JP3561546B2 - New 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compounds - Google Patents
New 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compounds Download PDFInfo
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- JP3561546B2 JP3561546B2 JP01643095A JP1643095A JP3561546B2 JP 3561546 B2 JP3561546 B2 JP 3561546B2 JP 01643095 A JP01643095 A JP 01643095A JP 1643095 A JP1643095 A JP 1643095A JP 3561546 B2 JP3561546 B2 JP 3561546B2
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- RZRDQZQPTISYKY-UHFFFAOYSA-N OCC(C(C(C1O)O)O)[n]2c1ncc2 Chemical compound OCC(C(C(C1O)O)O)[n]2c1ncc2 RZRDQZQPTISYKY-UHFFFAOYSA-N 0.000 description 4
- MWMLGILHKJPUNR-UHFFFAOYSA-N CC(NC(C1O)c2ncc[n]2C(CO)C1O)=O Chemical compound CC(NC(C1O)c2ncc[n]2C(CO)C1O)=O MWMLGILHKJPUNR-UHFFFAOYSA-N 0.000 description 2
- 0 *C(C1OCc2ccccc2)c2ncc[n]2C(COCc2ccccc2)C1OCc1ccccc1 Chemical compound *C(C1OCc2ccccc2)c2ncc[n]2C(COCc2ccccc2)C1OCc1ccccc1 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】
【産業上の利用分野】
本発明は、優れた糖加水分解酵素阻害活性を有し、抗肥満薬、抗糖尿病薬等として有用な５，６，７，８−テトラヒドロ−イミダゾ〔１，２−ａ〕ピリジン化合物に関する。
【０００２】
【従来の技術】このような薬効を示す物質として、天然に存在する下式で示されるナグスタチン（Ｎａｇｓｔａｔｉｎ）が知られている。
【化１】
ナグスタチンは、ストレプトマイセスチアマクサエンシスＭＧ８４６−ｆＦ３（streptomyces amakusaensis ＭＧ８４６−ｆＦ３）の培養液中より単離された化合物で、Ｎ−アセチル−β−Ｄ−グルコサミニダーゼ（ＮＡＧ−ase)に対して優れた阻害活性を有している(ジャーナル・オブ・アンチバイオティクス、45巻、１４０４頁、１９９２年）。糖タンパク質や糖脂質からＮ−アセチル−β−Ｄ−グルコサミンを切り離すエキソグリコシダーゼであるＮＡＧ−aseは、リソゾーム中に局在し、糖尿病、白血病および癌などの疾病時に活性が増加することが報告されている。また、この活性の増加は肝臓病や妊娠の指標でもある。ＮＡＧ−ase
のふるまいを調べることは、上述の疾病に加えて腎炎や免疫不全などの難病の原因や機構を解明する上で重要なことであり、その際、ナグスタチンのような特定阻害剤の作用が不可欠となるであろうと考えられる。また、イミダゾール環を含む複雑な縮環二環式化合物の合成研究は未だに報告されておらず、イミダゾール環と糖類とが縮環したナグスタチンの骨格を持つ類縁体を得ることは困難であった。
【０００４】
【発明が解決しようとする課題】
本発明は、糖加水分解酵素阻害活性を有する物質を、化学合成によって安価に量産することを目的とする。
【０００５】
【課題を解決するための手段】
本発明者らは、このような事情に鑑み鋭意試験検討を重ねた結果、Ｌ−リボースあるいはＬ−キシロース誘導体を出発原料にして、それぞれのＣ−１位にイミダゾール誘導体を求核反応させ、さらに、導入されたイミダゾール部分と糖鎖水酸基との分子内求核置換反応により、イミダゾール環を含む含窒素糖質であるナグスタチン類縁体を立体選択的に全合成することを可能とし、これらの化合物が種々のグルコシダーゼに対する阻害活性を有することを見いだし、本発明を完遂するに至った。
【０００６】
本発明は、以下の構造式によって表される６，７，８−トリヒドロキシ−５−ヒドロキシメチル−５，６，７，８−テトラヒドロイミダゾ〔１，２−ａ〕ピリジン系化合物及び８−アセトアミド−６，７−ジヒドロキシ−５−ヒドロキシメチル−５，６，７，８−テトラヒドロイミダゾ〔１，２−ａ〕ピリジン系化合物に関するものである。
【化２】
本発明化合物（イ、ロ、ニ、ホ、ヘ）及び本発明の参考化合物（ハ）の物性は、次のとおりである。
【化３】
【０００８】
本発明化合物イの物性
固体，mp＝〜80℃、〔α〕D
＋29.2°（ｃ1.6,CH3OH）
ＴＬＣ（シリカＧ,
クロロホルム／メタノール＝1/1,Ｉ2 ） Ｒｆ＝0.00〜0.25
ＮＭＲ（２７０ＭＨZ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.87(1H,dd,J=7,2Hz),4.03(2H,d,J=5Hz),4.23(1H,dt,J=5,4Hz),4.38(1H,dd,J=4,2Hz),4.76(1H,d,J=7Hz),7.05(1H,d,J=1Hz),7.36(1H,d,J=1Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(12),1638(72), 1489(59), 1450(63), 1360(73), 1305(67), 1264(71),1144(61), 1113(41),1086(45), 1065(43), 1051(41), 750(64), 686(66)ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【０００９】
