JP6810693B2 - カンタリジンおよび生理活性カンタリジン誘導体の商業的に実現可能な合成 - Google Patents
カンタリジンおよび生理活性カンタリジン誘導体の商業的に実現可能な合成 Download PDFInfo
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- JP6810693B2 JP6810693B2 JP2017532657A JP2017532657A JP6810693B2 JP 6810693 B2 JP6810693 B2 JP 6810693B2 JP 2017532657 A JP2017532657 A JP 2017532657A JP 2017532657 A JP2017532657 A JP 2017532657A JP 6810693 B2 JP6810693 B2 JP 6810693B2
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- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 title claims description 124
- 229930008397 cantharidin Natural products 0.000 title claims description 88
- 229940095758 cantharidin Drugs 0.000 title claims description 87
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 title claims description 87
- 230000015572 biosynthetic process Effects 0.000 title description 27
- 238000003786 synthesis reaction Methods 0.000 title description 26
- 230000000975 bioactive effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 177
- 238000006243 chemical reaction Methods 0.000 claims description 99
- 238000000034 method Methods 0.000 claims description 75
- 239000002841 Lewis acid Substances 0.000 claims description 53
- 150000007517 lewis acids Chemical class 0.000 claims description 53
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 41
- 238000006477 desulfuration reaction Methods 0.000 claims description 24
- 230000023556 desulfurization Effects 0.000 claims description 24
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 24
- 238000005984 hydrogenation reaction Methods 0.000 claims description 23
- 239000007868 Raney catalyst Substances 0.000 claims description 20
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 20
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 20
- 239000003638 chemical reducing agent Substances 0.000 claims description 19
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 14
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 13
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- UVMKWDWODUTHAV-UHFFFAOYSA-N cyclopentane;titanium(2+) Chemical compound [Ti+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1 UVMKWDWODUTHAV-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 0.000 claims description 9
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- 229910052759 nickel Inorganic materials 0.000 claims description 6
