JP2019513718A - 2’−フルオロ−6’−メチレン−炭素環アデノシン(fmca)及び2’−フルオロ−6’−メチレン−炭素環グアノシン(fmcg)の合成 - Google Patents
2’−フルオロ−6’−メチレン−炭素環アデノシン(fmca)及び2’−フルオロ−6’−メチレン−炭素環グアノシン(fmcg)の合成 Download PDFInfo
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- JP2019513718A JP2019513718A JP2018551831A JP2018551831A JP2019513718A JP 2019513718 A JP2019513718 A JP 2019513718A JP 2018551831 A JP2018551831 A JP 2018551831A JP 2018551831 A JP2018551831 A JP 2018551831A JP 2019513718 A JP2019513718 A JP 2019513718A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/28—Preparation of ethers by reactions not forming ether-oxygen bonds from acetals, e.g. by dealcoholysis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/253—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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Abstract
Description
B’は、
R7は、特に、C1−C20直鎖、分岐若しくは環状アルキル基、C1−C20直鎖、分岐若しくは環状アシル基、アルコキシアルキル基、フェノキシメチルなどのアリールオキシアルキル基、任意で置換されたアリール基(上述のような)及びアルコキシであって、これらはそれぞれ任意で置換されてもよい。
R8は、アミノ酸側鎖であり、好ましくは、アラニン、β−アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、シスチン、グルタミン酸、グルタミン、グリシン、フェニルアラニン、ヒスチジン、イソロイシン、リジン、ロイシン、メチオニン、プロリン、セリン、スレオニン、バリン、トリプトファン、又はチロシンから選択されるアミノ酸の側鎖である(好ましくは、R8は、アラニン、ロイシン、イソロイシン、又はスレオニンから得られ、より好ましくはアラニン−R8は、メチルである)。
R”は、C1−C20直鎖、分岐若しくは環状アルキル基、フェニル基、又はヘテロアリール基であって、それぞれ任意で置換されてもよい。
RPは、H、ニトロ、シアノ、メトキシ、又は任意で1つから3つのハロゲン置換基(好ましくはF)で置換されたC1−C3アルキル基である。
中間体8の好ましい合成
一実施形態では、本発明は、式8
FMCAは、化合物8
FMCGは、化合物8
(3aR,6R,6aR)−6−(tert−ブトキシメチル)−2,2−ジメチル−5−メチレンジヒドロ−3aH−シクロペンタ[d][1,3]ジオキソール−4(5H)−オン(2A):−78℃のTHF中の化合物1(15g、61.9mmol)の撹拌済み溶液に、滴下漏斗を用いてTHF中のLDA溶液(53.6ml、80mmol)を添加した。この溶液を−78℃で3時間撹拌し、エッシェンモーザー塩(45.8g、248mmol)を一度に添加した。この混合物を同じ温度で更に3時間、そして室温で8時間撹拌した。次にヨードメタン(131mL)を添加し、室温で更に4時間撹拌した。この混合物を、10%NaHCO3水溶液(100mL)で急冷して1時間撹拌し、塩化メチレン(2×300mL)を用いて抽出した。混ざり合った有機抽出物を10%NaHCO3水溶液(200mL)、それに続いて塩水(80mL)で洗浄し、乾燥させ(Na2SO4)、真空下で濃縮した。残渣をフラッシュシリカ(5%EtOAc/ヘキサン)で精製して、化合物2を淡黄色の油として得た。収率(11.4g、72.4%);1H NMR [500 MHz, CDCl3]: δ 6.22 (d, J = 2 Hz, 1 H), 5.52 (d, J = 1.5 Hz, 1 H), 4.59 (d, J = 5 Hz, 1 H), 4.48 (d, J = 4.5 Hz, 1 H), 3.64 (dd, J = 3.5, 8.5 Hz, 1 H), 3.46 (dd, J = 3.5, 8.5 Hz, 1 H), 3.09 (m, 1 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.08 (s, 9 H);
MS (ESI) m/z: 255 [M+H]+
MS (ESI) m/z: 257 [M+H]+
MS (ESI) m/z: 258 [M+H]+
MS (ESI) m/z: 512 [M+H]+
MS (ESI) m/z: 514 [M+H]+
(1) http://www.who.int/mediacentre/factsheets/fs204/en/
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実施例の第2のセット(図2及び3のスキーム1及び2と関連)
参考文献の第2のセットが適用される。