【化４】
【００１０】
本発明化合物ロの物性
無色固体、mp=169〜174
℃、〔α〕D −8.0 °(c0.97,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ） Ｒｆ＝0.00〜0.17
ＮＭＲ（２７０ＭＨZ，Ｄ2Ｏ）
δ
.85(1H,dd,J=10,9Hz),3.98(1H,J=10,9Hz),4.11(1H,dd,J=13,3Hz),4.12(1H,m),4.27(1H,dd,J=13,3Hz),4.72(1H,d,J=9Hz),7.30(1H,d,J=1.5Hz),7.43(1H,d,J=1.5Hz)ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(7),2913(47), 1491(52), 1448(60), 1419(59), 1319(58), 1268(67),1198(76), 1178(77),1118(42), 1089(44), 1069(48), 1057(48), 1029(46),749(62), 651(68)ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００１１】
【化５】
【００１２】
本発明の参考化合物ハの物性
固体，mp＝〜80℃、〔α〕D
＋25.3°（ｃ1.8,CH3OH）
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ） Ｒｆ＝0.00〜0.25
ＮＭＲ（４００ＭＨZ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.04(1H,dd,J=4,2Hz),4.07(1H,dd,J=12,6Hz),4.09(1H,dd,J=12,4Hz),4.21(1H,ddd,J=6,4,4Hz),4.34(1H,dd,J=4,2Hz),4.82(1H,d,J=4Hz),7.12(1H,d,J=1.5Hz),7.43(1H,d,J=1.5Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(26),2926(47), 1641(73), 1486(67), 1444(70), 1266(73), 1100(59),1075(58), 1048(63),768(72)ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００１３】
【化６】
【００１４】
本発明化合物ニの物性
無色固体、mp=111〜114
℃、〔α〕D −36.2°(c1.01,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝１／１）
Ｒｆ＝0.00〜0.37
ＮＭＲ（２７０ＭＨZ，pyridine-d5,ＴＭＳ）
δ
.39(1H,dd,J=13,4Hz),4.40(1H,dd,J=7.5,4Hz),4.41(1H,dd,J=13,4Hz),4.76(1H,ddd,J=9,4,4Hz),5.04(1H,dd,J=9,75Hz),5.66(1H,d,J=4Hz),7.39(1H,d,J=1.5Hz),7.78(1H,d,J=1.5Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(1), 2924(29),2862(30), 1638(55), 1490(30), 1442(34), 1422(37),1372(49), 1327(47), 1281(37),1182(58), 1133(32), 1096(12), 1067(18),1012(52), 900(33), 816(55), 762(27),720(36)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００１５】
【化７】
【００１６】
本発明化合物ホの物性
無色固体、mp=210〜212
℃（分解）、〔α〕D ＋75.8°(c1.1,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ） Ｒｆ＝0.32〜0.40
ＮＭＲ（２７０ＭＨZ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.07(3H,s,Ac),4.10(2H,d,J=6Hz),4.15(1H,dd,J=9,2Hz),4.34(1H,m),4.37(1H,dd,J=2,2Hz),5.08(1H,d,J=9Hz),7.39(1H,d,J=2Hz),7.78(1H,d,J=2Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(38),1639(51), 1557(63), 1487(77), 1442(78), 1374(77), 1115(72),1057(76)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２４２（Ｍ＋１）
【００１７】
【化８】
【００１８】
本発明化合物ヘの物性
無色固体、mp=249〜251
℃、(decomp.), 〔α〕D ＋52.6°(c0.90,H2O)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ） Ｒｆ＝0.34〜0.43
ＮＭＲ（５００ＭＨZ，pyridine-d5 ，ＴＭＳ）
δ
