JP2009514849A - (3r,5r)―7―[2―(4―フルオロフェニル)―5―イソプロピル―3―フェニル―4―[(4―ヒドロキシメチルフェニルアミノ)カルボニル]―ピロール―1―イル]―3,5―ジヒドロキシ―ヘプタン酸ヘミカルシウム塩の製法 - Google Patents
(3r,5r)―7―[2―(4―フルオロフェニル)―5―イソプロピル―3―フェニル―4―[(4―ヒドロキシメチルフェニルアミノ)カルボニル]―ピロール―1―イル]―3,5―ジヒドロキシ―ヘプタン酸ヘミカルシウム塩の製法 Download PDFInfo
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Abstract
【選択図】なし
Description
a)式IIのアミンを式IIIの酢酸メチルイソブチリルと反応させて、
(J.Med.Chem.,41,26,(1998),5297−5309およびTetrahydrofuran Lett.,43,30,(2002),5353に記載された手法に従って調製された)4−(テトラヒドロピラン−2−イルオキシメチル)フェニルアミン(70g,0.34モル,1当量)、酢酸メチルイソブチリル(49g,0.34モル,1当量)、トルエン(600mL)および1,2−エチレンジアミン(2.0g,0.034モル,0.1当量)の混合物を2口丸底フラスコに投入し、反応混合物をディーン−シュタルク設定下で還流した。反応の完了の後に、溶媒を真空下で除去した。粗生成物をそれ自体次の工程のために採取した。収率:116g(粗製)
MS(+イオンモード):m/z 320.16(M+1);1H NMR(CDCl3,300Hz):δ 1.27(d,J=6Hz,6H);1.33(s,2H);1.54−1.72(m,7H);2.74(sep,J=6Hz,1H);3.52−3.56(m,1H);3.61(s,2H);3.87−3.95(m,1H);4.47(d,J=12Hz,1H);4.68(m,1H);4.74(d,J=12Hz,1H);7.32(d,J=9Hz,2H);7.53(d,J=6Hz,2H);9.22(brs,1H)
粗製4−メチル−3−オキソ−ペンタン酸[4−(テトラヒドロピラン−2−イルオキシメチル)フェニル]アミン(100g,0.31モル,1当量)、β−アラニン(5.6g,0.063モル,0.2当量)、ベンズアルデヒド(30.5mL,0.31モル,1当量)、氷酢酸(10.6mL,0.19モル,0.6当量)およびヘキサン(500mL)の混合物を、ディーン−シュタルク設定を備えた2口フラスコに投入した。反応混合物を、水を共沸除去しつつ還流した。反応の最後に(TLCモニタリング)、溶媒を減圧下で蒸発させて、固体が得られ、これを熱ヘキサンで洗浄し、固体をブヒナー漏斗で収集した。粗製化合物をカラム(シリカゲル、100−200メッシュ、15%酢酸エチル/へキサン)で精製して、純粋な生成物を得た。収率:66.81g(52.36%)。
MS(+イオンモード):m/z 408.12(M+1);1H NMR(CDCl3,300Hz):δ 1.22(d,J=6.0Hz,6H);1.52−1.85(m,8H);3.35(sep,J=6Hz,1H);3.52−3.56(m,1H);3.87−3.91(m,1H);4.47(d,J=12Hz,1H);4.68−4.7(m,1H);4.75(d,J=12Hz,1H);7.32−7.64(m,11H)
2−ベンジリデン−4−メチル−3−オキソ−ペンタン酸[4−(テトラヒドロピラン−2−イルオキシメチル)フェニル]アミド(5.0g,0.012モル,1当量)、4−フルオロベンズアルデヒド(1.5mL,0.0013モル,1.1当量)、臭化3−エチル−5−(2−ヒドロキシエチル)−4−メチルチアゾリウム(0.77g,0.0003モル,0.25当量)、トリエチルアミン(乾燥,10mL,0.0072モル,5.8当量)の混合物を丸底フラスコに投入し、窒素ガスでパージした。反応混合物を90℃にて約6時間還流した。反応が完了した後に反応混合物を酢酸エチルで抽出し、水で洗浄し、無水硫酸ナトリウムで乾燥した。有機層を濃縮し、粗製混合物をカラム(シリカゲル,100−200メッシュ,17%酢酸エチル/へキサン)で精製して、純粋な生成物を得た。収率:2.52g(38.6%)
