JP4467976B2 - 14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 - Google Patents
14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 Download PDFInfo
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- JP4467976B2 JP4467976B2 JP2003538150A JP2003538150A JP4467976B2 JP 4467976 B2 JP4467976 B2 JP 4467976B2 JP 2003538150 A JP2003538150 A JP 2003538150A JP 2003538150 A JP2003538150 A JP 2003538150A JP 4467976 B2 JP4467976 B2 JP 4467976B2
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- JP
- Japan
- Prior art keywords
- baccatin iii
- iii
- hydroxy
- process according
- keto
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- 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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
-
- 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)
- Epoxy Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
a.下記式:
b.1及び14ヒドロキシ基を炭酸化し、下記式:
c.13位のケトンを還元し、7位の保護基を開裂させるか、又はその逆の工程。
AcOEt=酢酸エチル; TES=トリエチルシリル; TESCl=塩化トリエチルシリル; DCM=ジクロロメタン、THF=テトラヒドロフラン、HMPA=ヘキサメチルホスホルアミド、DMPU=1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)ピリミジノン。
10−デアセチル−13−ケト−バッカチンIII
10−デアセチル−バッカチンIII(3g、5mmol)を、DCM−MeOH 1:1(250ml)中に溶解し、−78℃まで冷却した。オゾン流(1.4g/ml)を、出発材料が消滅するまで、溶液中で泡立てた(2時間)。オゾン流を窒素に代えた。次に溶液を、硫化ジメチル(1ml)およびピリジン(1ml)で処理して、溶媒を留去させ、粗生成物をEtOAc(100ml)に溶解し、0.1N HClおよび氷で洗浄した。溶媒を留去させた後、標記生成物を収率90%で得た。
13−ケト−バッカチンIII
バッカチンIII(150g、0.25mol)を、アセトン(1.43l)中に溶解した。強力な撹拌下で、市販の二酸化マンガン(450g)を3回に分けて加えた。出発物質が消失後(4時間)、この懸濁液を濾過し、溶媒を留去した。粗生成物をEtOAc(100ml)に懸濁し、1時間還流し、次にc−Hex(100ml)を加えた。溶媒の蒸発後、標記化合物を、母液から白色の固体(140g、95%)として得た。
7−Boc−13−ケト−バッカチンIII
塩化メチレン(0.5ml)中の13−ケト−バッカチンIII(1.1g、1.9mmol)の溶液を、室温で四塩化炭素(14ml)中に溶解した。次に、強力な撹拌下で、1−メチルイミダゾール(35ml、0.282mmol)およびBoc2O(1.026g、4.7mmol)を加えた。溶液を20℃で撹拌下、18時間放置した。その後、溶媒をアセトン(5ml)に代え、溶液を水(5ml)に注ぎ、一晩撹拌しながら放置した。沈殿物をブフナー漏斗で収集し、n−ペンタンで洗浄し、乾燥させて、標記生成物1.1g(1.78mmol、94%)を得た。
14−ヒドロキシ−7−Boc−13−ケトバッカチンIII
THF−DMPU 8:2(10ml)中の7−Boc−13−ケト−バッカチンIII(0.65g、0.95mmol)の溶液を、無水THF(10ml)中のt−BuOK(0.425g、3.79mmol)の溶液に、撹拌下、−60℃で加えた。15分後、THF−DMPU 8:2(10ml)中のショウノウスルホニルオキサジリジン(2.63mmol)の溶液を加えた。出発材料が消失した後(45分)、反応を氷酢酸(0.4ml)でクエンチし、混合物を10%NH4Cl水溶液(25ml)で希釈した。有機層を水で洗浄し、硫酸ナトリウムで乾燥させ、減圧下で蒸発させた。生成物を、精製することなく、次の工程に使用した。
14β−ヒドロキシ−7−Boc−13−ケトバッカチンIII 1,14−カルボネート
14−ヒドロキシ−7−Boc−13−ケトバッカチンIII(2.0g)およびカルボニルジイミダゾール(0.65g、4.0mmol)を、トルエン(11ml)中に溶解し、90分間撹拌しながら75℃で加熱した。溶液を室温に冷却し、0.2N HCl(5ml)で処理した。有機層をEtOAc(15ml)で希釈し、水で洗浄し、乾燥させ、溶媒を留去した。標記化合物を、フラッシュクロマトグラフィー(シリカゲル、cHex/DCM/Et2O、14:3.5:2.5)により、白色の固体(0.87g、1.20mmol、2工程で82%)として得た。
14β−ヒドロキシ−7−Boc−バッカチンIII 1,14−カルボネート
THF(3ml)中の14β−ヒドロキシ−7−Boc−13−ケトバッカチンIII 1,14−カルボネートの溶液を、無水メタノール(11ml)中の水素化ホウ素テトラブチルアンモニウム(1.29g)の溶液に、不活性雰囲気下、−50℃で加えた。4時間後、反応を水(5ml)中のクエン酸(1.5g)の溶液で、クエンチした。混合物を酢酸エチルで抽出した。有機相を硫酸マグネシウムで乾燥させ、減圧下で蒸発させた。粗生成物をカラムクロマトグラフィーにより精製して、14β−ヒドロキシ−7−Boc−バッカチンIII 1,14−カルボネート(68%)および13−epi-14β−ヒドロキシ−7−Boc−バッカチンIII 1,14−カルボネート(28%)を、変換収率70%で得た。
14β−ヒドロキシ−バッカチンIII 1,14−カルボネート
97%のギ酸溶液(5ml)を、ジクロロメタン(3ml)中の14β−ヒドロキシ−7−Boc−バッカチンIII 1,14−カルボネート(0.50g、0.68mol)の溶液に−8℃で加えた。反応を撹拌下、5日間保持し、次に2Nアンモニアで中和した。有機相を酢酸エチルで抽出し、乾燥させ、減圧下で蒸発させた。シリカゲルクロマトグラフィー(ヘキサン−酢酸エチル=1.0:1.3)により、生成物を白色の固体として収率65%で得た。
Claims (8)
- 工程a)が、−40〜−78℃の温度で、オキサジリジン誘導体の存在下で、ヘキサメチルホスホルアミド(HMPA)又は1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)ピリミジノン(DMPU)と混合したエーテル中で、カリウムt−ブトキシド又はカリウムビス(トリメチルシリル)アミドでの処理によって行われる、請求項1記載の方法。