.11(3H,s,Ac),4.34(1H,ddd,J=9,5,2.5Hz),4.40(1H,dd,J=11,5Hz),4.44(1H,dd,J=9,9Hz),4.57(1H,dd,J=9,9Hz),4.66(1H,dd.J=11,2.5Hz),5.85(1H,dd,J=9,9Hz),7.35(1H,d,J=1.5Hz),7.68(1H,d,J=1.5Hz),9.17(1H,d,J=9Hz,NH)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(30),3308(21), 3072(50), 2911(61), 2854(61), 1659(12), 1565(26),1479(50), 1244(50),1135(54), 1103(45), 1052(50), 1003(51), 770(50),730(67), 690(65)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２４２（Ｍ＋１）
【００１９】
【実施例】
（例１）
中間化合物Ａ及びＢの合成
アルゴン雰囲気下、Ｎ−トリチルイミダゾール1.98g(6.38mmol) および乾燥テトラヒドロフラン（以下、ＴＨＦという）80mlからなる溶液に、−５℃で 1.6Ｍｎ−ブチルリチウム−ヘキサン溶液4.01ml(6.42mmol)を加え、10分間攪拌した後、次いで2,3,5−トリ−Ｏ−ベンジル−Ｌ−リボフラノース1.21g(2.90mmol) および乾燥ＴＨＦ８mlから成る溶液を０℃で加え、さらに３０分間攪拌した。反応終了後、系に少量のドライアイスを加えた後、飽和食塩水20mlを加えて分液し、有機層を減圧下に乾固した。この乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ160g, ベンゼン／酢酸エチル＝１／１）に付し、下式で示されるＬ−アロース誘導体（以下、中間化合物Ｂという）0.821g(1.12mmol,38.7mol%)
を得た。
【００２０】
【化９】
次いで、前記反応混合物の他の成分を再度シリカゲルカラムクロマトグラフィ−（シリカＧ 120g，クロロホルム／酢酸エチル＝２／１）に付し、下式で示されるＬ−アルトロース誘導体（以下、中間化合物Ａという）0.994g(1.36mmol,46.9mol%)を得た。
【化１０】
前記中間化合物Ａの物性
固体、mp= 62〜67 ℃、〔α〕D −111.8 °(c1.0,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／１） Ｒｆ＝0.61〜0.7
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 ＴＭＳ）
δ
.98(1H,br.d,J=6Hz),3.54(1H,dd,J=10,6Hz),3.59(1H,dd,J=10,4Hz),3.83(1H,dd,J=8,2Hz),3.92(1H,ddd,J=8,6,4Hz),4.00(1H,dd,J=8,2Hz),4.25(1H,d,J=11Hz),4.43(1H,d,J=11Hz),4.45(1H,d,J=12Hz),4.51(1H,d,J=12Hz),4.52(2H,s),4.53(dd,J=8,6Hz),6.83(1H,d,J=2Hz),7.09(1H,d,J=2Hz),7.0〜7.4(30H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(69),3357(72), 3059(66), 3028(60), 2858(56), 1493(35), 1448(26),1215(55), 1089(19),1069(18), 1029(36), 1000(55), 906(69), 746(12),699(7), 642(53)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ７３１（Ｍ＋１）
【００２３】
前記中間化合物Ｂの物性
無色結晶、mp=132.5〜133.5
℃、(AcOEt), 〔α〕D −31.0°(c1.05,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／１） Ｒｆ＝0.38〜0.50
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 ，ＴＭＳ）
δ
.86(1H,dd,J=8,2Hz),3.29(1H,dd,J=10,2Hz),3.39(1H,dd,J=10,7Hz),3.45(1H,d,J=10Hz),3.50(1H,dd,J=8,4Hz),3.82(1H,ddd,J=7,4,2Hz),3.87(1H,d,J=10Hz),4.05(1H,d,J=10Hz),4.17(1H,d,J=10Hz),4.37(1H,d,J=10Hz),4.45(1H,d,J=12Hz),4.50(1H,dd,J=10,2Hz),4.51(1H,d,J=12Hz),6.9〜6.7(3H,m),7.0〜7.4(29H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(75),1493(80), 1448(77), 1102(64), 1030(76), 746(59), 700(51)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ７３１（Ｍ＋１）
【００２４】
（例２）
中間化合物Ｃ及びＤの合成
アルゴン雰囲気下、Ｎ−トリチルイミダゾール1.53ｇ(4.94mmol)および乾燥ＴＨＦ70mlからなる溶液に、−10℃で 1.6Ｍｎ−ブチルリチウム−ヘキサン溶液3.10ml(4.96mmol)を加え、10分間攪拌した後、次いで2,3,5−トリ−Ｏ−ベンジル−Ｌ−キシロフラノース1.02g(2.42mmol) および乾燥ＴＨＦ８mlから成る溶液を−10℃で加え、さらに30分間攪拌した。反応終了後、系に少量のドライアイスを加えた後、飽和食塩水20mlを加えて分液し、有機層を減圧下に乾固した。この乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ550g, ベンゼン/ 酢酸エチル＝１／２）に付し、下式で示されるＬ−グロース誘導体（以下、中間化合物Ｃという）0.497g(0.681mmol,28.0mol%) 及びＬ−イドース誘導体（以下、中間化合物Ｄという）0.161g(0.22mmol,9.1mol%) を得た。