- ARUXRBUQJOYABI-UHFFFAOYSA-L cyclopentane;titanium(2+);trifluoromethanesulfonate Chemical compound [Ti+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F ARUXRBUQJOYABI-UHFFFAOYSA-L 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- OFTAVORSNHLQHT-UHFFFAOYSA-L cyclopentane;oxolane;trifluoromethanesulfonate;zirconium(2+) Chemical compound [Zr+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.C1CCOC1.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F OFTAVORSNHLQHT-UHFFFAOYSA-L 0.000 claims description 3
- CFKRLDXQSIPSFB-UHFFFAOYSA-N oxolane;trifluoromethanesulfonic acid Chemical compound C1CCOC1.OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F CFKRLDXQSIPSFB-UHFFFAOYSA-N 0.000 claims description 3
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- UFYRWFCDYKWHJS-UHFFFAOYSA-N cyclopentane;zirconium(2+) Chemical compound [Zr+2].[CH]1[CH][CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1 UFYRWFCDYKWHJS-UHFFFAOYSA-N 0.000 claims 2
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- RHWXXFCIPRZHCO-UHFFFAOYSA-K CS(=O)(=O)[O-].[B+3].CS(=O)(=O)[O-].CS(=O)(=O)[O-] Chemical compound CS(=O)(=O)[O-].[B+3].CS(=O)(=O)[O-].CS(=O)(=O)[O-] RHWXXFCIPRZHCO-UHFFFAOYSA-K 0.000 claims 1
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 24
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- 201000005884 exanthem Diseases 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
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- 239000003673 groundwater Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000001771 hobnail hemangioma Diseases 0.000 description 1
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- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical compound [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
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- 201000002597 ichthyosis vulgaris Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- 150000003891 oxalate salts Chemical class 0.000 description 1
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- NTCFJVDQPLISRK-UHFFFAOYSA-N oxolane;trifluoromethanesulfonic acid Chemical compound C1CCOC1.OS(=O)(=O)C(F)(F)F NTCFJVDQPLISRK-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 150000003141 primary amines Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
Landscapes
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- Life Sciences & Earth Sciences (AREA)