本発明者らは、VinceラクタムによるFMCAの効率的かつ立体選択的な合成を発表している13。しかしながら、Vinceラクタムによる過去に説明された合成における、ヒドロキシ基の配置の反転を含めたアミノ基のジアゾ化−脱離ステップの低い収率は、その合成経路をFMCAの大規模合成について不可能とする。FMCAの合成のための新しい現実的な手法の探求において、本発明者らの研究グループは、このヌクレオシドの相当量の合成のために利用できる全ての合成の可能性を再検討した。この実施例のセットでは、本発明者らは、工業規模の合成で用いられることができる、中間体8を介したFMCAの実行可能かつ極めて実用的な合成を報告する。ここで説明する経路は、収率がより良好であり、中間体形成に関するステップが少なく、更にいくつかのステップにおいて高価なカラムクロマトグラフィによる精製を効率的に回避している。これらの改善により、FMCAの大規模合成のためのより要求にかなう合成経路が提供される。過去の文書で明らかにされているように13、Boc保護アデニンによる縮合の前に、重要な中間体(フッ化糖)のヒドロキシル基の配置の反転が必要であったが、本発明の合成ではこのステップが排除される。光延結合の標的のヌクレオシドを良好な収率で生成する条件下で、供給された中間体8をdi−Bocアデニンと直接結合させる。以前の合成経路からこれらの問題を排除することによって、本発明の合成は遥かに実用的となり、7ステップでのFMCAの大規模合成を実現可能とする。
薬剤耐性変異体HBVに対するFMCA及びFMCAP、あるいはFMCG及びFMCGPの更に保証されるインビボの生物学的スクリーニングのために、要求にかなうスケーラブルなFMCAの合成が必要とされており、これは本明細書では市販のケトン1を用いて記載される。化合物2の保護基の選択的な開環及びこれに続く化合物3のアリル保護により、化合物4が良好な収率で得られる。TBDPSの脱保護を含む化合物4のフッ素化により、重要な中間体8が得られる。この中間体にBoc保護アデニンとの光延結合を用い、それに続く脱保護によって、標的化合物10(FMCA)が7ステップで、およそ6.7%の全収率で得られる。クロロリン酸11AとFMCAとの更なる結合により、ホスホロアミダイトプロドラッグ12(FMCAP)が良好な収率で生成される。この合成におけるステップの削減及び安価な試薬の使用は、この合成が代替的な既知の手法よりもFMCAの大規模調製に関してはるかに都合が良いことを実証する。この合成の熟練した尽力の間に、重要な2’−デオキシ糖6が単離された。化合物6は、現在使用されている抗HBV薬のエンテカビルの合成を含む、多様な2’−デオキシヌクレオシ(チ)ドの合成に使用されることができる。
一般的な分析方法
試薬及び無水溶媒を購入し、更に精製することなく使用した。反応を薄層クロマトグラフィプレート(TLCシリカゲルGF250ミクロン)で監視し、これはUVランプ(254nm)を用いて可視化され、メタノール中の硫酸の15%溶液を用いて展開した。融点をデジタル融点測定装置で記録し、これは補正されない。核磁気共鳴スペクトルを、テトラメチルシランを内部標準として用いて、1H NMR、19F NMRに関しては500MHzで、13C NMRに関しては125MHzで記録した。CFCl3(トリクロロ−フルオロメタン)を、19F−NMRのための内部標準(基準)として使用した。化学シフト(δ)は、s(シングレット)、bs(ブロードシングレット)、d(ダブレット)、t(トリプレット)、q(カルテット)、m(マルチプレット)、dd(ダブルダブレット)及びdt(ダブルトリプレット)として示される。旋光度をデジタル旋光計で測定した。ESI高分解能質量スペクトルをQ−TOF質量分析計で記録した。シリカゲルでコーティングしたガラス上で薄層クロマトグラフィを行った。以下の合成ステップは、添付の図2のスキーム1及び図3のスキーム2に示される。
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Claims (29)
- 化合物8
化合物1を溶媒中の強塩基と低温で反応させることによって、化合物1のケト基にα位のメチレン基を導入した後、エッシェンモーザー塩と、それに続いてヨードメタンとを添加して、以下の化合物2A
あるいは、化合物1を、溶媒中のジイソプロピルアンモニウムトリフルオロ酢酸塩及びジイソプロピルアミンの存在下で、パラホルムアルデヒドと反応させて化合物2Aを生成した後に、化合物2Aのケト基を、低温の溶媒中のルイス酸の存在下で、水素化ホウ素ナトリウムを用いて立体選択的に還元して化合物2を生成することによって、化合物1から化合物2を生成するステップと、
化合物2を溶媒中のAlMe3と反応させて、化合物3
化合物3を、弱塩基中の塩化tert−ブチルジフェニルシリルと反応させて、化合物4
化合物4を、フッ素化剤(好ましくは三フッ化ジエチルアミノ硫黄DAST)でフッ素化して2’位を立体選択的にフッ素化することにより、化合物7
を含み、化合物8の合成は、ワンポットで、又は化合物2A、2、3、4、7及び8のいずれか1つ以上を生成するためのいずれか1つ以上のステップでの任意の分離及び/又は精製を伴う複数のステップで行われることができる、プロセス。 - 化合物8
化合物1を、溶媒中のジイソプロピルアンモニウムトリフルオロ酢酸塩及びジイソプロピルアミンの存在下で、パラホルムアルデヒドと反応させて、化合物2A
化合物2を溶媒中のAlMe3と反応させて、化合物3
化合物3を、弱塩基中の塩化tert−ブチルジフェニルシリルと反応させて、化合物4
化合物4を三フッ化ジエチルアミノ硫黄(DAST)でフッ素化して、化合物4の2’位を立体選択的にフッ素化することにより、化合物7
を含み、化合物8の合成は、ワンポットで、又は化合物2A、2、3、4、7及び/又は8を生成するためのいずれか1つ以上のステップでの任意の分離及び/又は精製を伴う複数のステップで行われることができる、プロセス。 - 化合物2は化合物1から、精製及び/又は分離を行わずにワンポットで調製される、請求項2に記載のプロセス。
- 化合物8
化学構造
化合物8Pを脱保護して、化合物10(FMCA)