【００２５】
中間化合物Ｃの構造式は次のとおりであり、
【化１１】
中間化合物Ｄの構造式は次のとおりである。
【化１２】
中間化合物Ｃの物性
無色固体、mp=40〜44℃、〔α〕D −55.1°(c0.87,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／２） Ｒｆ＝0.58〜0.73
ＮＭＲ（４００ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.01(1H,br.d,J=4Hz,OH),3.45(2H,d,J=6Hz),3.74(1H,dd,J=4,3.5Hz),3.98(1H,dt,J=6,4Hz),4.15(1H,dd,J=9,3.5HzC3-H),4.40(2H,s),4.43(1H,d,J=12Hz),4.48(1H,d,J=12Hz),4.48(1H,d,J=10Hz),4.51(1H,br.dd,J=9,4Hz),4.59(1H,d,J=10Hz),6.85(1H,d,J=2Hz),6.9〜7.4(31H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(62),3060(65), 3029(64), 2864(69), 1493(58), 1448(48), 1228(68),1121(51), 1088(45),1068(40), 1029(55), 747(31), 699(18)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ７３１（Ｍ＋１）
【００２８】
中間化合物Ｄの物性
無色固体、mp=43〜46℃、〔α〕D ＋18.0°(c1.21,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／２） Ｒｆ＝0.65〜0.79
ＮＭＲ（４００ＭＨZ，acetone-d6, ＴＭＳ）
δ
.19(1H,dd,J=6.5,2.5Hz),3.25(1H,dd,J=6.5,2.5Hz),3.32(1H,dd,J=9,6.5Hz),3.37(1H,dd,J=9,6.5Hz),3.49(1H,d,J=6.5Hz),3.54(1H,m),3.58(1H,d,J=9Hz),4.32(1H,d,J=11.5Hz),4.34(1H,dd,J=9,2.5Hz),4.35(1H,J=10.5Hz),4.37(1H,d,J=12Hz),4.41(1H,d,J=11.5Hz),4.43(1H,d,J=12Hz),4.52(1H,d,J=10.5Hz),6.82(1H,d,J=1.5Hz),7.05(1H.d,J=1.5Hz),7.1〜7.4(30H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(36),3059(42), 3029(41), 2918(52), 2862(45), 1598(75), 1493(28),1449(20), 1394(55),1359(58), 1227(41), 1177(61), 1116(13), 1065(17),1030(27), 1003(52), 907(69),748(7), 700(3), 641(66)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ７３１（Ｍ＋１）
【００２９】
（例３）
中間化合物Ｅの合成
Ｌ−アロース誘導体（中間化合物Ｂ）1.01g(1.39mmol) およびピリジン30mlからなる溶液に、０℃にてベンジルスルホニルクロライド0.397g(2.08mmol) を加え、０℃で１時間攪拌した。反応終了後、エタノール 0.1mlを加え10分間攪拌した後減圧下に濃縮し、ついで少量のトルエンを加え、減圧下に共沸乾固した。この乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ50g, ベンゼン／酢酸エチル＝４／１）に付し、下式で示される目的物1.02g(1.14mmol, 82.7mol%) を得た。
【００３０】
【化１３】
中間化合物Ｅの物性
固体、mp= 〜60℃、〔α〕D
−43.7°(c1.4,CHCl3 )
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝４／１） Ｒｆ＝0.53〜0.60
ＮＭＲ（４００ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.50(1H,d,J=10Hz),3.20(1H,dd,J=12,2Hz),3.54(1H,dd,J=12,9Hz),3.73(1H,dd,J=10,2Hz),3.74(1H,d,J=10Hz),4.03(1H,d,J=10Hz),4.07(1H,dJ=10z),4.31(2H,s),4.37(1H,d,J=10Hz),4.42(1H,J=12Hz),4.45(1H,d,J=12Hz),4.46(1H,s),5.08(1H,ddd,J=9,2,2Hz),6.7〜6.8 ＆ 7.0〜7.5(32H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(74),3029(71), 2922(82), 2864(80), 1493(47), 1449(43), 1361(42),1329(62), 1218(55),1174(35), 1098(28), 1030(39), 1001(68), 909(41),747(25), 699(12)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ８８５（Ｍ＋１）
【００３２】
（例４）
中間化合物Ｆの合成
