JP6097405B2 - 10−デアセチルバッカチンiiiからカバジタキセルを高収率で製造する新規方法 - Google Patents
10−デアセチルバッカチンiiiからカバジタキセルを高収率で製造する新規方法 Download PDFInfo
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- JP6097405B2 JP6097405B2 JP2015546380A JP2015546380A JP6097405B2 JP 6097405 B2 JP6097405 B2 JP 6097405B2 JP 2015546380 A JP2015546380 A JP 2015546380A JP 2015546380 A JP2015546380 A JP 2015546380A JP 6097405 B2 JP6097405 B2 JP 6097405B2
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- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims description 52
- 229960001573 cabazitaxel Drugs 0.000 title claims description 52
- 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 claims description 43
- 238000000034 method Methods 0.000 title description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
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- 238000004519 manufacturing process Methods 0.000 claims description 33
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- 239000002253 acid Substances 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
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- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
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- 125000000217 alkyl group Chemical group 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 230000001035 methylating effect Effects 0.000 claims description 5
- 238000007069 methylation reaction Methods 0.000 claims description 5
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 3
- -1 trimethyloxonium tetrafluoroborate Chemical compound 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000005105 dialkylarylsilyl group Chemical group 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 claims description 2
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- 235000011090 malic acid Nutrition 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
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- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 49
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 18
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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- 229910000104 sodium hydride Inorganic materials 0.000 description 6
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
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- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Description
1)式(2)の10−デアセチルバッカチンIIIをシリル化剤と反応させ、7位のヒドロキシ基がシリル化されたラジカルで保護された式(3)の中間体を得る工程と、
2)式(3)の中間体の10位のヒドロキシ基をメチル化して、式(4)の中間体を得る工程と、