- オキサジリジン誘導体が、N−ベンゼンスルホニルフェニルオキサジリジン、N−ベンゼンスルホニルm−ニトロフェニルオキサジリジン及びショウノウスルホニルオキサジリジンから選択される、請求項2記載の方法。
- 工程b)が、−40℃〜室温の範囲の温度で、塩基の存在下、塩素化溶媒中でのカルボニルジイミダゾール又はホスゲンによる処理によって行われる、請求項1〜3のいずれか1項記載の方法。
- 工程c)が、−20〜−50℃の温度で、水素化物による処理によって行われる、請求項1〜4のいずれか1項記載の方法。
- 水素化物が、水素化ホウ素テトラブチルアンモニウム、水素化ホウ素テトラエチルアンモニウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリアセトキシ水素化ホウ素ナトリウムから選択され、そして反応が、エタノール、メタノール、イソプロパノール、又はメタノールとテトラヒドロフランの混合物中で行われる、請求項5記載の方法。
- 7位のヒドロキシルが保護された13−ケト−バッカチンIIIが、10−デアセチル−バッカチンIIIの10位のヒドロキシルを選択的アセチル化してバッカチンIIIを得、バッカチンIIIの13位のヒドロキシルを酸化し、次いで7位のヒドロキシルを保護することにより調製される、請求項1〜6のいずれか1項記載の方法。
- 13−ケト−バッカチンIIIが、無水酢酸によるデアセチルバッカチンIIIの10位での選択的アセチル化と、これに続く0〜60℃での非プロトン性溶媒中での二酸化マンガンによる酸化、又はバッカチンIIIのオゾンによる酸化によって得られる、請求項7記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2001MI002185A ITMI20012185A1 (it) | 2001-10-19 | 2001-10-19 | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
PCT/EP2002/008007 WO2003035634A1 (en) | 2001-10-19 | 2002-07-18 | A process for the preparation of the 14beta-hydroxy-baccatin iii-1,14-carbonate |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2009244284A Division JP2010047600A (ja) | 2001-10-19 | 2009-10-23 | 14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2005509638A JP2005509638A (ja) | 2005-04-14 |
JP4467976B2 true JP4467976B2 (ja) | 2010-05-26 |
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Application Number | Title | Priority Date | Filing Date |
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JP2003538150A Expired - Fee Related JP4467976B2 (ja) | 2001-10-19 | 2002-07-18 | 14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 |
JP2009244284A Pending JP2010047600A (ja) | 2001-10-19 | 2009-10-23 | 14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 |
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Application Number | Title | Priority Date | Filing Date |
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JP2009244284A Pending JP2010047600A (ja) | 2001-10-19 | 2009-10-23 | 14ベータ−ヒドロキシ−バッカチンiii−1,14−カルボネートの調製方法 |
Country Status (23)
Country | Link |
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US (1) | US7317113B2 (ja) |
EP (1) | EP1436278B1 (ja) |
JP (2) | JP4467976B2 (ja) |
KR (1) | KR100896543B1 (ja) |
CN (1) | CN100338049C (ja) |
AT (1) | ATE466847T1 (ja) |
AU (1) | AU2002363080B2 (ja) |
BR (1) | BR0213329A (ja) |
CA (1) | CA2464336C (ja) |
DE (1) | DE60236303D1 (ja) |
DK (1) | DK1436278T3 (ja) |
ES (1) | ES2341611T3 (ja) |
HK (1) | HK1080475A1 (ja) |
HU (1) | HU229256B1 (ja) |
IL (4) | IL161444A0 (ja) |
IT (1) | ITMI20012185A1 (ja) |
MX (1) | MXPA04003517A (ja) |
NO (1) | NO328534B1 (ja) |
PL (1) | PL207878B1 (ja) |
PT (1) | PT1436278E (ja) |
RU (1) | RU2285000C2 (ja) |
SI (1) | SI1436278T1 (ja) |
WO (1) | WO2003035634A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20012186A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
AU2002324091A1 (en) * | 2002-09-16 | 2004-04-30 | Nokia Corporation | Direct conversion receiver and receiving method |
ES2389518T3 (es) | 2008-01-18 | 2012-10-26 | Indena S.P.A. | Formas sólidas de ortataxel |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH0620877A (ja) * | 1992-03-02 | 1994-01-28 | Du Pont Japan Ltd | タンタル固体電解コンデンサ |