Ｌ−グロース誘導体（中間化合物Ｃ）1.11g(1.52mmol) およびピリジン34mlからなる溶液に、−10℃にてベンジルスルホニルクロライド0.444g(2.33mmol)を加え、−10℃で30分間攪拌した。反応終了後、飽和炭酸水素ナトリウム水溶液１mlを加え、10分間攪拌した後減圧下に濃縮し、ついで少量のトルエンを加え、減圧下に共沸乾固した。この乾固物を酢酸エチル30mlで抽出した後、抽出液を減圧下に乾固した。この乾固物をシリカゲルカラムクロマトグラフィー(シリカＧ 120g,ベンゼン／酢酸エチル＝４／１）に付し、下式で示される目的物1.05g(1.23mmol, 81.1mol%) を得た。
【００３３】
【化１４】
中間化合物Ｆの物性
無色固体、mp=66〜69℃、〔α〕D −66.4°(c1.06,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝３／１） Ｒｆ＝0.48〜0.55
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.96(1H,br.J=5Hz,OH),3.65(1H,dd,J=12,6Hz),3.74(1H,dd,J=12,3Hz),4.04(1H,dd,J=8,2Hz),4.14(1H,d,J=14Hz),4.19(1H,dd,J=8,2Hz),4.28(1H,d,J=14Hz),4.10(1H,d,J=11Hz),4.42(2H,d,J=12Hz),4.47(1H,d,J=12Hz),4.49(1H,d,J=11Hz),4.54(1H,dd,J=8,4Hz),4.58(1H,d,J=12Hz),5.04(1H,ddd,J=8,6,3Hz),6.82(1H,d,J=2Hz),6.9〜7.4(37H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(60),3446(63), 3060(68), 3030(67), 2925(74), 2863(75), 1493(57),1449(50), 1361(42),1173(40), 1122(52), 1086(45), 1071(43), 1028(57),914(50), 747(33), 700(15),
【００３５】
（例５）
中間化合物Ｇの合成
ベンジルスルホニル化合物（中間化合物Ｅ）0.224g(0.25mmol)、ピリジン５mlおよび無水酢酸 0.4mlの三者からなる系を60℃で 1.5時間加熱攪拌した。反応終了後、系にエタノール0.5mlを加え、室温で10分間攪拌したのち減圧下に濃縮した。濃縮物を酢酸エチルに溶解し飽和炭酸水素ナトリウム水溶液で中和し、有機層を減圧下に濃縮し、少量のトルエンを加えて共沸乾固した。この乾固物をシリカゲルカラムクロマトグラフィー(
リシカＧ 11g, ベンゼ／酢酸エチル＝１／１）に付し、下式で示される目的物 0.127g(0.249mmol, 98.3mol%)をシラップとして得た。
【００３６】
【化１５】
中間化合物Ｇの物性
油状物質〔α〕D ＋75.0°(c1.4,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／２） Ｒｆ＝0.53〜0.59
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.06(3H,s,Ac),3.81(1H,dd,J=10,8Hz),3.98(1H,dd,J=5,2Hz),4.00(1H,dd,J=10,3Hz),4.21(1H,dd,J=6,2Hz),4.45(1H,ddd,J=8,6,3Hz),4.49(2H,s),4.57(1H,d,J=12Hz),4.69(1H,d,J=12Hz),4.70(1H,d,J=12Hz),4.76(1H,d,J=12Hz),6.22(1H,d,J=5Hz),7.08(1H,d,J=1Hz),7.15(1H,d,J=1Hz),7.2〜7.4(15H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(73),3030(66), 2922(67), 2871(64), 1744(38), 1493(64), 1452(52),1367(46), 1304(64),1227(34), 1093(39), 1079(40), 1044(45), 1026(45),967(69), 740(43), 698(42)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ５１３（Ｍ＋１）
【００３８】
（例６）
中間化合物Ｈの合成
中間化合物Ｇ0.485g(0.947mmol)を乾燥メタノール10mlに溶解し、これに28％ナトリウムメトキシドのメタノール溶液29μl(0.24mmol) を加え室温で1.5時間攪拌した。反応終了後、減圧下に乾固し、乾固物をシリカゲルカラムクロマトグラフィー( シリカＧ 50g, クロロホルム／アセトン＝２／１）に付し、下式で示される目的物0.427g(0.906mmol, 95.7mol%)を得た。
【００３９】
【化１６】
中間化合物Ｈの物性
無色結晶、mp=112〜113
℃、(hexane/AcOEt=1/1), 〔α〕D ＋38.6°(c1.0,CHCl3)
ＴＬＣ（シリカＧ，クロロホルム／アセトン＝２／１） Ｒｆ＝0.26〜0.35
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.84(1H,dd,J=10,7.5Hz),3.94(1H,dd,J=10,3Hz),4.02(1H,dd,J=5.5,2Hz),4.35(1H,dd,J=5,2Hz),4.39(1H,ddd,J=7.5,5,3Hz),4.49(2H,s),4.64(1H,d.J=12Hz),4.75(1H,d,J=12Hz),4.82(1H,d,J=12Hz),4.87(1H,d,J=12Hz),5.17(1H,d,J=5.5Hz),6.98(1H,d,J=1.5Hz),7.10(1H,d,J=1.5Hz),7.2〜7.6(15H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(46),2898(48), 2862(48), 1495(41), 1467(47), 1451(33), 1366(38),1327(47), 1311(53),1289(58), 1234(61), 1210(65), 1180(59), 1128(12),1101(8), 1052(34), 1023(29),1006(40), 966(67), 934(65), 907(69),733(6), 694(14)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ４７１（Ｍ＋１）
