JP6104504B2 - ヌクレオシド類似体 - Google Patents
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- 0 C[C@@](C(O)=O)NP(O)(OC[C@]([C@@]([C@@]1(C)F)O)O[C@]1N(C=CC(N1)=*)C1=O)=O Chemical compound C[C@@](C(O)=O)NP(O)(OC[C@]([C@@]([C@@]1(C)F)O)O[C@]1N(C=CC(N1)=*)C1=O)=O 0.000 description 1
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Description
本願は、2008年12月23日出願の米国仮特許出願第61/140,441号明細書に対する優先権を請求するものであり、その内容全体が参照により組み込まれる。
Flaviviridaeウイルス科は少なくとも次の3つの全く異なる属を含む。すなわち、畜牛および豚の疾病の原因となるペスチウイルス属;デング熱や黄熱病などの疾病の主因であるフラビウイルス属;そしてHCVを唯一の成員とするヘパシウイルスである。フラビウイルスは、血清学的関連性に基づいて複数の群に分けられる68超の成員を含む(Calisheret al.、J.Gen.Virol、1993、70、37−43)。臨床的症候はさまざまであり、発熱、脳炎および出血熱を含む(Fields Virology、Editors:Fields、B.N.、Knipe、D.M.およびHowley、P.M.、Lippincott−Raven Publishers、Philadelphia、PA、1996、Chapter31、931−959)。ヒトの疾病に結びつけられる世界的関心の的であるフラビウイルスには、デング出血熱ウイルス(DHF)、黄熱病ウイルス、ショック症候群および日本脳炎ウイルスが含まれる(Halstead、S.B.、Rev.Infect.Dis.、1984、6、251−264;Halstead、S.B.、Science、239:476−481、1988;Monath、T.P.、New Eng.J.Med、1988、319、64 1−643)。
という構造式Iで表わされる精製化合物または構造式IIで表わされる精製化合物において、
RがOMe、OEt、−N(−CH2CH2CH2−)(アゼチジン−1−イル)またはOHである化合物、
あるいはその塩、薬学的に許容される塩、水和物、溶媒和物または結晶質形態を対象としている。
本明細書中で使用するある物という語句は、1つ以上のその物、例えば、1つ以上の化合物または少なくとも1つの化合物を指す化合物を意味する。したがってその物、「1つ以上」および「少なくとも1つ」という用語は、本明細書において互換的に使用可能である。
という構造式Iで表わされる精製化合物または構造式IIで表わされる精製化合物において、
RがOMe、OEt、−N(−CH2CH2CH2−)(アゼチジン−1−イル)、OHである;
化合物、
あるいはその塩、薬学的に許容される塩、水和物、溶媒和物または結晶質形態を対象としている。
という構造式Iで表わされる精製化合物において、
Rが−N(−CH2CH2CH2−)(アゼチジン−1−イル)である;
化合物、
あるいはその塩、薬学的に許容される塩、水和物、溶媒和物または結晶質形態を対象としている。
本発明の第6の実施形態は、本明細書中で開示されているいずれかのウイルス因子の治療用組成物において、賦形剤、担体、希釈剤および等価の媒質から選択された薬学的に許容される媒質と;構造式Iで表わされる精製化合物または構造式IIで表わされる精製化合物、あるいはその塩、薬学的に許容される塩、水和物、溶媒和物または結晶質形態、を含む組成物を対象としている。