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- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Description
本願は、参照によってその全体が本明細書に完全に組み込まれる2014年12月17日に出願された米国仮特許出願第62/093,396号明細書の利益を主張する。
(b)第1の化合物から、式(2)を有する第2の化合物:
(c)第2の化合物に対して環化付加反応を実施して、式(3)を有する第3の化合物:
(d)第3の化合物から、カンタリジンまたはその誘導体を産生することと
を含むプロセスを提供する。
本明細書に提供する側面のいくつかの態様では、該プロセスは、式(5)を有する第5の化合物:
本明細書に提供する側面のいくつかの態様では、該プロセスは、式(6)を有する第6の化合物:
本明細書に提供する側面のいくつかの態様では、該プロセスは、式(7)を有する第7の化合物:
本明細書に提供する側面のいくつかの態様では、該プロセスは、式(8)を有する第8の化合物:
Na2S (8)
から、第6の化合物を産生することをさらに含む。
本明細書に提供する側面のいくつかの態様では、該プロセスは、式(9)を有する第9の化合物:
本明細書に提供する側面のいくつかの態様では、(b)は、第1の化合物を脱水反応にかけることを含む。本明細書に提供する側面のいくつかの態様では、該脱水反応は、第1の化合物をハロゲン化アシルに曝露させることを含む。本明細書に提供する側面のいくつかの態様では、ハロゲン化アシルは、塩化アセチルである。本明細書に提供する側面のいくつかの態様では、(c)は、第2の化合物を少なくとも1種のルイス酸に曝露させることを含む。本明細書に提供する側面のいくつかの態様では、該少なくとも1種のルイス酸は、表1から選択される。本明細書に提供する側面のいくつかの態様では、該少なくとも1種のルイス酸は、Li(I)、Mg(II)、B(III)、Al(III)、Ti(IV)、Zr(IV)、Zn(II)、Cu(I)、Cu(II)、Sn(II)、Sn(IV)、Si(IV)、La(III)、Sc(III)、Yb(III)、Eu(III)、Ga(III)、Sb(V)、Nb(V)、Fe(III)、およびCo(III)からなる群から選択されるルイス金属を含有する。本明細書に提供する側面のいくつかの態様では、該少なくとも1種のルイス酸は、過塩素酸マグネシウム、塩化アルミニウム、トリフルオロメタンスルホン酸リチウム、トリフルオロメタンスルホン酸スズ(II)、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体、ビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)、三フッ化ホウ素ジエチルエーテル、および塩化ガリウム(III)から選択される。本明細書に提供する側面のいくつかの態様では、該少なくとも1種のルイス酸は、テトラフルオロホウ酸銅(II)水和物、臭化アルミニウム、塩化ニオブ(V)、トリフルオロメタンスルホン酸イッテルビウム(III)、トリフルオロメタンスルホン酸スカンジウム(III)、トリフルオロメタンスルホン酸マグネシウム、トリフルオロメタンスルホン酸トリメチルシリル、およびトリフルオロメタンスルホン酸銅(II)から選択される。本明細書に提供する側面のいくつかの態様では、(c)は、第2の化合物をフランと反応させることを含む。本明細書に提供する側面のいくつかの態様では、(d)は、第3の化合物を還元反応にかけることを含む。本明細書に提供する側面のいくつかの態様では、該還元反応は、単一の還元剤を使用して実施される水素化および脱硫反応を含む。本明細書に提供する側面のいくつかの態様では、該単一の還元剤は、ラネーニッケルである。本明細書に提供する側面のいくつかの態様では、該還元反応は、別々の還元剤を使用して実施される水素化および脱硫反応を含む。本明細書に提供する側面のいくつかの態様では、該水素化反応は、Pd/C、Pd、PdCl2、PtO2、またはPt/Cを使用して実施される。本明細書に提供する側面のいくつかの態様では、脱硫反応は、表2から選択される還元剤を使用して実施される。本明細書に提供する側面のいくつかの態様では、該還元剤は、ラネーニッケルである。本明細書に提供する側面のいくつかの態様では、該還元反応は、式(10)を有する第10の化合物:
本明細書に提供する側面のいくつかの態様では、該水素化反応は、Pd/C、Pd、PdCl2、PtO2、またはPt/Cを使用して実施される。本明細書に提供する側面のいくつかの態様では、該プロセスは、第10の化合物を酸化反応にかけることをさらに含む。本明細書に提供する側面のいくつかの態様では、該酸化反応は、表3から選択される少なくとも1種の酸化剤を使用して実施される。本明細書に提供する側面のいくつかの態様では、(d)は、第3の化合物を酸化反応にかけることを含む。本明細書に提供する側面のいくつかの態様では、該酸化反応は、表3から選択される少なくとも1種の酸化剤を使用して実施される。本明細書に提供する側面のいくつかの態様では、該誘導体は、以下:
(a)式(1)の第1の化合物:
(b)第1の化合物を、NaOHを使用して実施される加水分解反応にかけることによって、第1の化合物から、式(2)を有する第2の化合物:
(a)式(1)の第1の化合物:
(b)第1の化合物を、該式(1)の化合物をハロゲン化アシルに曝露させることを含む脱水反応にかけることによって、第1の化合物から、式(2)を有する第2の化合物:
