JP2011520995A - コルヒチンおよびチオコルヒチンのグリコシド化の方法 - Google Patents
コルヒチンおよびチオコルヒチンのグリコシド化の方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 28
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 title description 17
- 229960001338 colchicine Drugs 0.000 title description 9
- 238000005858 glycosidation reaction Methods 0.000 title description 5
- CMEGANPVAXDBPL-INIZCTEOSA-N n-[(7s)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC CMEGANPVAXDBPL-INIZCTEOSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 235000000346 sugar Nutrition 0.000 claims description 10
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical group CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 7
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 5
- 125000003147 glycosyl group Chemical group 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000002243 precursor Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- -1 thiocolchicine glycosides Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- PKYOHQGXPPVIGD-HNNXBMFYSA-N n-[(7s)-3-hydroxy-1,2-dimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound O=C1C(SC)=CC=C2C3=C(OC)C(OC)=C(O)C=C3CC[C@H](NC(C)=O)C2=C1 PKYOHQGXPPVIGD-HNNXBMFYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- 0 COc(c(*=*)c(cc1CC[C@@](*=C)C2=C3)O)c1C2=CC=C(*)C3=O Chemical compound COc(c(*=*)c(cc1CC[C@@](*=C)C2=C3)O)c1C2=CC=C(*)C3=O 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZYPMNZKYVVSXOJ-YNEHKIRRSA-N [(2r,3s,4r)-2,3,4-triacetyloxy-5-oxopentyl] acetate Chemical compound CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C=O ZYPMNZKYVVSXOJ-YNEHKIRRSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- PDNVQOUXEOAXBR-RSJOWCBRSA-N (2S,3R,4R,5S)-2,3,4,5-tetrahydroxyhexanoyl fluoride Chemical class C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(F)=O PDNVQOUXEOAXBR-RSJOWCBRSA-N 0.000 description 1
- IJPVCOQVFLNLAP-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoyl fluoride Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(F)=O IJPVCOQVFLNLAP-SQOUGZDYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- UXAFRQPVHYZDED-ZZEDUEFDSA-N Colchicoside Chemical compound C1([C@@H](NC(C)=O)CCC2=C3)=CC(=O)C(OC)=CC=C1C2=C(OC)C(OC)=C3O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UXAFRQPVHYZDED-ZZEDUEFDSA-N 0.000 description 1
- UXAFRQPVHYZDED-UHFFFAOYSA-N Colchicoside Natural products C1=C2CCC(NC(C)=O)C3=CC(=O)C(OC)=CC=C3C2=C(OC)C(OC)=C1OC1OC(CO)C(O)C(O)C1O UXAFRQPVHYZDED-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LEQAKWQJCITZNK-AXHKHJLKSA-N N-[(7S)-1,2-dimethoxy-10-(methylthio)-9-oxo-3-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(C)=O)CCC2=C3)=CC(=O)C(SC)=CC=C1C2=C(OC)C(OC)=C3O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LEQAKWQJCITZNK-AXHKHJLKSA-N 0.000 description 1
- LEQAKWQJCITZNK-MSQQGMGVSA-N N-[1,2-dimethoxy-10-(methylthio)-9-oxo-3-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide Chemical compound C1=C2CCC(NC(C)=O)C3=CC(=O)C(SC)=CC=C3C2=C(OC)C(OC)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LEQAKWQJCITZNK-MSQQGMGVSA-N 0.000 description 1
- LPTITAGPBXDDGR-UHFFFAOYSA-N Penta-Ac-Mannose Natural products CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O LPTITAGPBXDDGR-UHFFFAOYSA-N 0.000 description 1
- CYAYKKUWALRRPA-RGDJUOJXSA-N [(2r,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-bromooxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O CYAYKKUWALRRPA-RGDJUOJXSA-N 0.000 description 1
- LPTITAGPBXDDGR-LYYZXLFJSA-N [(2r,3s,4s,5r,6s)-3,4,5,6-tetraacetyloxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O LPTITAGPBXDDGR-LYYZXLFJSA-N 0.000 description 1
