hydroxyl protecting groups of a compound of formula IV to obtain a compound of formula V.
- the lactonization and deprotection reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20 9 C and 40 9 C, preferably between 20 9 C and 25 9 C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
- a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
- the instant invention relates to the novel ketone compounds of formula I:
- Ri is (C ⁇ . 6 ) alkyl, benzyl, or an acid labile hydroxyl protecting group
- R 2 is (Ci-e) alkyl, or benzyl
- R 3 is hydrogen, (C ⁇ - 6 ) alkyl, benzyl, C(0)(CM 2 ) alkyl, C(O)Ph, 0(0)0(0 ! . 12 )alkyl, C(O)OPh, C(0)NH(CM2)alkyl, C(O)NHPh, or an acid labile hydroxyl protecting group;
- R 4 is hydrogen or methyl;
- X is O, NH, NCH 3) S or CH 2 .
- Preferred compounds are those of formula la:
- R and R 2 ' is (Ci-e) alkyl
- X is O, or CH 2 ; and R 3 and R 4 are as defined above.
- More preferred compounds are those of formula lb:
- R 3 ' is (d ⁇ alkyl, CfOXC M ⁇ alkyl, benzyl, C ⁇ Ofd. ⁇ alkyl, or an acid labile hydroxyl protecting group; and Ri' and R ' are as defined above.
- R 3 " is an acid labile hydroxyl protecting group.
- (C ⁇ - 6 ) alkyl refers to a straight or branched chain group consisting solely of carbon and hydrogen and having from 1 to 6 carbon atoms
- (CM 2 ) alkyl refers to a straight or branched chain group consisting solely of carbon and hydrogen and having from 1 to 12 carbon atoms
- alkyl groups include methyl, ethyl, propyl, butyl, pentyl, 3- methylpentyl, etc.
- acid labile hydroxyl protecting groups refers to any oxygen bound group that can be removed upon exposure to an acid. Numerous examples of these groups are known by those skilled in the art and can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley & Sons, New York, 1991. Specific examples include, but are not limited to, f-butyldimethylsilyl, triethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, and tetrahydropyranyl.
- the instant invention relates to a process for preparing the novel compounds of formula I. More particularly, the compounds of formula I may be prepared as depicted below:
- Step A involves the addition of a methyl or ethyl group to an aldehyde compound of formula VI to obtain an alcohol compound of formula VII.
- the addition is carried out in the presence of: 1 ) an organometallic reagent, preferably an alkyllithium or alkylmagnesium halide such as methylmagnesium bromide; and 2) a polar organic solvent, preferably an ether such as diethyl ether, at a temperature of between - 78 9 C and 40 9 C, preferably at -78 9 C and 0 9 O, more preferably at about -40 9 O, for a period of between 5 minutes and 24 hours, preferably between 30 minutes and 2 hours, more preferably for about 1 hour.
- an organometallic reagent preferably an alkyllithium or alkylmagnesium halide such as methylmagnesium bromide
- a polar organic solvent preferably an ether such as diethyl ether
- Step B involves the oxidation of an alcohol compound of formula VII to obtain the desired ketone compound of formula I.
- the oxidation is carried out in the presence of: 1) an oxidant, preferably a combination of dimethylsulfoxide and an activating agent, more preferably a combination of dimethylsulfoxide and sulfur trioxide complex with pyridine; 2) a base, preferably an organic base, more preferably a trialkylamine such as triethylamine; and 3) a polar organic solvent, preferably a chlorinated hydrocarbon such as dichloromethane.
- an oxidant preferably a combination of dimethylsulfoxide and an activating agent, more preferably a combination of dimethylsulfoxide and sulfur trioxide complex with pyridine
- a base preferably an organic base, more preferably a trialkylamine such as triethylamine
- a polar organic solvent preferably a chlorinated hydrocarbon such as dichloromethane.
- the oxidation is suitably carried out a temperature of between -78 9 C and 40 9 C, preferably between 5 9 C and 20 9 C, for a period of between 5 minutes and 24 hours, preferably between 1 hour and 12 hours, more preferably between 4 and 6 hours.
- aldehyde compounds of formulae II and VI are either known or may be prepared analogous to processes set forth in the literature for other structurally similar aldehydes.