【００４１】
（例７）
中間化合物Ｉの合成
Ｌ−アルトロース誘導体（中間化合物Ａ）0.535g(0.733mmol) およびピリジン15mlから成る溶液に、−15℃にてベンジルスルホニルクロライド0.279g(1.46mmol) を加え、−15℃で１時間攪拌した。次いでこの系に無水酢酸 0.5mlを加え、０℃で１時間攪拌した後、さらに60℃で 1.5時間加熱攪拌した。次いで例５と同様の後処理を行い、下式で示される目的物0.179g(0.350mmol, 47.9mol%)を得た。
【００４２】
【化１７】
中間化合物Ｉの物性
油状物質〔α〕D −3.0 °(c1.05,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／２） Ｒｆ＝0.40〜0.46
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.93(1H,dd,J=10,8Hz),3.97(1H,dd,J=10,4Hz),4.09(1H,dd,J=5,2Hz),4.21(1H,dd,J=4,2Hz),4.35(1H,ddd,J=8,4,4Hz),4.65(1H,d,J=12Hz),4.66(1H,d,J=12Hz),4.76(1H,d,J=12Hz),4.80(1H,d,J=12Hz),6.25(1H,d,J=5Hz),7.18(1H,s),7.20(1H,s),
.2〜7.4(15H,m)ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(72),3061(59), 3030(55), 2918(56) ,2870(53), 1735(44), 1494(60),1482(62), 1452(53),
(51), 1306(62), 1233(46), 1136(55), 1117(50),1098(50), 1073(48), 1023(52),
(52),698(52)ＭＳ：（ＦＡＢ＋）ｍ／ｚ５１３（Ｍ＋１）
【００４４】
（例８）
中間化合物Ｊの合成
中間化合物Ｉ
.181g(0.353mmol)を感想メタノール10mlに溶解し、これに28％ナトリウムメトキシドのメタノール溶液15μl(0.07mmol) を加え室温で1.5時間攪拌した。反応終了後、減圧下に乾固し、乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ 10g, クロロホルム／アセトン＝２／１）に付し、下式として示される目的物0.139g(0.296mmol, 83.6mol%)を得た。
【００４５】
【化１８】
中間化合物Ｊの物性
無色結晶、mp=77〜78℃、(heaxane/AcOEt=3/1),〔ａ〕D -78°(cl.O,CHCl3)
ＴＬＣ（シリカＧ，クロロホルム／アセトン＝２／１） Ｒｆ＝0.25〜0.36
ＮＭＲ（２７０ＭＨz,ＣＤＣｌ3 ，ＴＭＳ）
δ
.90(2H,d,J=6Hz),3.97(1H,dd,J=4,2Hz),4.24(1H,dd,J=5,2Hz),4.30(1H,dt,J=6,5Hz),4.51(1H,d,J=12Hz),4.54(1H,d,J=12Hz),4.67(1H,d,J=12Hz),4.72(1H,d,J=12Hz),4.90(1h,d,J=12Hz),4.92(1H,d,J=12Hz),5.02(1H,d,J=4Hz),7.07(1H,d,J=2Hz),7.11(1H,d,J=2Hz),7.2〜7.4(15H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(17),3029(14), 2880(16), 2864(15), 1493(18), 1452(14), 1406(51),1356(22), 1334(33),1302(35), 1265(34), 1208(41), 1139(15), 1120(5),1077(1), 1026(13), 933(64),733(1), 697(4)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ４７１（Ｍ＋１）
【００４７】
（例９）
中間化合物Ｋの合成
アルゴン雰囲気下、中間化合物Ｊ 60.5mg(0.127mmol)およびトリn-ブチルフォスフィン38.1μl(0.152mmol)の乾燥ＴＨＦ６ml溶液に４％アジ化水素酸−トルエン溶液189μg(0.153mmol)およびジエチルアゾジカルボメート24.1μl(0.152mmol)を加え、室温にて30分間攪拌した。反応終了後、減圧下に乾固し、シリカゲルカラムクロマトグラフィー（シリカＧ5g ，ベンゼン／酢酸エチル＝５／１）に付し、下式で示される目的物 37.4mg(0.076mmol, 59.1mol%)を得た。
【００４８】
【化１９】
中間化合物Ｋの物性
油状物質〔α〕D ＋98.1°(c1.2,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝５／１） Ｒｆ＝0.38〜0.50
ＮＭＲ（２７０ＭＨZ，ＣＤＣｌ3 , ＴＭＳ）
δ