- DWZNQQMVUFPQMQ-UHFFFAOYSA-N acetonitrile;2-methoxy-2-methylpropane Chemical compound CC#N.COC(C)(C)C DWZNQQMVUFPQMQ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical group C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- LPTITAGPBXDDGR-IBEHDNSVSA-N beta-d-glucose pentaacetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O LPTITAGPBXDDGR-IBEHDNSVSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008195 galaktosides Chemical class 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- CMEGANPVAXDBPL-UHFFFAOYSA-N n-(1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl)acetamide Chemical compound C1CC(NC(C)=O)C2=CC(=O)C(SC)=CC=C2C2=C1C=C(OC)C(OC)=C2OC CMEGANPVAXDBPL-UHFFFAOYSA-N 0.000 description 1
- JRRUSQGIRBEMRN-HNNXBMFYSA-N n-[(7s)-3-hydroxy-1,2,10-trimethoxy-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound O=C1C(OC)=CC=C2C3=C(OC)C(OC)=C(O)C=C3CC[C@H](NC(C)=O)C2=C1 JRRUSQGIRBEMRN-HNNXBMFYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000008265 rhamnosides Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000020347 spindle assembly Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960000287 thiocolchicoside Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/248—Colchicine radicals, e.g. colchicosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/34—Benzoheptalenes; Hydrogenated benzoheptalenes
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
− R1は、メトキシ基またはメチルチオ基であり;
− R2は、O−グリコシルオキシ残基である〕
を有する化合物の調製方法に関する。
− R1が、メトキシ基またはメチルチオ基であり;
− R2が、O−グリコシルオキシ残基である
式Iを有するコルヒチンまたはチオコルヒチングリコシドを形成する。
− 1−ハロ糖のような適切に活性化されたグリコシル反応体の調製のバイパス;
− 安定した容易に調製される1−アセチル保護グリコース(例えば、過アセチルグリコース)の使用;
− 粗反応混合物から最終生成物を直接結晶化する可能性;
− ガラクトシド、ラムノシドなどのような、従来技術の方法により得ることが難しいグリコシルコルチノイドの調製。
3−O−デメチルチオコルヒチン(2.0g)を、窒素雰囲気下、室温でアセトニトリル(20ml)に懸濁し、続いて、1,1,3,3−テトラメチルグアニジン(1.8ml)、1,2,3,4,6−ペンタ−O−アセチル−β−D−グルコピラノース(5.60g)のアセトニトリル(10ml)溶液、最後に三フッ化ホウ素(7.2ml)を連続して添加する。
3−O−デメチルチオコルヒチン(1.0g)を、窒素雰囲気下、室温でアセトニトリル(10ml)に懸濁し、続いて、1,1,3,3−テトラメチルグアニジン(0.9ml)、1,2,3,4,6−ペンタ−O−アセチル−β−D−ガラクトピラノース(2.80g)のアセトニトリル(10ml)溶液、最後に三フッ化ホウ素(3.6ml)を連続して添加する。
3−O−デメチルチオコルヒチン(2.0g)を、窒素雰囲気下、室温でアセトニトリル(20ml)に懸濁し、続いて、1,1,3,3−テトラメチルグアニジン(1.8ml)、1,2,3,4−テトラ−O−アセチル−β−L−ラムノピラノース(4.77g)のアセトニトリル(10ml)溶液、最後に三フッ化ホウ素(8.4ml)を連続して添加する。
15.0gの3−O−デメチルチオコルヒチンを、窒素雰囲気下、140mlのアセトニトリルに撹拌しながら懸濁する。
2.0gの3−O−デメチルコルヒチンを、窒素雰囲気下、18mlのアセトニトリルに撹拌しながら懸濁する。
Claims (10)
- D系またはL系のいずれかの前記1−アセチル糖がエステル基で保護されている、請求項1に記載の方法。
- 前記エステル基がアセチル基である、請求項2に記載の方法。
- 前記保護基が塩基性加水分解によって開裂される、請求項1から3に記載の方法。
- 前記保護基が、アミンとの反応による求核置換を介して開裂される、請求項1から3に記載の方法。
- 反応が、アセトニトリル、ニトロメタン、ハロゲン化炭化水素およびそれらの混合物からなる群から選択される溶媒において実施される、請求項1に記載の方法。
- 反応がルイス酸の存在下で実施される、請求項1に記載の方法。
- ルイス酸が三フッ化ホウ素である、請求項7に記載の方法。
- 反応が有機塩基の存在下で実施される、請求項1に記載の方法。
- 前記塩基が1,1,3,3−テトラメチルグアニジンである、請求項9に記載の方法。
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EP08157069.9 | 2008-05-28 | ||
EP08157069A EP2128170B1 (en) | 2008-05-28 | 2008-05-28 | "Process for the glycosidation of colchicine and thiocolchicine" |
PCT/EP2009/002623 WO2009143930A1 (en) | 2008-05-28 | 2009-04-09 | Process for the glycosidation of colchicine and thiocolchicine |
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JP2011520995A true JP2011520995A (ja) | 2011-07-21 |
JP5478612B2 JP5478612B2 (ja) | 2014-04-23 |
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JP2011510851A Active JP5478612B2 (ja) | 2008-05-28 | 2009-04-09 | コルヒチンおよびチオコルヒチンのグリコシド化の方法 |
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US (1) | US8742080B2 (ja) |
EP (1) | EP2128170B1 (ja) |
JP (1) | JP5478612B2 (ja) |
KR (1) | KR101625161B1 (ja) |