機械的撹拌器、添加用漏斗および温度計の備わった乾燥した5Lの三つ口丸底フラスコに、ラクトン((2R,3R,4R)−3−(ベンゾイルオキシ)−4−フルオロ−4−メチル−5−オキソテトラヒドロフラン−2−イル)メチルベンゾエート))(1.379g、1.018mol)を投入した。固体を無水THF(1.75L)中に溶解させ、窒素雰囲気下で−30℃まで冷却した。リチウムトリ−tert−ブトキシアルミノヒドリドの溶液(THF中1.0M、1.527L)を、1時間にわたり撹拌し−30℃の温度に保ちながら、ラクトン溶液に添加した。添加を終えた後、温度をゆっくりと上昇させ、TLCにより反応を追跡した(ラクトールRf0.4、30%のヘキサン中EtOAc)。反応は1時間15分後に完了した(温度は−10℃に達した)。添加用漏斗を介して酢酸エチル(900mL)を添加することにより反応を急冷した。飽和NH4Cl(40mL)を0℃で添加した。曇った混合物を10L丸底フラスコ中に傾瀉する。残った固体残渣を濾過し、酢酸エチル(2×200mL)で洗浄した。濾液を、傾瀉済み溶液と合わせ、合わせた溶液を減圧下で濃縮した。油性残渣を酢酸エチル(2L)中に溶解させ、3NのHCl(600mL)で洗浄した。水層を酢酸エチル(3×400mL)で逆抽出した。合わせた有機層を水(3×800mL)、飽和NaHCO3(400mL)および塩水(400mL)で洗浄した。有機溶液をMgSO4上で乾燥させ、濾過し、減圧下で濃縮して、明褐色の油性残渣を得た。吸引およびヘキサン中の酢酸エチル5%、10%、20%および30%の段階的勾配を用いて(各々約5L)残渣をプラグカラム(6Lの焼結ガラス漏斗内に詰めた40〜63ミクロンのシリカゲル2.2kg、シリカゲルの長さ22cm、直径15cm)により精製した。生成物含有画分を合わせ、無色の非常に濃い液体(310.4g)まで減圧下で濃縮した。
1H−NMR(DMSO−d6)β−異性体、δ=5.20(dd、1H、OH);α−異性体、δ=5.40(dd、1H、OH)。(β−ラクトール)。(DMSO−d6):δ7.99(m、2H、芳香族)、7.93(m、2H、芳香族)、7.70(m、1H、芳香族)、7.61(m、1H、芳香族)、7.55(m、2H、芳香族)、7.42(m、2H、芳香族)、7.32(dd、1H、C1H)、5.54(dd、1H、C3−H)、5.20(dd、1H、OH)、4.55−4.50(m、1H、C5−Ha)、4.46−4.40(m、2H、C5−HbおよびC4−H)、1.42(d、3H、CH3)。
無水ジロクロメタン(5.6L)を反応装置内に投入し、−22℃以下まで冷却した。トリフェニルホスフィン(205.4g、0.783mol)を低温溶媒に添加し、懸濁液を撹拌して溶液を形成させた。固体形態のラクトール(2、209.4g、0.559mol)を低温溶液に添加し、15分間撹拌した。溶液温度を窒素ガス流の下で−22℃〜−20℃の間に維持する一方で、四臭化炭素(278.2g、0.839mol)を少量ずつ添加した(約30分)。CBr4の添加を終了した後、温度を−17℃まで20分間にわたりゆっくりと上昇させた。TLC(Rfs0.61(α)、0.72(β)、0.36ラクトール;ヘキサン中20%EtOAc)により反応が95%超完了と判断した。反応溶液を直ちに、フラッシュクロマトグラフィグレードのシリカゲル(40〜63ミクロン)が230g入った容器に移した。撹拌した混合物を、2.5L焼結ガラス製ブフナー漏斗中にシリカゲルパッド(680g)を通して通過させた。減圧下で濾液を約800mLまで濃縮させ、粗製生成物のα/β異性体の比は1H−NMRにより決定した場合、10:1であった。(CDCl3)δ=6.35(s、α C1−H)、6.43、(d、β C1−H)。6Lの焼結ガラス製ブフナー漏斗中で2.1kgのシリカゲルを用いてプラグカラムクロマトグラフィにより残渣を精製し、ヘキサン中1%、5%、8%、12%のEtOAcの段階的勾配溶離(各々約4L)で(吸引によって)溶出して非極性不純物を除去し、それに続いてヘキサン中12%、25%EtOAc(合計6L)で生成物を溶出した。