MS(+イオンモード):m/z 532.17(M+1);1H NMR(CDCl3,300Hz);δ 1.15(d,J=6.0Hz,3H);1.23(d,J=6.0Hz,3H);1.45−1.851(m,6H);2.85−3.05(m,1H);3.20−3.55(m,1H);3.70−3.95(m,1H);4.40−4.53(m,2H);4.67−4.72(m,2H);5.34(d,J=9.0Hz,1H);7.01−7.28(m,12H);7.95−8.00(m,2H)
2−[2−(4−フルオロフェニル)−2−オキソ−1−フェニルエチル]−4−メチル−3−オキソ−ペンタン酸[4−(テトラヒドロピラン−2−イルオキシメチル)フェニル]アミド(2.0g,0.004モル,1当量)、式IXのアミン(1.5g,0.006モル,1.5当量)、ピバル酸(0.45mL,0.004モル,1.03当量)、およびヘプタン:トルエン:テトラヒドロフラン(4:1:1,24ml)の混合物をディーン−シュタルク設定を備えた丸底フラスコに投入した。反応混合物を、水を共沸除去しつつ還流した。反応の完了の後(TLCモニタリング)、溶媒をロータリーエバポレーターで除去した。残渣を酢酸エチルで希釈し、重炭酸ナトリウムの飽和溶液をこの溶液に加えた。水性層を酢酸エチルで抽出し、有機層を水、ブラインで洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。粗製混合物をカラム(シリカゲル,100−200メッシュ,15%酢酸エチル/へキサン)で精製して、純粋な生成物を得た。収率:1.0g(34.6%)。
MS(+イオンモード):m/z 769.45(M+1);1H NMR(CDCl3,300Hz):δ 0.9−1.1(m,2H);1.30(s,1H),1.36(s,3H);1.43(s,9H);1.50−1.77(m,14 6H);2.20−2.40(m,2H);3.52−3.70(m,3H);3.85−3.89(m,2H);4.05−4.25(m,2H);4.40(d,J=12Hz,1H);4.64−4.70(m,2H);6.86−7.25(m,14H)
[(4R,6R)−6−(2−{2−(4−フルオロフェニル)−5−イソプロピル−3−フェニル−4−[4−(テトラヒドロピラン−2−イルオキシメチル)フェニルアミノ]カルボニル}−ピロール−1−イル]エチル)−2,2−ジメチル−[1,3]ジオキサン−4−イル]−酢酸tert−ブチルエステル(0.8g,0.0015モル,1当量)、および比率2:5:5の1N塩酸:メタノール:テトラヒドロフランの混合物(24mL)の混合物を一口フラスコに投入した。反応混合物を室温で攪拌した。減圧下で反応混合物を溶媒を蒸発させることによって濃縮した。粗製化合物を酢酸エチルで抽出し、酢酸エチル層をブラインで洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。粗製混合物をカラム(シリカゲル,100−200メッシュ,60%酢酸エチル/へキサン)で精製して、純粋な生成物を得た。収率:446mg,66.56%)。
MS(+イオンモード):m/z/645.32(M+1);1H NMR(CDCl3,300Hz):δ 1.15−1.30(m,2H);1.45(s,9H);1.47−1.62(m,8H);2.32(d,J=6.0Hz,2H);3.53−3.60(m,2H);3.69−3.92(m,1H);4.08−4.13(m,2H);4.58(s,2H);6,87(s,1H);6.97−7.25(m,13H)