3)式(4)の中間体の7位のヒドロキシ基を脱保護して、式(5)の中間体を得る工程と、
4)式(5)の中間体の7位のヒドロキシ基をメチル化して、式(6)の中間体を得る工程と、
5)式(6)の中間体の13位のヒドロキシ基を、式(8)のオキサゾリジン酸誘導体の存在下でエステル化して、式(7)の中間体を得る工程と、
6)式(7)の中間体を酸で処理して、式(1)のカバジタキセルを得る工程と、
を含むカバジタキセルの製造方法を提供する。
TESCl:トリエチルシリルクロリド
DCM:ジクロロメタン
EA:酢酸エチル
sat.NaCl:飽和塩化ナトリウム
conc.HCl:濃塩酸
DMAP:4−ジメチルアミノピリジン
NaH:水素化ナトリウム
THF:テトラヒドロフラン
MeOH:メタノール
DMF:N,N−ジメチルホルムアミド
DCC:N,N’−ジシクロヘキシルカルボジイミド
TLC:薄膜クロマトグラフィー(TLC展開液:ヘキサン/酢酸エチル=1/2)
HPLC:高速液体クロマトグラフィー
100gの10−デアセチルバッカチンIIIを550mLのDCMに溶解した後、そこに100gのDMAPとTESCl 35mLを加えた。反応混合物を2時間撹拌した後、TLCにより反応終了を確認し、そこに5%NH4Clを添加して、抽出した。抽出後、得られた有機層をMgSO4で乾燥した後、ろ過して、濃縮した。濃縮液を0.1Lのアセトンに溶解した後、そこに1Lのヘキサンを加え、沈澱を形成させた。ヘキサン添加完了後、さらに30分間撹拌し、ろ過した後、40℃のオーブンで減圧乾燥して、式(3)の中間体130gを白色の固体で得た。得られた乾固物の純度は93%であった(HPLC)。
得られた式(3)の中間体130gを2.8LのTHFに溶解し、得られた溶液を−20℃に冷却した後、そこに59mLのMe2SO4を加えた。次いで、そこに、40gのNaH(鉱油中60%分散物)をゆっくり加えた後、約2時間撹拌した。HPLCを利用して反応終了を確認した後、飽和NH4ClとDCMを添加して、抽出した。得られたDCM層をMgSO4で乾燥した後、ろ過して、濃縮した。濃縮液を0.1LのDCMに溶解した後、そこに1Lのヘキサンを加え、沈澱を形成させた。ヘキサン添加完了後、30分間、さらに撹拌し、ろ過した後、40℃のオーブンで減圧乾燥して、式(4)の中間体124gを白色の固体で得た(純度82%)。
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 5.60 (d, J = 7.0 Hz, 1H), 4.99 - 4.87 (m, 3H), 4.43 (dd, J = 10.5, 6.7 Hz, 1H), 4.30 (d, J = 8.1 Hz, 1H), 4.14 (d, J = 8.3, Hz, 1H), 3.88 (d, J = 6.6 Hz, 1H), 3.41 (s, 3H), 2.52-2.45 (m, 1H), 2.28 (s, 3H), 2.26 (s, 1H), 2.11 (s, 3H), 2.08 (d, J = 5.1 Hz, 1H), 1.92-1.85 (m, 1H), 1.67 (s, 3H), 1.59 (s, 1H), 1.58 (s, 1H), 1.17 (s, 3H), 1.07 (s, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.65 - 0.50 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 204.60, 170.97, 167.21, 143.07, 134.02, 133.68, 130.24, 129.61, 128.69, 84.47, 82.83, 81.19, 78.96, 77.23, 74.98, 73.10, 68.20, 58.40, 55.96, 47.48, 43.02, 38.49, 37.49, 27.01, 22.89, 19.72, 15.34, 10.04, 6.95, 5.58;
LRMS (ESI) m/z 695.7 (M+Na)+
得られた式(4)の中間体124gを455mLのメタノールに溶解した後、得られた混合物を0℃に冷却した。そこに4N HCl 455mLをゆっくり添加した後、さらに約2時間撹拌した。TLCで反応完了を確認した後、5%NaHCO3溶液5.2Lを加え、沈澱を形成させた。形成された沈澱をろ過し、蒸留水で洗浄した。得られた沈澱物を40℃のオーブンで減圧乾燥して、式(5)の中間体83gを得た(純度75%、10−デアセチルバッカチンIIIからの累積収率57%)。
得られた式(5)の中間体83gを400mLのDMFに溶解し、得られた溶液を−30℃に冷却した後、ここに35mLのMe2SO4を添加した。次いで、そこに14gのNaH(鉱油中60%分散物)をゆっくり添加し、約1時間撹拌した。HPLCを利用して反応終了を確認した後、4Lの5%NH4Cl水溶液をゆっくり加え、沈澱を形成させた。形成された沈澱をろ過し、過剰量の蒸留水で洗浄した後、40℃のオーブンで減圧乾燥して、式(6)の中間体69gを白色の固体で得た(純度73%、収率79%、10−デアセチルバッカチンIIIからの累積収率45%)。
式(8)のオキサゾリジン酸誘導体137gを2LのEAに溶解した後、そこに227gのDCC及び23gのDMAPを添加した。得られた溶液に、得られた式(6)の中間体69gを添加し、室温で約3時間撹拌した。反応終了後、不溶性物質をろ過で除去し、減圧下で有機相を濃縮した。濃縮液を0.1LのDCMに溶解した後、そこに1Lのヘキサンを加え、沈澱を形成させた。ヘキサン添加完了後、30分間、さらに撹拌し、ろ過した後、40℃のオーブンで減圧乾燥して、式(7)の中間体78gを白色の固体で得た(純度88%、収率84%、10−デアセチルバッカチンIIIからの累積収率38%)。