CN (2) | CN102046644A (ja) |
AT (1) | ATE492556T1 (ja) |
AU (1) | AU2009253483B2 (ja) |
BR (1) | BRPI0912287A2 (ja) |
CA (1) | CA2725842C (ja) |
CO (1) | CO6290769A2 (ja) |
DE (1) | DE602008004113D1 (ja) |
DK (1) | DK2128170T3 (ja) |
ES (1) | ES2356494T3 (ja) |
HR (1) | HRP20110186T1 (ja) |
MX (1) | MX2010012884A (ja) |
PL (1) | PL2128170T3 (ja) |
PT (1) | PT2128170E (ja) |
RU (1) | RU2488589C2 (ja) |
SI (1) | SI2128170T1 (ja) |
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SG10201703586PA (en) | 2012-11-02 | 2017-06-29 | Murray & Poole Entpr Ltd | Treatment or prevention of cardiovascular events via the administration of a colchicine derivative |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2112131A1 (en) * | 1970-11-06 | 1972-06-16 | Roussel Uclaf | 2-and 3-glucose-2-yl-demethylthiololchicines - antimitotic agents,prepared from colchicine |
JPH09309896A (ja) * | 1996-02-08 | 1997-12-02 | Indena Spa | コルヒチン誘導体をグリコシド化する方法、及びその生成物 |
JPH10507169A (ja) * | 1994-10-05 | 1998-07-14 | インデナ・ソチエタ・ペル・アチオニ | コルヒチン誘導体及びその治療的利用 |
WO1999061457A1 (fr) * | 1998-05-27 | 1999-12-02 | Sanofi-Synthelabo | Derive de thiocolchicoside, sa preparation et son application en therapeutique |
Family Cites Families (3)
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SU508204A3 (ru) * | 1972-05-05 | 1976-03-25 | Руссель-Уклаф (Фирма) | Способ получени 3-глюкоз-2-ил3-деметилтиоколхицина или 2-глюкоз2-ил-2-деметилтиоколхицина |
IT1285777B1 (it) | 1996-10-07 | 1998-06-18 | Indena Spa | Processo di biotrasformazione di composti colchicinoidi nei corrispondenti 3-glicosilderivati |
ITMI20031144A1 (it) * | 2003-06-06 | 2004-12-07 | Indena Spa | Analoghi del colchicoside. |
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- 2009-04-09 CN CN201610052127.7A patent/CN105713054A/zh active Pending
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2112131A1 (en) * | 1970-11-06 | 1972-06-16 | Roussel Uclaf | 2-and 3-glucose-2-yl-demethylthiololchicines - antimitotic agents,prepared from colchicine |
JPH10507169A (ja) * | 1994-10-05 | 1998-07-14 | インデナ・ソチエタ・ペル・アチオニ | コルヒチン誘導体及びその治療的利用 |
JPH09309896A (ja) * | 1996-02-08 | 1997-12-02 | Indena Spa | コルヒチン誘導体をグリコシド化する方法、及びその生成物 |
WO1999061457A1 (fr) * | 1998-05-27 | 1999-12-02 | Sanofi-Synthelabo | Derive de thiocolchicoside, sa preparation et son application en therapeutique |
Non-Patent Citations (1)
Title |
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JPN6013043037; J. Med. Chem. V50, 2007, P2245-2248 * |
Also Published As
Publication number | Publication date |
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ATE492556T1 (de) | 2011-01-15 |
JP5478612B2 (ja) | 2014-04-23 |
PT2128170E (pt) | 2011-02-23 |
EP2128170A1 (en) | 2009-12-02 |
ZA201008480B (en) | 2012-02-29 |
ES2356494T3 (es) | 2011-04-08 |
DE602008004113D1 (de) | 2011-02-03 |
MX2010012884A (es) | 2010-12-14 |
WO2009143930A1 (en) | 2009-12-03 |
CN102046644A (zh) | 2011-05-04 |
RU2010147934A (ru) | 2012-05-27 |
KR20110010739A (ko) | 2011-02-07 |
AU2009253483A1 (en) | 2009-12-03 |
CN105713054A (zh) | 2016-06-29 |
RU2488589C2 (ru) | 2013-07-27 |
HRP20110186T1 (hr) | 2011-04-30 |
DK2128170T3 (da) | 2011-02-28 |
US20110130554A1 (en) | 2011-06-02 |
BRPI0912287A2 (pt) | 2015-08-04 |
EP2128170B1 (en) | 2010-12-22 |
CO6290769A2 (es) | 2011-06-20 |
AU2009253483B2 (en) | 2013-08-22 |
US8742080B2 (en) | 2014-06-03 |
KR101625161B1 (ko) | 2016-05-27 |
CA2725842C (en) | 2016-11-22 |
PL2128170T3 (pl) | 2011-05-31 |
SI2128170T1 (sl) | 2011-04-29 |
CA2725842A1 (en) | 2009-12-03 |
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