工程1:メタノール−テトラヒドロフラン(1:1)の混合液中の(3R,5R)−7−[2−(4−フルオロフェニル)−4−(4−ヒドロキシメチルフェニルアミノ)カルボニル]−5−イソプロピル−3−フェニルピロール−1−イル]−3,5−ジヒドロキシヘプタン酸tert−ブチルエステルを0℃まで冷却し、水酸化ナトリウムペレットを加えた。次いで、反応混合物を雰囲気温度で攪拌した。エステルの加水分解の最後に、溶媒を除去し、残渣を水に溶解させ、水性層をエーテルで洗浄した。
MS(正イオンモード):m/z589(酸+1);融点=189−204℃;1H NMR(DMSO−d6):δ1.22−1.62(m,11H),1.98(dd,J=15 & 8.1Hz,1H),2.06−2.16(m,1H),3.25−3.37(m,2H),3.57(brs,2H),3.80(brs,1H),4.43(s,2H),7.03−7.28(m,12H),7.50(d,J=6H,2H),9.80(s,1H)
Claims (7)
- a)式IIのアミンを式IIIの酢酸メチルイソブチリルと反応させて、
ことを含む、式I:
式I
の(3R,5R)―7―[2―(4―フルオロフェニル)―5―イソプロピル―3―フェニル―4―[(4―ヒドロキシメチルフェニルアミノ)カルボニル]―ピロール―1―イル]―3,5―ジヒドロキシ―ヘプタン酸ヘミカルシウム塩の製法。 - 式IIのアミンの反応を、
i)1以上の有機塩基の存在下で;および
ii)1以上の芳香族溶媒中で、
行う請求項1記載の製法。 - 式IVの化合物の反応を、
i)ピペリジン、ピリジンまたはβ―アラニンから選択される1以上の有機塩基の存在下で;あるいは氷酢酸または安息香酸から選択される1以上の有機酸の存在下で、あるいは有機塩基または有機酸の混合物の存在下で;および
ii)(ヘキサンまたはヘプタンから選択される)炭化水素溶媒、(ジクロロメタン、ジクロロエタンまたはクロロホルムから選択される)ハロゲン化溶媒、(トルエンまたはキシレンから選択される)芳香族溶媒、またはその混合液から選択される1以上の溶媒中で、
行う請求項1記載の製法。 - 式Vの化合物の反応を、
i)シアン化ナトリウム、臭化3―エチル―5―(2―ヒドロキシエチル)―4―メチルチアゾリウム、塩化3―ベンジル―5―(2―ヒドロキシエチル)―4―メチルチアゾリウム、またはその混合物から選択される1以上の触媒の存在下で;
ii)トリエチルアミン、ピリジンまたはその混合物から選択される1以上の有機塩基の存在下で;
および
iii)無溶媒条件にて、あるいは(メタノール、エタノール、プロパノール、イソプロパノールまたは水から選択される)プロトン性極性溶媒、(ジオキサンまたはテトラヒドロフランから選択される)エーテルまたはその混合物から選択される1以上の溶媒中で;
行う請求項1記載の製法。 - 式VIの化合物の反応を、
i)ピバル酸、p―トルエンスルホン酸またはその混合物から選択される1以上の有機酸の存在下で;および
ii)(キシレンまたはトルエンから選択される)芳香族溶媒、(ヘキサンまたはヘプタンから選択される)炭化水素溶媒、(テトラヒドロフラン、ジオキサまたはジエチルエーテルから選択される)エーテル、またはその混合物から選択される1以上の溶媒の存在下で、
行う請求項1記載の製法。 - 式VIIIの化合物のケタールおよびヒドロキシ保護基の開裂を、
i)塩酸、臭化水素酸、ヨウ化水素酸またはその混合物から選択される1以上の鉱酸の存在下で;および
ii)(メタノール、エタノール、プロパノールまたは水から選択される)プロトン性極性溶媒、(テトラヒドロフランまたはジエチルエーテルから選択される)エーテル、またはその混合物から選択される1以上の溶媒の存在下で、
行う請求項1記載の製法。 - 式IXの化合物の加水分解を、
i)水酸化リチウム、水酸化ナトリウム、水酸化カリウムまたはその混合物から選択される1以上の塩基の存在下で;および
ii)(メタノール、エタノール、プロパノール、イソプロパノールまたは水から選択されるプロトン性極性溶媒、(テトラヒドロフランまたはジエチルエーテルから選択される)エーテル、またはその混合物から選択される1以上の溶媒の存在下で、
行う請求項1記載の製法。
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