生成物含有画分を合わせて2つの画分の形に分け、減圧下で濃縮し、無色の油になるまで、真空下で乾燥させた(0.1mmHg、周囲温度、20時間)。主画分(197g、89%α/β=20:1)。数週間にわたり0℃に放置した時点でわずかな分量の油からアルファ異性体が結晶化して、mp59−61℃の大きく薄い平板を提供した。早期のより選択性の低いラン(run)由来のアルファおよびベータ生成物油の混合物から、純粋なベータ異性体が結晶化して、mp77〜79℃の針状物を提供した。
1H−NMR(β−ブロミド)(CDCl3):δ=8.08(m、2H、芳香族)、8.04(m、2H、芳香族)、7.62(m、1H、芳香族)、7.54−7.45(m、3H、芳香族)、7.35(m、2H、芳香族)、6.43(d、1H、C1−H)、6.04(dd、1H、C3H)、4.78−4.73(m、2H、C4−HおよびC5−Ha)、4.63−4.58(m、1H、C5−Hb)、1.76(d、3H、CH3)。α−ブロミド、α/β=20:1)(CDCl3):δ8.13(m、2H、芳香族)、8.02(m、2H、芳香族)、7.63−7.56(m、2H、芳香族)、7.50−7.42(m、4H、芳香族)、6.34(s、1H、C1−H)、5.29(dd、1H、C3H)、4.88(m、1H、C4−H)、4.78(dd、1H、C5−Ha)、4.63(dd、1H、C5−Hb)、1.72(d、3H、CH3)。
12L3つ口丸底フラスコに、6−クロロ−2−アミノプリン(225.4g、1.329mol)を投入した。無水tert−BuOH(4.5L)を添加し、溶液を周囲温度で機械的撹拌器を用いて撹拌した。撹拌しながら窒素ガス流の下でカリウムtert−ブトキシド(固体、151.6g、1.35mol)を少量ずつ添加した。混合物をさらに30分間室温で撹拌した。5L丸底フラスコに対しα−ブロミド(3、197g、0.451mol)および3Lの無水アセトニトリルを周囲温度で装填した。ブロミド溶液を、1分間にわたり周囲温度でプリンベースの懸濁液に添加した。5Lフラスコをアセトニトリル(2×1L)で洗い流して、ブロミドを反応混合物に完全に移した。加熱マントルおよびコントローラを用いて混合物を2時間にわたり50℃まで漸進的に加熱し、20時間撹拌した。反応は、TLCベータ(Rf0.28、ヘキサン中の30%のEtOAc)が示す通り、ほぼ完全であった。飽和NH4Cl(200mL)を添加することで反応を急冷して懸濁液を形成した。懸濁した固体1を、2.5Lの磁器製ブフナー漏斗中の3cmセライトパッドを通した濾過により除去した。トルエン(3×100mL)で固体を洗浄した。合わせた濾液を、pH7まで6NのHCl溶液(約220mL)を添加することで中和した。減圧下で混合物を濃縮した。混合物の体積が約3分の1に減少した時点で、同様に濾過により追加の沈殿固体を除去した。濾液を約800mLの体積までさらに濃縮した。残渣をプラグカラム(6Lの焼結ガラス製ブフナー漏斗中の1.6kgのフラッシュグレードのシリカゲル)上に装填し、非極性不純物を除去するためのヘキサン中10%の酢酸エチル(6L)、少量のラクトールを提供するためのヘキサン中30%の酢酸エチル(6L)そして次に、主要量の生成物を溶出するためのヘキサン中40%〜45%の酢酸エチルの勾配で(吸引によって)溶出した。生成物含有画分を合わせ、減圧下で濃縮し、真空下で乾燥させ(0.2mmHg、24時間、周囲温度)、白色発泡体固体(150.7g、NMRによるβ/α=14:1)を得た。
1H−NMR(CDCl3)ベータ:δ=1.33(d、22.4Hz、2’−C−CH3)、アルファ:1.55(d、22Hz、2’−C−CH3)。