.81(1H,dd,J=7,1.5Hz),3.83(2H,d,J=6Hz),4.24(1H,dd,J=4,1.5Hz),4.28(1H,dt,J=6,4Hz),4.49(1H,d,J=12Hz),4.52(1H,d,J=12Hz),4.62(1H,d,J=12Hz),4.74(1H,d,J=12Hz),4.77(1H,d,J=12Hz),4.84(1H,d,J=12Hz),5.00(1H,d,J=7Hz),7.07(1H,d,J=1Hz),7.11(1H,d,J=1Hz),7.2〜7.4(15H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(71),3030(61), 2910(56), 2870(52), 2105(22), 1792(47), 1727(67),1495(55), 1481(57),1453(46), 1359(48), 1300(48), 1259(41), 1209(45),1117(35), 1094(30), 1026(48),738(35), 698(36)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ４９６（Ｍ＋１）
【００５０】
（例１０）
中間化合物Ｋの合成
アルゴン雰囲気下、中間化合物Ｈ 0.120g(0.255mmol)およびトリn-ブチルフォスフィン 78.0μl(0.306mmol)の乾燥ＴＨＦ12ml溶液に４％アジ化水素酸−トルエン溶液473μg(0.506mmol)およびジエチルアゾジカルボメート49μl(0.306mmol)を加え、室温にて30分間攪拌した。反応終了後、減圧下に乾固し、シリカゲルカラムクロマトグラフィー（シリカＧ5g , ベンゼン／酢酸エチル＝５／１）に付し、目的物 88mg(0.178mmol, 69.2mol%)を得た。
【００５１】
（例１１）
中間化合物Ｌの合成
中間化合物Ｋ0.171g(0.345mmol)、酢酸４mlおよび10％パラジウム−炭素0.22ｇを、室温にて水素圧４気圧で15時間攪拌した。反応終了後、メタノールで希釈し遠心分離した後上澄み液をろ過し、さらに沈殿物をメタノールで３回洗浄し同じく上澄み液をろ過し、ろ液を減圧下に乾固し、水で２回共沸乾固して、下式で示される目的物67.0mgを得た。
【００５２】
【化２０】
中間化合物Ｌの物性
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ）Ｒｆ＝0.00〜0.27
ＮＭＲ（２７０ＭＨｚ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.09(1H,dd,J=12,7Hz),4.13(1H,dd,J=12,4.5Hz),4.29(1H,dd,J=9.5,2Hz),4.42(1H,dd,J=2,2Hz),4.52(1H,m),4.83(1H,d,J=9.5Hz),7.74(1H,d,J=1.5Hz),8.06(1H,d,J=1.5Hz)
【００５４】
（例１２）
中間化合物Ｍの合成
ベンジルスルホニル化合物（中間化合物Ｆ）0.997g(1.16mmol), ピリジン20mlおよび無水酢酸２mlの三者から成る系を、50℃で８時間加熱攪拌した。次いで例５と同様の後処理を行い、下式で示される目的物0.501g(0.980mmol,84.0mol%)をシラップとして得た。
【００５５】
【化２１】
中間化合物Ｍの物性
油状物質、〔α〕D −50.2°(c0.96,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／１） Ｒｆ＝0.42〜0.48
ＮＭＲ（２７０ＭＨｚ，acetone-d6，ＴＭＳ）
δ
.84(3H,s,Ac),3.83(1H,dd,J=10,5Hz),4.04(1H,dd,J=10,3Hz),4.16(1H,dd,J=8.5,4Hz),4.24(1H,ddd,J=7,5,3Hz),4.29(1H,dd,J=8.5,7Hz),4.51(1H,d,J=11Hz),4.57(1H,d,J=11Hz),4.63(1H,d,J=11Hz),4.66(1H,d,J=11Hz),4.87(1H,d,J=11Hz),4.92(1H,d,J=11Hz),6.50(1H,d,J=4Hz),6.98(1H,d,J=1.5Hz),7.2〜7.5(16H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(64),
(55), 2922(57), 2868(50), 1742(22), 1493(49), 1452(42),1367(34), 1311(59),1228(22), 1106(25), 1080(30), 1029(33), 947(50),738(30), 699(30)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ５１３（Ｍ＋１）
【００５７】
（例１３）
中間化合物Ｎの合成
中間化合物Ｍ0.157g(0.307mmol)を乾燥メタノール４mlに溶解し、これに28％ナトリウムメトキシドのメタノール溶液15μl(0.07mmol) を加え室温で1.5時間攪拌した。反応終了後、減圧下に乾固し、乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ 10g, クロロホルム／アセトン＝２／１）に付し、目的物0.134g(0.285mmol,
.0mol%) を得た。
【００５８】
【化２２】
中間化合物Ｎの物性
無色結晶、mp=116.5〜117.5
℃、(hexane/EtOAc=2/1)，〔α〕D −4.0 °(c0.95,CHCl3)
ＴＬＣ（シリカＧ，クロロホルム／アセトン＝２／１） Ｒｆ＝0.14〜0.30
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ3 , ＴＭＳ）
δ