(a)式(1)の第1の化合物:
を提供することと;
(b)第1の化合物から、該第1の化合物を、表1、過塩素酸マグネシウム、塩化アルミニウム、トリフルオロメタンスルホン酸リチウム、トリフルオロメタンスルホン酸スズ(II)、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体、ビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)、三フッ化ホウ素ジエチルエーテル、塩化ガリウム(III)、テトラフルオロホウ酸銅(II)水和物、臭化アルミニウム、塩化ニオブ(V)、トリフルオロメタンスルホン酸イッテルビウム(III)、トリフルオロメタンスルホン酸スカンジウム(III)、トリフルオロメタンスルホン酸マグネシウム、トリフルオロメタンスルホン酸トリメチルシリル、およびトリフルオロメタンスルホン酸銅(II)からなる群から選択される少なくとも1種のルイス酸に曝露させることを含む環化付加反応にかけることによって、第1の化合物から、式(2)を有する第2の化合物:
を形成すること。
(a)以下のいずれか1つから選択される第1の化合物を提供することと:
(a)式(1)または(2)の化合物:
(b)式(1)または(2)の化合物から、該式(1)または(2)の化合物を酸化反応にかけることによって、以下
(a)以下
(b)(a)で提供された化合物から、該(a)で提供された化合物を酸化反応にかけることによって、以下
この明細書で言及したすべての刊行物、特許、および特許出願を、まるで、それぞれ個々の刊行物、特許、および特許出願が参照によって組み込まれることが具体的にかつ個々に示された場合と同じ程度まで、参照によって本明細書に組み込む。
カンタリジンまたはその誘導体を調製するためのプロセスは、化合物(1)を提供することと、化合物(1)から化合物(2)を産生することを含む。
Na2S (9)
反応時間は、30秒、1分、5分、10分、30分、1時間、2時間、3時間、4時間、または5時間以上であり得る。反応は、還流させることができる。
高品質の生成物、および合成スケールアップを容易にする向上した収率を提供するために、向上した収率および向上した純度で、化合物(2)を調製する。
このプロセスは、化合物(2)のフランとのディールス・アルダー反応を含む。この反応が、過塩素酸リチウムまたはリチウムトリフルオロメタンスルホンイミド以外の多くのルイス酸によって促進されることは、予想外である。Griecoの研究は、この特定の環化付加反応のための触媒としての過塩素酸リチウムの使用の独自性を暗示する。本発明者らは、低レベルの望ましくないエンド異性体と共に高収率の環化付加物(3)を与えるようにこの反応を触媒し、かつ、リチウムトリフルオロメタンスルホンイミドプロセスに対する有意な改善を提供することができる、いくつかのルイス酸(表1参照)を特定する。これらの代替ルイス酸は、Griecoによって記載されたジエチルエーテル/過塩素酸リチウム系の不利益を被らない。これらのルイス酸は、Li(I)、Mg(II)、B(III)、Al(III)、Ti(IV)、Zr(IV)、Zn(II)、Cu(I)、Cu(II)、Sn(II)、Sn(IV)、Si(IV)、La(III)、Sc(III)、Yb(III)、Eu(III)、Ga(III)、Sb(V)、Nb(V)、Fe(III)、およびCo(III)からなる群から選択されるルイス金属を含有することができる。これらのルイス酸は、表1から選択することができる。これらのルイス酸は、過塩素酸マグネシウム、塩化アルミニウム、トリフルオロメタンスルホン酸リチウム、トリフルオロメタンスルホン酸スズ(II)、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体、ビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)、三フッ化ホウ素ジエチルエーテル、および塩化ガリウム(III)から選択することができる。これらのルイス酸は、テトラフルオロホウ酸銅(II)水和物、臭化アルミニウム、塩化ニオブ(V)、トリフルオロメタンスルホン酸イッテルビウム(III)、トリフルオロメタンスルホン酸スカンジウム(III)、トリフルオロメタンスルホン酸マグネシウム、トリフルオロメタンスルホン酸トリメチルシリル、およびトリフルオロメタンスルホン酸銅(II)から選択することができる。
bisoxa=
fod=
、NTf2=[(CF3SO2)2N]−であり、−OTf=CF3SO3 −であり、Tf=CF3SO2である。
(3)からのカンタリジンの合成の最終ステップは、炭素−炭素二重結合の還元、および脱硫を含む。オレフィンの単一ステップ還元を、およびラネーニッケルを用いる脱硫を使用する(3)のカンタリジンへの直接的転換のための元々のDauben手順は、生産規模での高収率かつ安定した収量のカンタリジンを与えるラネーニッケル触媒の安定した生成を含む特有の困難を被っている。このステップに伴う1つの主な問題点は、合成における後期段階での生成物の深刻な喪失をもたらす逆−ディールス・アルダー反応を直ちに受けることができる不安定なオレフィン(19)の産生であり得る。本発明者らは、脱硫前のオレフィン水素化遅延に起因する喪失を最小限にする、特定の市販品として入手可能なラネーニッケル触媒を特定する。