1H−NMR(純粋β−アノマー、CDCl3):δ=8.03(m、2H、芳香族)、7.93(m、2H、芳香族)、7.88(s、1H、C8−H)、7.60(m、1H、芳香族)、7.50(m、1H、芳香族)、7.44(m、2H、芳香族)、7.33(m、2H、芳香族)、6.44(dd、1H、C1’−H)、6.12(d、1H、C3’−H)、5.35(s、2H、NH2)、5.00(dd、1H、C5’−Ha)、4.76(m、1H、C4’−H)、4.59(dd、1H、C5’−Hb)、1.33(d、3H、CH3)。
1H−NMR(α−異性体、CDCl3):δ=8.11−8.09(m、3H、芳香族およびC8−H)、8.01(m、2H、芳香族)、7.63(m、1H、芳香族)、7.55(m、1H、芳香族)、7.48(m、2H、芳香族)、7.39(m、2H、芳香族)、6.35(d、1H、C1’−H)、5.76(dd、1H、C3’−H)、5.18(s、2H、NH2)、4.93−4.89(m、1H、C4’−H)、4.75−4.71(m、1H、C5’−Ha)、4.58−4.54(m、1H、C5’−Hb)、1.55(d、3H、CH3)。
乾燥した350mL密閉圧力フラスコ(Chemglass)に、(2R,3R,4R,5R)−5−(2−アミノ−6−クロロ−9H−プリン−9−イル)−2−(ベンゾイルオキシメチル)−4−フルオロ−4−メチルテトラヒドロフラン−3−イルベンゾエート(4、3.6g、6.85mmol)と150mLの純粋エタノールを添加した。アゼチジンヒドロクロリド(2.56g、27.4mmol)を添加し、その後続けてトリエチルアミン(4.16g、41.1mmol)を添加した。懸濁液を密閉状態で5時間攪拌し70℃まで加熱した。全ての出発材料が消費されたが、TLCにより示されるようにベンゾイル基だけは残留した。ナトリウムメトキシド(7.8mL、34.3mmol、メタノール中の25%溶液)を混合物に添加し、50℃で加熱した。反応は、3.5時間後に完了した。反応混合物を室温まで冷却し、氷酢酸(0.41g、6.85mmol)の添加により中和した。混合物を減圧下で濃縮し、その後残渣を酢酸エチルで研和した。得られた固体を濾過により除去し、固体をEtOAc(2×15mL)で洗浄した。濾液を減圧下で濃縮し、残渣をカラムクロマトグラフィ(Analogix、120gのカートリッジ、DCM中0〜15%MeOHの勾配)によって精製した。純粋な生成物含有画分を合わせ、減圧下で濃縮し、乾燥させて(50℃、0.2mmHg、17時間)、明るいピンク色の発泡体固体(2.15g、6.35mmol、93%)を得た。
1H−NMR(DMSO−d6)δ=8.00(s、1H、C8−H)、6.03(s、2H、NH2)、6.00(d、1H、C1’−H)、5.64(d、1H、3’−OH)、5.24(t、1H、5’−OH)、4.24−4.10(m、5H、アゼチジンのN−CH2、C3’−H)、3.90−3.81(m、2H、C4’−HおよびC5’−Ha)、3.69−3.64(m、1H、C5’−Hb)、2.37(ペンタ、2H、アゼチジンの中心CH2)、1.05(d、3H、C2’−CH3)。
乾燥した500mL丸底フラスコに、(2R,3R,4R,5R)−5−(2−アミノ−6−クロロ−9H−プリン−9−イル)−2−(ベンゾイルオキシメチル)−4−フルオロ−4−メチルテトラヒドロフラン−3−イルベンゾエート(4、8.0g、15.2mmol)および無水ベンジルアルコール(128mL)を添加した。別の乾燥した250mL丸底フラスコに、NaH(鉱物油中60%、2.44g、60.8mmol)および無水DMF(40mL)を投入した。懸濁液を氷水浴中で0℃で撹拌した。シリンジによってベンジルアルコール(27mL)を滴下により添加した。溶液をゆっくりと形成させ、室温で窒素雰囲気下において素早くヌクレオシド懸濁液にそれを移した。混合物を50℃まで加熱し、撹拌した。反応は3時間後に完了し、これを周囲温度まで冷却した。4NのHCl(12mL)を添加することにより約pH=7までそれを中和した。