- the instant invention relates to the novel ⁇ -hydroxy- ketone compounds of formula III and the novel 1 ,3-diol compounds of formula IV.
- the solution is then diluted with 200 mL of ether, and then extracted successively with 200 mL of a 1 M sodium hydrogen sulfate solution and 200 mL of brine.
- the organic layer is then dried over sodium sulfate and the crude product mixture is purified by flash chromatography employing hexane as the eluent initially and then an eluent mixture of 5% ethyl acetate in hexane to yield the desired compound as a clear oil.
- the mixture is then washed with 100 mL of 1 M sodium hydrogen sulfate solution and partitioned with two 150 mL portions of ether. The organic layers are then combined and dried over sodium sulfate.
- the crude product mixture is then chromatographed employing an eluent mixture of 20 % ethyl acetate in hexane initially and then an eluent mixture of 40% ethyl acetate in hexane to yield two diastereomers as light yellow oils which are used in the next step without further purification.
- the reaction is then quenched with 8 mL of methanol (the pH of which is adjusted to 7 with 12 mL of buffer solution) and 4 mL of 50% hydrogen peroxide solution at 0 9 C. After stirring for 2 hours at 25 9 C, the organic layers are separated. The aqueous layer is then extracted five times with 25 mL portions of dichloromethane. The combined organic layers are then dried over magnesium sulfate, concentrated using a rotary evaporator and chromatographed (Biotage, silica gel, gradient 10- 30% ethyl acetate/hexane) to yield the desired compound as a colorless, highly viscous oil.
- the mixture is then allowed to warm slowly to ambient temperature, after which it is diluted with methylene chloride and washed with saturated sodium bicarbonate.
- the aqueous layer is then extracted four times with methylene chloride.
- the combined organic layers are then washed with brine, dried with sodium sulfate and concentrated in vacuo.
- the resultant residue is then purified by flash chromatography (Biotage, silica gel, gradient 10-30% ethyl acetate/hexane) to yield the desired compound as a white solid.
- aqueous layer is then extracted three times with 30 mL portions of ethyl acetate, and the combined extracts are dried over sodium sulfate. Filtration and concentration followed by flash chromatography employing an eluent mixture of 50% methylene chloride in ethyl acetate initially and then 100% ethyl acetate yields (+)- discodermolide.
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Abstract
Description
Claims
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
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HU0300742A HUP0300742A3 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
SK156-2003A SK1562003A3 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
SI200130625T SI1309583T1 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
KR1020037001704A KR100796396B1 (en) | 2000-08-07 | 2001-08-06 | Process for Preparing Discodermolide and Analogues Thereof |
MXPA03001192A MXPA03001192A (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof. |
NZ523999A NZ523999A (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
BR0112876-0A BR0112876A (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and its analogs |
AU9372601A AU9372601A (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
DE60120991T DE60120991T2 (en) | 2000-08-07 | 2001-08-06 | PROCESS FOR PREPARING DISCODERMOLIDES AND SIMILAR COMPOUNDS |
PL01358839A PL358839A1 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
AU2001293726A AU2001293726B2 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
EP01974118A EP1309583B1 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
JP2002518197A JP2004505963A (en) | 2000-08-07 | 2001-08-06 | Method for producing discodermolide and its analogues |
CA002416769A CA2416769C (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
IL15410901A IL154109A0 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
IL154109A IL154109A (en) | 2000-08-07 | 2003-01-23 | Process for preparing discodermolide and analogues thereof |
NO20030587A NO328365B1 (en) | 2000-08-07 | 2003-02-06 | Process for the preparation of discodermolide and analogs thereof |
HK03108266A HK1055962A1 (en) | 2000-08-07 | 2003-11-13 | Process for preparing discodermolide and analoguesthereof |