これらの記載した手順を使用して、生理活性を有することができるカンタリジン誘導体およびカンタリジン類似体を作製することもできる。これらの分子としては、限定はされないが、硫化物(3)および(10);そのそれぞれのスルホキシド誘導体(11)、(12)、(14)、および(15);ならびにそのそれぞれのスルホン誘導体(13)および(16)が挙げられる。表3に列挙した試薬の少なくとも1種を用いる、(3)もしくは(10)またはこれらの混合物の酸化によって、スルホキシド(αまたはβ異性体)(11)、(12)、(14)、および(15)またはスルホン(13)および(16)またはこれらの混合物の少なくとも1種を得ることができる。表3に列挙した試薬の少なくとも1種を用いる、少なくとも1種の(11),(12),(14)、および(15)またはこれらの混合物の酸化は、スルホン(13)および(16)の少なくとも1種を得ることができる。これらの硫化物、スルホキシド、およびスルホン誘導体は、生物活性であり得る。これらの硫化物、スルホキシド、およびスルホン誘導体は、医薬的に許容され得る。これらの硫化物、スルホキシド、およびスルホン誘導体は、医薬的に許容し得る塩であり得る。
ステップ1についての実験方法:クロロメチルトリメチルシラン(50.0g、407.5ミリモル(mmol))とヨウ化テトラブチルアンモニウム(7.52g、20.3mmol)を、硫化ナトリウム水和物(23.1g、203.5mmol)を100mLの水に入れた水溶液に添加する。この混合物を、還流温度で5時間攪拌し、次いで、室温に冷却する。有機層を分離し、水層をMTBE(2×50mL)で抽出する。合わせた溶液を、MgSO4で乾燥させ、濾過し、減圧下で濃縮する。淡黄色の油としてもたらされた未精製生成物(7)を、さらなる精製を行わずに次のステップに直接用いる(40g、95%)。
ステップ2についての実験方法:DCM(15vol)に入れた化合物(7)(30g、145.2mmol)を、−78℃に冷却する。DCM(5vol)に入れたm−CPBA(分子ふるい4Aで予備乾燥済み)を、ゆっくりと添加する。この混合物を、−78℃で1時間攪拌する。出発材料の消失を、TLC分析により確認し、混合物を0℃に温める。混合物を、飽和NaHCO3の氷冷溶液に添加し、層を分離する。有機層をMgSO4で乾燥させ、濾過し、5〜10℃浴温にて減圧下で濃縮して、スルホキシド生成物(5)を定量的に得る。この未精製生成物を、精製を行わずに次のステップに直接用いる。
ステップ3についての実験方法:化合物(5)(32.0g、145.6mmol)とアセチレンジカルボン酸ジメチル(10.34g、72.8mmol)との混合物(DMPU(1vol)中)を、100℃で、あらかじめ加熱したDMPUの溶液に添加する。得られた混合物を、100℃で30分間攪拌し、次いで、氷水(250g)に注ぐ。混合物をジクロロメタン(500mL)で抽出し、MgSO4で乾燥させ、濾過し、減圧下で濃縮する。この未精製材料を、カラムクロマトグラフィーによって精製して、淡黄色の油としてエステル(4)(8.5g、60.0%)を得る。
ステップ4についての実験方法:化合物(4)(8.5g、42mmol)を、THFと水(85mL、10vol)の1:1混合物に溶解する。NaOH(6.73g、168.3mmol)を室温で添加し、得られた混合物を室温で4時間攪拌する。TLCによって出発材料の消失を確認した後、混合物をMTBEで2回洗浄して、未反応の材料および不純物を除去する。水溶液のpHを、1N HCl溶液で〜4に調整し、酢酸エチル(2×100mL)で抽出する。合わせた有機層をMgSO4で乾燥させ、濾過し、減圧下で濃縮して、オフホワイトの固体として生成物(1)を得る(6.05g、83%)。
ステップ5についての実験方法:化合物(1)(6.05g、34.7mmol)の塩化アセチル(30mL、5vol)溶液を、1時間還流させる。この反応混合物を減圧下で濃縮し、少量のジクロロメタンに溶解し、ヘプタンで粉砕する。得られた固体を、濾過し、高真空中で一晩乾燥させて、オフホワイトの固体として生成物(2)(4.47g、84%)を得る。
ステップ6についての実験方法:LiClO4の5.0M溶液(ジエチルエーテル(25.15g、235.6mmol)中)を、アルゴン雰囲気中にて室温で、フラン(5.45g、80.1mmol)と化合物(2)(2.5g、16.0mmol)との攪拌混合物に添加する。得られた混合物を、10時間攪拌し、水(80ml)を添加する。この混合物を、MTBE(3×50mL)で抽出する。この未精製材料を、少量のDCMに溶解し、シリカのパッドを通過させ、ジクロロメタンで洗浄する。合わせた濾液を蒸発させて、白色固体をもたらし、この生成物と出発材料との75:25混合物を、さらなる精製を行わずに次のステップで使用する。
ステップ7についての実験方法:化合物(3)(0.25g、1.11mmol)の酢酸エチル(10mL)溶液に、ラネーニッケル2800型(Aldrich、2.5g(4mLの水中))スラリー(水中)を添加する。この混合物を、4時間還流させ、熱いうちにセライトのパッドを通して濾過し、熱いアセトン(40mL)で洗浄する。濾液を蒸発乾固させ、未精製の生成物を酢酸エチルで粉砕し、得られた固体を濾過して、白色固体としてカンタリジンを得ることができる(50mg、23%)。
ステップ8についての実験方法:化合物(3)(0.4g、1.78mmol)の酢酸エチル(10mL)溶液を、4時間、水素雰囲気中で10% Pd/C(40mg)の存在下で水素付加する。TLCは、部分的な転換しか示さない。追加の10%の触媒(40mg)を添加し、完全な転換のために、混合物を一晩攪拌する。この混合物を、セライトのパッドを通して濾過し、酢酸エチルで洗浄する。得られた固体を、少量のジクロロメタンに溶解し、シリカゲルクロマトグラフィーによって精製して、白色の結晶性固体として、化合物(10)を得る(0.2g、50%)。