溶液を減圧(4mbar、90℃の浴)下で濃縮した。曇った残渣をジクロロメタン(100mL)で希釈し、水(3×30mL)、塩水(30mL)で洗浄し、Na2SO4上で乾燥させた。懸濁液を濾過し、濾液を減圧下で濃縮して油性残渣を得た。これをカラムクロマトグラフィ(Analogix、DCM中MeOH 0〜8%の勾配)により精製した。生成物はDCM中4%のMeOHで溶出した。生成物含有画分を合わせ、減圧下で濃縮し、乾燥させて(50℃、0.2mmHg、17時間)、白色発泡体固体(4.57g、11.7mmol、77.2%)を得た。
1H−NMR(DMSO−d6)δ=8.18(s、1H、8−H)、7.53−7.51(m、2H、芳香族−H)、7.43−7.34(m、3H、芳香族−H)、6.66(s、2H、NH2)、6.05(d、1H、C1’−H)、5.67(d、1H、3’−OH)、5.48(dd、2H、ベンジルのCH2)、5.25(t、1H、5’−OH)、4.18(dt、1H、C3’−H)、3.92−3.82(m、2H、C4’−HおよびC5’−Ha)、3.71−3.66(m、1H、C5’−Hb)、1.07(d、3H、C2’−CH3)。
MeOH(10ml)中の4の懸濁液(500mg、0.951mmolに、MeOH中のNaOMe(25%、0.90ml)を添加した。3時間50℃まで混合物を加熱した。その後、それをAcOHで中和した。それを濃縮し、EtOAC(30ml)を添加した。不溶性固体を濾過により除去した。濾液を濃縮し、溶離剤としてCH2Cl2中の0〜15%のMeOHを用いてシリカゲル上のフラッシュカラムクロマトグラフィによって精製した。白色固体として化合物7(203mg、68.3%)を得た:1H NMR(400MHz、DMSO−d6)δ8.17(s、1H)、6.61(s、2H)、6.05(d、J=17.6Hz、1H)、5.67(d、J=7.2Hz、1H)、5.25(t、J=4.8Hz、1H)、4.18(dt、J=25.6、8.0Hz、1H)、3.96(s、3H)、3.91(dm、J=9.2Hz、1H)、3.85(ddd、J=2.0、5.2、12.8Hz、1H)、3.69(ddd、J=2.8、3.2、12.0Hz、1H)、1.06(d、J=22.8Hz、3H);tR=0.52(99.1%);C12H17FN5O4314.3についてのLRMS(ESI)[M+H]+計算値、実際値314.2。
乾燥した100mL丸底フラスコに、フェニルジクロロホスフェート(1.72g、8.15mmol)および無水ジクロロメタン(17mL)を添加した。アミノエステル(1.42g、10.2mmol)を添加し、懸濁液を−5℃まで冷却した。N−メチルイミダゾール(3.34g、40.7mmol)をシリンジによって一度に添加し、溶液を窒素雰囲気下で1時間−5℃で撹拌した。その後ヌクレオシド(5、1.38g、4.07mmol)(発泡体固体)を一度に添加し、溶液を1時間にわたり周囲温度まで暖めることができた。周囲温度で4時間の後、TLC(DCM中5%のMeOH)は、不完全な反応(SM(出発材料)が約30%残留)だけでなく、より極性の低い不純物の成長も示していた。飽和NH4Cl(20ml)を添加することにより反応を急冷し、ジクロロメタン(20mL)で希釈した。有機層を分離し、水(5×30mL)、塩水(20mL)で洗浄し、Na2SO4上で乾燥させた。生成物含有溶液を濾過し、減圧下で濃縮して、粗製油性残渣3.26gを得た。これをカラムクロマトグラフィ(Analogix、40gのカートリッジ、DCM中のMeOHの勾配0%〜10%)によって精製した。生成物はDCM中4%のMeOHで溶出した。純粋な生成物含有画分を合わせ、減圧下で濃縮し、乾燥させて(50℃、0.2mmHg、17時間)白色発泡体固体(1.322g、2.28mmol、56%)を得た。HPLC純度99.25%。生成物のNMRスペクトルは、それが55:45の比での2つのジアステレオ異性体の混合物であることを示していた。