得られた式(7)の中間体78gを4Lのメタノールと4LのDCMに溶解し、0℃に冷却し、そこに1N HCl 78mLをゆっくり添加した。得られた混合物を約1時間撹拌した後、そこに飽和NH4ClとDCMを添加して、抽出した。得られたDCM層をMgSO4で乾燥した後、ろ過して、濃縮した。濃縮液を0.1Lのメタノールに溶解した後、ここに1.2Lの蒸留水を加え、沈澱を形成させた。蒸留水添加完了後、30分間、さらに撹拌し、ろ過した後、40℃のオーブンで減圧乾燥して、カバジタキセル乾固物59gを白色の固体で得た(純度90%)。HPLC分析により、得られた乾固物のカバジタキセル含有量は72%であり、出発物質である10−デアセチルバッカチンIIIからカバジタキセル含有乾固物までの全収率は28%であった。
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.35-7.30 (m, 5H), 6.21 (t, J = 8.6 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 5.45 (d, J = 9.6 Hz, 1H), 5.27 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 7.6 Hz, 1H), 4.79 (s, 1H), 4.62 (s, 1H), 4.29 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 3.88-3.80 (m, 2H), 3.45 (s, 3H), 3.30 (s, 3H), 2.73-2.66 (m, 1H), 2.36 (s, 3H), 2.31-2.27 (m, 2H), 1.87 (s, 3H), 1.83-1.76 (m, 1H), 1.71 (s, 3H), 1.36 (s, 9H), 1.25 (s, 1H), 1.21 (s, 3H), 1,20 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 204.94, 172.69, 170.43, 166.97, 155.30, 138.67, 138.36, 135.61, 133.64, 129.18, 128.81, 128.64, 128.05, 126.83, 84.09, 82.64, 81.75, 80.75, 80.23, 78.73, 77.23, 74.52, 73.69, 72.56, 57.34, 57.04, 56.91, 56.18, 47.39, 43.29, 35.22, 32.12, 28.21, 26.83, 22.69, 20.68, 14.64, 10.34;
LRMS (ESI) m/z 858.7 (M+Na)+
Claims (9)
- 1)N,N−ジメチルアミノピリジンの存在下で極性又は非極性有機溶媒中で式(2)の10−デアセチルバッカチンIIIをシリル化剤と反応させ、7位のヒドロキシ基がシリル化されたラジカルMで保護された式(3)の中間体を得る工程と、
2)式(3)の中間体の10位のヒドロキシ基をメチル化して、式(4)の中間体を得る工程と、
3)式(4)の中間体の7位のヒドロキシ基を脱保護して、式(5)の中間体を得る工程と、
4)式(5)の中間体の7位のヒドロキシ基をメチル化して、式(6)の中間体を得る工程と、
5)式(6)の中間体の13位のヒドロキシ基を、式(8)のオキサゾリジン酸誘導体の存在下でエステル化して、式(7)の中間体を得る工程と、
6)式(7)の中間体を酸で処理して、式(1)のカバジタキセルを得る工程と、
を含むカバジタキセルの製造方法。
- シリル化剤が、クロロトリエチルシラン、t−ブチルジメチルシリルクロリド、t−ブチルクロロジフェニルシラン及びこれらの組み合わせよりなる群から選択される請求項1に記載のカバジタキセルの製造方法。
- 極性有機溶媒が、炭素数1〜5のアルコール、アセトニトリル、ジメチルスルホキシド、ジメチルホルムアミド、アセトン、テトラヒドロフラン、1,4−ジオキサン及びこれらの組み合わせよりなる群から選択され、
非極性有機溶媒が、ジエチルエーテル、トルエン、ベンゼン、ヘキサン、ジクロロメタン、酢酸エチル、クロロホルム及びこれらの組み合わせよりなる群から選択される請求項1に記載のカバジタキセルの製造方法。 - ヒドロキシ基のメチル化反応が、硫酸ジメチル、ヨウ化メチル及びトリメチルオキソニウムテトラフルオロボレートよりなる群から選択された1種以上のメチル化剤を用いて行われる請求項1に記載のカバジタキセルの製造方法。
- ヒドロキシ基の脱保護反応が、酸、または酸と有機溶媒との混合物を用いて行われる請求項1に記載のカバジタキセルの製造方法。
- 酸が、ハロゲン化水素酸、硫酸、硝酸、リン酸、スルファミン酸、過塩素酸、クロム酸、亜硫酸、亜硝酸、ハロゲン化酸、ギ酸、酢酸、オキサロ酢酸、プロピオン酸、シュウ酸、グリコール酸、酒石酸、クエン酸、フマル酸、リンゴ酸、コハク酸、酪酸、トリフルオロ酢酸及びこれらの組み合わせよりなる群から選択される請求項5に記載のカバジタキセルの製造方法。
- 有機溶媒が、炭素数1〜4の直鎖または分岐鎖アルコールである請求項5に記載のカバジタキセルの製造方法。
- 工程1)〜5)において、各工程の中間体が結晶化方法により得られ、さらに精製することなく次の工程で使用される請求項1に記載のカバジタキセルの製造方法。
- 各工程で得られた物質を精製する一つ以上の工程をさらに含む請求項1に記載のカバジタキセルの製造方法。
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