を含み、上記の合成は、ワンポットで、又は化合物8P及び化合物10のいずれかの生成について分離及び/又は精製を伴う複数のステップで行われることができる、プロセス。 - 少なくとも化合物10は精製及び単離される、請求項6に記載の方法。
- 化合物8
化学構造
化合物9Pを脱保護し、6−クロロ基をケトン基へ変換して、化合物11(FMCG)
を含み、上記の合成は、ワンポットで、又は化合物9P及び/又は化合物11の生成について分離及び/又は精製を伴う複数のステップで行われることができる、プロセス。 - 各中間体及び最終生成物(化合物2A、2、3、4、7及び8)は、分離及び精製される、請求項1に記載の方法。
- 化合物2A、2、3、4、7及び8のいずれか1つ以上が分離及び/又は精製される、請求項1に記載の方法。
- 化合物8のみが分離及び/又は精製される、請求項1に記載の方法。
- 化合物2、3、4、7及び8が分離及び精製される、請求項2に記載の方法。
- 化合物2、3、4、7及び8のいずれか1つ以上が分離及び/又は精製される、請求項2に記載の方法。
- 化合物8Pが分離及び精製される、請求項4又は5に記載の方法。
- 化合物9が分離及び精製される、請求項6に記載の方法。
- 化合物8P及び化合物10の両方が分離及び精製される、請求項4又は5に記載の方法。
- 化合物10が分離及び精製される、請求項4又は5に記載の方法。
- 化合物9及び化合物10の両方が分離及び精製される、請求項6に記載の方法。
- 化合物9P及び/又は化合物11が分離及び精製される、請求項8又は9に記載の方法。
- 化合物9P及び化合物11の両方が分離及び精製される、請求項8又は9に記載の方法。
- 前記脱保護のステップは、高温の溶媒中のトリフルオロ酢酸及び水の存在下で行われる、請求項4〜11のいずれかに記載の方法。
- Rはメチル又はイソプロピルである、請求項24に記載の方法。
- 前記化合物2A、2、3、4、5、6、7、8、8P、9、9P、9G、10、11、12若しくは12G、10P又はそれらの塩のいずれか1つ以上。
- 化合物2A、2、3、4、5、6、7、8、8P、9、9P又は9Gのいずれか1つ以上。
- 請求項28に記載の方法であって、
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US201662319694P | 2016-04-07 | 2016-04-07 | |
US62/319,694 | 2016-04-07 | ||
PCT/US2017/020165 WO2017176392A1 (en) | 2016-04-07 | 2017-03-01 | Synthesis of 2'-fluoro-6'-methylene-carbocyclic adenosine (fmca) and 2'-fluoro-6'-methylene-carbocyclic guanosine (fmcg) |
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US9700560B2 (en) * | 2009-11-16 | 2017-07-11 | University Of Georgia Research Foundation, Inc. | 2′-fluoro-6′-methylene carbocyclic nucleosides and methods of treating viral infections |
CN109232637B (zh) * | 2018-10-29 | 2020-11-24 | 常州博海威医药科技股份有限公司 | 一种恩替卡韦中间体的制备方法 |
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US8816074B2 (en) * | 2009-11-16 | 2014-08-26 | University of Georgia Foundation, Inc. | 2′-fluoro-6′-methylene carbocyclic nucleosides and methods of treating viral infections |
US9700560B2 (en) * | 2009-11-16 | 2017-07-11 | University Of Georgia Research Foundation, Inc. | 2′-fluoro-6′-methylene carbocyclic nucleosides and methods of treating viral infections |
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MY192374A (en) | 2022-08-17 |
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PH12018501899A1 (en) | 2019-05-15 |
HK1257543A1 (zh) | 2019-10-25 |
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EP3440041A4 (en) | 2019-10-23 |
AU2017247103A1 (en) | 2018-09-27 |
US10533008B2 (en) | 2020-01-14 |
JP6975166B2 (ja) | 2021-12-01 |
PH12021550639A1 (en) | 2021-11-15 |
KR20180134374A (ko) | 2018-12-18 |
EP3440041B1 (en) | 2020-11-18 |
EP3789374A3 (en) | 2021-07-21 |
WO2017176392A1 (en) | 2017-10-12 |
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