1H−NMR(DMSO−d6)δ=7.80(s、1H、1つの異性体の8−H)、7.80(s、1H、別の異性体の8−H)、7.38−7.33(m、2H、芳香族−H)、7.22−7.14(m、3H、芳香族−H)、6.09(s、2H、NH2)、6.12−6.02(m、2H、C1’−HおよびNH)、5.83(d、1H、1つの異性体の3’−OH)、5.77(d、1H、別の異性体の3’−OH)、4.46−4.05(m、8H、アゼチジンのNCH2、アミノエステルのα−H、C3’−H、C4’−H、C5’−Ha)、3.89−3.79(m、1H、C5’−Hb)、3.56(s、3H、1つの異性体中のアミノエステルのOCH3)、3.54(s、3H、別の異性体中のアミノエステルのOCH3)、2.37(ペンタ、2H、アゼチジンの中心CH2)、1.21(d、3H、1つの異性体中のアミノエステルのα−CH3)、1.19(d、3H、別の異性体中のアミノエステルのα−CH3)、1.08(d、3H、C2’−CH3)。
31PNMR(DMSO−d6):δ4.85(1つの異性体)、4.77(その他の異性体)。
乾燥した100mL丸底フラスコに、フェニルジクロロホスフェート(3.29g、15.58mmol)と無水ジクロロメタン(24mL)を投入する。アミノエステルトシレート(白色粉末)を添加し、溶液を窒素下で−5℃まで冷却する。N−メチルイミダゾール(4.92g、59.94mmol)を乾燥したシリンジによって一度に添加し、得られた無色透明溶液を1時間−5℃で撹拌する。その後、ヌクレオシド(6)固体を窒素下で一度に溶液に添加し(2.334g、5.99mmol)、混合物を周囲温度まで温めて無色の溶液を得る。反応の進捗はTLC(ジクロロメタン中の5%エタノール)により監視する。ジクロロメタン(30mL)と1NのHCl(60mL)を添加することによって反応をなおも急冷する。有機層を分離し、水層をジクロロメタン(2×20mL)で抽出する。合わせた有機層を水(2×40mL)、飽和NaHCO3(30mL)、水そして塩水で洗浄する。有機層をNa2SO4上で乾燥させる。濾過による固体の除去の後、濾液を減圧下で濃縮してゴム状残渣(7.28g)を得る。カラムクロマトグラフィ(Analogix、80gのカートリッジ、DCM中0〜10%のMeOHの勾配)によって残渣を精製する。生成物はDCM中2%のMeOHで溶出する。生成物含有画分を合わせ、減圧下で濃縮し、乾燥させて(50℃、0.2mmHg、17時間)、白色発泡体固体を得る。出発ヌクレオシドの一部(0.257g)も回収する。収量は、消費された出発材料に基づいている。
出発材料(9、1.92g、2.8mmol)の入った乾燥した250mL丸底フラスコに、純粋無水エタノール(50mL)を添加する。木炭上のパラジウム(10%、120mg)を添加する。フラスコ中の雰囲気を水素と交換し、混合物を室温で3.5時間1atmの水素ガス下で撹拌する。TLCにより反応は完了と判断され、木炭上のPdを濾過によって除去し、エタノール(2×10mL)で洗浄する。濾液を減圧下で濃縮して、固体の残渣を得る。固体をシリカゲル(10g)と混合して、カラムクロマトグラフィ(Analogix、40gのカートリッジ、DCM中1%〜16%のMeOHの勾配)により精製する。生成物含有画分を合わせ、減圧下で濃縮し、乾燥させて(50℃、0.2mmHg、17時間)、白色粉末(1.43g、86%)を得る。HPLC純度99.55%。