CY20061101284T CY1105338T1 (en) | 2000-08-07 | 2006-09-07 | PROCEDURE FOR THE PREPARATION OF DISCODEPMOLIDE AND ITS ANALOGS |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63375300A | 2000-08-07 | 2000-08-07 | |
US09/633,753 | 2000-08-07 |
Publications (2)
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WO2002012220A2 true WO2002012220A2 (en) | 2002-02-14 |
WO2002012220A3 WO2002012220A3 (en) | 2002-06-13 |
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PCT/EP2001/009068 WO2002012220A2 (en) | 2000-08-07 | 2001-08-06 | Process for preparing discodermolide and analogues thereof |
Country Status (30)
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EP (1) | EP1309583B1 (en) |
JP (1) | JP2004505963A (en) |
KR (1) | KR100796396B1 (en) |
CN (1) | CN1293067C (en) |
AR (1) | AR032761A1 (en) |
AT (1) | ATE330948T1 (en) |
AU (2) | AU9372601A (en) |
BR (1) | BR0112876A (en) |
CA (1) | CA2416769C (en) |
CY (1) | CY1105338T1 (en) |
CZ (1) | CZ300855B6 (en) |
DE (1) | DE60120991T2 (en) |
DK (1) | DK1309583T3 (en) |
EC (1) | ECSP034459A (en) |
ES (1) | ES2266266T3 (en) |
HK (1) | HK1055962A1 (en) |
HU (1) | HUP0300742A3 (en) |
IL (2) | IL154109A0 (en) |
MX (1) | MXPA03001192A (en) |
MY (1) | MY127609A (en) |
NO (1) | NO328365B1 (en) |
NZ (1) | NZ523999A (en) |
PE (1) | PE20020263A1 (en) |
PL (1) | PL358839A1 (en) |
PT (1) | PT1309583E (en) |
RU (1) | RU2283309C2 (en) |
SK (1) | SK1562003A3 (en) |
TW (1) | TWI251591B (en) |
WO (1) | WO2002012220A2 (en) |
ZA (1) | ZA200300590B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004009574A1 (en) * | 2002-07-22 | 2004-01-29 | Novartis Ag | Synthesis of discodermolide |
WO2004022552A1 (en) * | 2002-09-06 | 2004-03-18 | University Of Pittsburgh | Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof |
US7214708B2 (en) | 2004-11-18 | 2007-05-08 | Kosan Biosciences Incorporated | Synthetic discodermolide analogs |
US7321046B2 (en) | 2002-09-06 | 2008-01-22 | University Of Pittsburgh | Analogs of dictyostatin, intermediates therefor and methods of synthesis thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991001982A1 (en) * | 1989-08-11 | 1991-02-21 | Harbor Branch Oceanographic Institution, Inc. | Discodermolide compounds, compositions containing same and methods of preparation and use |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9315802D0 (en) * | 1993-07-30 | 1993-09-15 | Roussel Lab Ltd | Chemical compounds |
US5789605A (en) * | 1996-12-03 | 1998-08-04 | Trustees Of The University Of Pennsylvania | Synthetic techniques and intermediates for polyhydroxy, dienyl lactones and mimics thereof |
US6096904A (en) * | 1996-12-03 | 2000-08-01 | The Trustees Of The University Of Pennsylvania | Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives |
WO1998048791A1 (en) * | 1997-04-30 | 1998-11-05 | The Regents Of The University Of California | Synthesis of discodermolide and analogs |
GB0101599D0 (en) * | 2001-01-22 | 2001-03-07 | Novartis Ag | Organic compounds |
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2001
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- 2001-08-06 KR KR1020037001704A patent/KR100796396B1/en not_active IP Right Cessation
- 2001-08-06 AU AU2001293726A patent/AU2001293726B2/en not_active Ceased
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2003
- 2003-01-22 ZA ZA200300590A patent/ZA200300590B/en unknown
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991001982A1 (en) * | 1989-08-11 | 1991-02-21 | Harbor Branch Oceanographic Institution, Inc. | Discodermolide compounds, compositions containing same and methods of preparation and use |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004009574A1 (en) * | 2002-07-22 | 2004-01-29 | Novartis Ag | Synthesis of discodermolide |
WO2004022552A1 (en) * | 2002-09-06 | 2004-03-18 | University Of Pittsburgh | Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof |
US7122686B2 (en) | 2002-09-06 | 2006-10-17 | University Of Pittsburgh | Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof |
US7321046B2 (en) | 2002-09-06 | 2008-01-22 | University Of Pittsburgh | Analogs of dictyostatin, intermediates therefor and methods of synthesis thereof |
US7968736B2 (en) | 2002-09-06 | 2011-06-28 | University of Pittsburgh—of the Commonwelth Systems of Higher Education | Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof |
US7214708B2 (en) | 2004-11-18 | 2007-05-08 | Kosan Biosciences Incorporated | Synthetic discodermolide analogs |
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