過塩素酸リチウムを使用しない、カンタリジンのための2または3ステップ合成を決定するために、実験を行い、以下の最終の還元/脱硫反応がもたらされた。
以前の研究では、ワンポット内でラネーニッケルによって媒介される水素化および脱硫中の、カンタリジン(例えば10〜12%)の低収率が示された。いくらかの収穫物は、二重結合還元の前にいったん硫黄が消失すると、逆−DA化学で失われ得る。ラネーニッケルでの脱硫後の、Pd−Cおよび水素を使用する二重結合還元の2ステッププロセスを研究した。
Claims (19)
- カンタリジンまたはその誘導体を調製するための方法であって、
a)式(1)の第1の化合物:
b)前記第1の化合物から、式(2)を有する第2の化合物:
c)前記第2の化合物を、トリフルオロメタンスルホン酸スズ(II)、ビス(シクロペンタジエニル)ジルコニウム(IV)トリフラート、ビス(シクロペンタジエニル)チタン(IV)トリフラート、三フッ化ホウ素ジエチルエーテル、および塩化ガリウム(III)からなる群から選択されるルイス酸を用いてフランと環化付加反応を実施して、式(3)を有する第3の化合物:
d)前記第3の化合物から、カンタリジンを産生すること
を含む方法。 - ルイス酸が、トリフルオロメタンスルホン酸スズ(II)、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体、ビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)、三フッ化ホウ素ジエチルエーテル、塩化ガリウム(III)からなる群から選択される、請求項1に記載の方法。
- ルイス酸が、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体およびビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)からなる群から選択される、請求項1に記載の方法。
- ルイス酸が、ビス(シクロペンタジエニル)ジルコニウム(IV)・ビス(トリフルオロメタンスルホナート)テトラヒドロフラン錯体である、請求項1に記載の方法。
- ルイス酸が、ビス(シクロペンタジエニル)チタン(IV)・ビス(トリフルオロメタンスルホナート)である、請求項1に記載の方法。
- ステップc)の環化付加反応が、Me3Alの存在下で行われる、請求項1〜5のいずれか一項に記載の方法。
- 式(3)の化合物が少なくとも85:15のエキソ−対−エンド生成物比において形成される、請求項1〜6のいずれか一項に記載の方法。
- 式(3)の化合物が少なくとも95:5のエキソ−対−エンド生成物比において形成される、請求項1〜6のいずれか一項に記載の方法。
- 式(3)の化合物が少なくとも99:1のエキソ−対−エンド生成物比において形成される、請求項1〜6のいずれか一項に記載の方法。
- ステップa)が、さらに式(4)の第4の化合物:
- ステップ(b)が、前記第1の化合物を脱水反応にかけることを含む、請求項1〜10のいずれか一項に記載の方法。
- ステップ(d)が、式(3)の化合物を水素化して化合物(10)
- 水素化のステップがPd/Cおよび水素の存在下において行われる、請求項12に記載の方法。
- 化合物(10)を脱硫してカンタリジン
- 脱硫のステップが、ラネーニッケル、Ni(II)/NaBH4、Co(II)/NaBH4、Li/EtNH2、LAH/TiCl3、LAH/CuCl2、Ni(II)/Zn、Ni(II)/Al、LAH/Cp2Niの存在下において行われる、請求項14に記載の方法。
- 脱硫のステップが、ラネーニッケルの存在下において行われる、請求項14または15に記載の方法。
- a)以下のいずれか1つから選択される第1の化合物を提供すること:
b)前記第1の化合物から、前記第1の化合物を、還元剤を使用して実施される脱硫反応および任意に別の還元剤を使用して実施される水素化反応を含む還元反応にかけることによって、前記カンタリジンを産生すること、ここで、前記脱硫反応は、Ni(II)/NaBH4、Co(II)/NaBH4、Li/EtNH2、LAH/TiCl3、LAH/CuCl2、Ni(II)/ZnもしくはNi(II)/Al、LAH/Cp2Ni、およびラネーニッケルからなる群から選択される還元剤を使用して実施される、
を含む、カンタリジンを調製するための方法。 - 水素化反応がPt/Cおよび水素の存在下において行われる、請求項17に記載の方法。
- 脱硫反応がラネーニッケルの存在下において行われる、請求項17または18に記載の方法。
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US62/093,396 | 2014-12-17 | ||
PCT/US2015/066487 WO2016100732A2 (en) | 2014-12-17 | 2015-12-17 | Commercially viable synthesis of cantharidin and bioactive cantharidin derivatives |
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