THF(1.5ml)中の7(50mg、0.16mmol)およびN−メチルイミダゾール(0.10ml、1.3mmol)の溶液に、0℃で滴下により、THF中のホスホロクロリデート(1.0M、0.48ml)を添加した。反応物をゆっくりと室温まで温め、1時間撹拌した。その後水(0.1ml)とEtOAc(5ml)を添加した。飽和一塩基性クエン酸ナトリウム水(2ml×2)、飽和NaHCO3水(2mL×1)を用いて有機溶液を洗浄し、乾燥させ(MgSO4)、濃縮した。粗製油を、溶離剤としてCH2Cl2中の0〜8%のiPrOHを用いたシリカゲル上のフラッシュカラムクロマトグラフィによって精製して、白色固体としてホスホラミデート(36mg、39%、2:1のジアステレオマー混合物)を得た:1H NMR(400MHz、DMSO−d6)δ7.97(s、0.66H)、7.95(s、0.34H)、7.39−7.30(m、2H)、7.25−7.13(m、3H)、6.63(bs、2H)、6.11(d、J=18.8Hz、0.34H)、6.09(d、J=19.2Hz、0.66H)、6.06−5.88(m、1H)、5.90−5.78(m、1H)、4.80(septet、J=6.8Hz、1H)、4.45−4.24(m、3H)、4.16−4.05(m、1H)、3.96(s、3H)、3.84−3.70(m、1H)、1.28−1.03(J=7.2Hz、12Hとしてmは1.20でのdを含む);31P NMR(162MHz、DMSO−d6)δ4.91、4.72;tR=1.16(33.1%)、1.18(63.9%);C24H33FN6O8PについてのLRMS(ESI)[M+H]+計算値583.5、実際値583.4。
化合物8(150mg、0.269mmol)をトリエチルアミン(2mL)および水(0.5mL)の中に懸濁させ、20時間60℃で加熱した。その後、揮発性構成成分を減圧下で蒸発させた。溶離剤としてiPrOH中の0〜15%のNH4OHを用いてシリカゲル上のフラッシュカラムクロマトグラフィにより粗製生物を精製した。白色固体として生成物を得た(101mg、80%):1H NMR(400 MHz、DMSO−d6)δ7.93(s、1H)、6.10(bs、2H)、5.97(d、J=17.2Hz、1H)、4.44−3.86(m、10H)、2.37(quintet、J=7.6Hz、2H)、1.10(d、J=6.8Hz、3H)、1.05(d、J=22.4Hz、3H);31P NMR(162MHz、DMSO−d6)δ8.72;tR=0.55(97.4%);C17H26FN7O7PについてのLRMS(ESI)[M+H]+計算値490.4、実際値、490.4。
化合物10(110mg、0.204mmol)をトリエチルアミン(2mL)および水(0.5mL)の中に懸濁させ、20時間60℃で加熱した。その後揮発性構成成分を減圧下で蒸発させた。溶離剤としてiPrOH中の0〜20%のNH4OHを使用するシリカゲル上のフラッシュカラムクロマトグラフィにより粗生成物を精製した。白色固体として生成物を得た(74mg、81%):1H NMR(400MHz、DMSO−d6)δ7.88(s、1H)、6.68(bs、2H)、5.93(d、J=18.0Hz、1H)、4.42−3.83(m、6H)、1.11(d、J=7.2Hz、3H)、1.07(d、J=22.4Hz、3H);31P NMR(162MHz、DMSO−d6)δ8.90;tR=0.50(98.7%)C14H21FN6O8Pについての;LRMS(ESI)[M+H]+計算値451.3、実際値451.3。
化合物11(110mg、0.189mmol)をトリエチルアミン(2mL)および水(0.5mL)の中に懸濁させ、48時間60℃で加熱した。その後揮発性構成成分を減圧下で蒸発させた。溶離剤としてiPrOH中の0〜20%のNH4OHを使用するシリカゲル上のフラッシュカラムクロマトグラフィにより粗生成物を精製した。白色固体として生成物を得た(88mg、97%):1H NMR(400MHz、DMSO−d6)δ8.08(s、1H)、6.67(bs、2H)、6.03(d、J=18.0Hz、1H)、4.44−3.70(mは3.96でのsを含む、8H)、3.39(m、1H)、1.10(d、J=7.2Hz、3H)、1.05(d、J=22.8Hz、3H);31P NMR(162MHz、DMSO−d6)δ8.52;tR=0.61(96.3%);C15H23FN6O8PについてのLRMS(ESI)[M+H]+計算値465.3、実際値465.3。