IT1254517B (it) | 1992-03-06 | 1995-09-25 | Indena Spa | 14-beta idrossi-10-deacetil-baccatina iii, suoi derivati, loro prepazione ed impiego terapeutico |
US5475011A (en) * | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
IT1275936B1 (it) | 1995-03-17 | 1997-10-24 | Indena Spa | Derivati della 10-deacetilbaccatina iii e della 10-deacetil-14b- idrossibaccatina iii loro metodo di preparazione e formulazioni |
FR2732341A1 (fr) | 1995-03-27 | 1996-10-04 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
IT1275435B (it) | 1995-05-19 | 1997-08-07 | Indena Spa | Derivati della 10-desacetil-14beta-idrossibaccatina iii,loro metodo di preparazione e formulazioni che li contengono |
IT1283633B1 (it) * | 1996-05-10 | 1998-04-23 | Indena Spa | Derivati tassanici loro sintesi e formulazioni che li contengono |
US5811452A (en) * | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US5917062A (en) * | 1997-11-21 | 1999-06-29 | Indena S.P.A | Intermediates and methods useful in the semisynthesis of paclitaxel and analogs |
IT1318678B1 (it) | 2000-08-10 | 2003-08-27 | Indena Spa | Procedimento per la preparazione di derivati della baccatina iii. |
IT1320107B1 (it) * | 2000-11-28 | 2003-11-18 | Indena Spa | Procedimento per la preparazione di derivati tassanici. |
IT1319682B1 (it) * | 2000-12-06 | 2003-10-23 | Indena Spa | Procedimento di sintesi del paclitaxel. |
ITMI20012186A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20021921A1 (it) * | 2002-09-10 | 2004-03-11 | Indena Spa | Funzionalizzazione della posizione 14 dei nuclei tassanici e sintesi di nuovi derivati antitumorali. |
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- 2001-10-19 IT IT2001MI002185A patent/ITMI20012185A1/it unknown
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2002
- 2002-07-15 US US10/492,589 patent/US7317113B2/en not_active Expired - Lifetime
- 2002-07-18 MX MXPA04003517A patent/MXPA04003517A/es active IP Right Grant
- 2002-07-18 AT AT02801856T patent/ATE466847T1/de active
- 2002-07-18 JP JP2003538150A patent/JP4467976B2/ja not_active Expired - Fee Related
- 2002-07-18 SI SI200230907T patent/SI1436278T1/sl unknown
- 2002-07-18 CN CNB028205235A patent/CN100338049C/zh not_active Expired - Fee Related
- 2002-07-18 DK DK02801856.2T patent/DK1436278T3/da active
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- 2002-07-18 RU RU2004111670/04A patent/RU2285000C2/ru active
- 2002-07-18 KR KR1020047004622A patent/KR100896543B1/ko active IP Right Grant
- 2002-07-18 WO PCT/EP2002/008007 patent/WO2003035634A1/en active Application Filing
- 2002-07-18 HU HU0402020A patent/HU229256B1/hu not_active IP Right Cessation
- 2002-07-18 EP EP02801856A patent/EP1436278B1/en not_active Expired - Lifetime
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- 2002-07-18 IL IL16144402A patent/IL161444A0/xx unknown
- 2002-07-18 PL PL367981A patent/PL207878B1/pl unknown
- 2002-07-18 AU AU2002363080A patent/AU2002363080B2/en not_active Ceased
- 2002-07-18 CA CA002464336A patent/CA2464336C/en not_active Expired - Lifetime
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