化合物15は化合物14と類似の方法で調製するように企図されている。
化合物16((2S)−イソプロピル2−((((2R,3R,4R,5R)−5−(2,4−ジオキソ−3,4−ジヒドロピリミジン−1(2H)−イル)−4−フルオロ−3−ヒドロキシ−4−メチルテトラヒドロフラン−2−イル)メトキシ)(フェノキシ)ホスホリル−アミノ)プロパノエート)を、特定されたその主題全体が参照により本明細書に組み込まれている2008年3月21日出願の米国特許出願第12/053,015号明細書(代理人整理番号第60137,0034USU1)の652〜669頁に開示されている手順にしたがって調製した(化合物16は米国特許出願第12/053,015号の674頁に化合物25として特定されている)。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20220052883A (ko) * | 2020-10-10 | 2022-04-28 | 하이 로보틱스 씨오., 엘티디. | 창고 저장 시스템, 화물 운반 방법, 제어 단말, 로봇 및 저장매체 |
US11971711B2 (en) | 2020-10-10 | 2024-04-30 | Hai Robotics Co., Ltd. | Warehousing system |
Also Published As
Publication number | Publication date |
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BRPI0922508A8 (pt) | 2016-01-19 |
BRPI0922508A2 (pt) | 2015-08-11 |
NZ593649A (en) | 2013-11-29 |
NZ617066A (en) | 2015-02-27 |
JP2015221802A (ja) | 2015-12-10 |
MX2011006890A (es) | 2011-07-20 |
PA8855701A1 (es) | 2010-07-27 |
CO6400227A2 (es) | 2012-03-15 |
AU2009329917A1 (en) | 2011-07-14 |
CA2748034A1 (en) | 2010-07-01 |
IL213700A0 (en) | 2011-07-31 |
US8551973B2 (en) | 2013-10-08 |
AR074882A1 (es) | 2011-02-16 |
CN102753563A (zh) | 2012-10-24 |
AU2009329917B2 (en) | 2016-03-31 |
JP2012516287A (ja) | 2012-07-19 |
KR20110098849A (ko) | 2011-09-01 |
EA201100851A1 (ru) | 2012-04-30 |
SG172361A1 (en) | 2011-07-28 |
EP2376514A2 (en) | 2011-10-19 |
US20100286083A1 (en) | 2010-11-11 |
WO2010075517A3 (en) | 2012-06-21 |
WO2010075517A2 (en) | 2010-07-01 |
CL2009002208A1 (es) | 2010-10-29 |
TW201026716A (en) | 2010-07-16 |
ZA201104638B (en) | 2012-11-28 |
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