.69(1H,dd,J=10,6Hz),3.79(1H,dd,J=10,3.5Hz),3.96(1H,dd,J=8,4Hz),4.15(1H,ddd,J=6,6,3.5Hz),4.20(1H,dd,J=8,6Hz),4.44(1H,d,J=12Hz),4.49(1H,d,J=12Hz),4.60(1H,d,J=11Hz),4.72(1H,d,J=12Hz),4.83(1H,d,J=12Hz),4.92(1H,d,J=11Hz),5.13(1H,d,J=4Hz),7.01(1H,d,J=1.5Hz),7.10(1H,d,J=1.5Hz),7.2〜7.4(15H,m)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(75),2890(73), 2861(71), 1453(79), 1143(70), 1117(54), 1084(55),1051(66), 736(51),697(60)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ４７１（Ｍ＋１）
【００６０】
（例１４）
中間化合物Ｏの合成
Ｌ−イドース誘導体（中間化合物Ｄ）0.106g(0.146mmol) およびピリジン３mlから成る溶液に、−15℃にてベンジルスルホニルクロライド0.052g(0.274mmol)を加え、−15℃で１時間攪拌した。次いでこの系に無水酢酸 0.2mlを加え、０℃で１時間攪拌した後、さらに60℃で 1.5時間加熱攪拌した。以下例５と同様の後処理を行い、下式で示される目的物
.016g(0.031mmol, 21.4mol%)を得た。
【００６１】
【化２３】
中間化合物Ｏの物性
油状物質
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝１／１） Ｒｆ＝0.35〜0.38
ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3 , ＴＭＳ）
δ
.08(3H,s,Ac),3.70(1H,dd,J=10,6Hz),3.79(1H,dd,J=10,4Hz),3.96(1H,dd,J=7,7Hz),4.08(1H,dd,J=7,6Hz),4.27(1H,ddd,J=7,6,4Hz),4.43(1H,d,J=12Hz),4.46(1H,d,J=12Hz),4.52(1H,d,J=11.5Hz),4.76(1H,d,J=11.5Hz),4.77(1H,d,J=11.5Hz),4.81(1H,d,J=11.5Hz),6.11(1H,d,J=6Hz),7.04(1H,d,J=1Hz),7.11(1H,d,J=1Hz),7.15〜7.4(15H,m)
【００６３】
（例１５）
中間化合物Ｐの合成
中間化合物Ｏ7.2mg(0.014mmol) を乾燥メタノール 0.2mlに溶解し、これに28％ナトリウムメトキシドのメタノール溶液２μl(0.01mmol) を加え室温で1.5時間攪拌した。反応終了後、減圧下に乾固し、乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ 0.5g,クロロホルム／アセトン＝２／１）に付し、下式で示される目的物
.1mg(0.009mmol, 62.0mol%) を得た。
【００６４】
【化２４】
中間化合物Ｐの物性
無色固体、〔α〕D ＋10.3°(c0.95,CHCl3)
ＴＬＣ（シリカＧ，クロロホルム／アセトン＝２／１）Ｒｆ＝0.20〜0.28
ＮＭＲ（４００ＭＨｚ，acetone-d6，ＴＭＳ）
δ 3.84(1H,dd,J=10,5Hz),3.97(1H,dd,J=7.5,6Hz),4.01(1H,dd,J=10,3.5Hz),4.06(1H,dd,J=7.5,7.5Hz),4.30(1H,m),4.52(1H,d,J=12Hz),4.54(1H,d,J=12Hz),4.63(1H,d,J=11Hz),4.79(1H,d,J=6Hz),4.85(1H,d,J=11Hz),4.92(1H,d,J=11Hz),5.01(1H,d,J=11Hz),6.95(1H,s),7.19(1H,s),7.2〜7.5(15H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(56),3030(54), 2908(56), 2869(53), 1493(58), 1452(57), 1361(62),1311(65), 1282(69),1207(69), 1144(54), 1114(50), 1084(49), 1053(53),1028(55), 736(50), 698(51)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ４７１（Ｍ＋１）
【００６６】
（例１６）
中間化合物Ｑの合成
アルゴン雰囲気下、（中間化合物Ｎ）0.141g(0.30mmol)およびトリn-ブチルフォスフィン 112μl(0.45mmol) の乾燥テトラヒドロフラン 1.5ml溶液に４％アジ化水素酸−トルエン溶液558μg(0.45mmol) およびジエチルアゾジカルボメート71μl(0.45mmol) を加え、室温にて30分間攪拌した。反応終了後、減圧下に乾固し、シリカゲルカラムクロマトグラフィー（シリカＧ35g,ベンゼン／酢酸エチル＝３／１）に付し、下式で示される目的物 0.104g(0.210mmol, 70.0mol%)を得た。
【００６７】
【化２５】
中間化合物Ｑの物性
油状物質、〔α〕D ＋58.8°(c1.06,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝３／１） Ｒｆ＝0.32〜0.40
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ3 ＴＭＳ）
δ
.68(1H,dd,J=10,5Hz),3.79(1H,dd,J=10,3.5Hz),3.88(1H,dd,J=8,7Hz),3.96(1H,dd,J=7,7Hz),4.15(1H,ddd,J=8,5,3.5Hz),4.39(1H,d,J=12Hz),4.45(1H,d,J=12Hz),4.55(1H,d,J=12Hz),4.73(1H,d,J=7Hz),4.80(1H,d,J=11Hz),4.88(1H,d,J=11Hz),4.89(1H,d,J=12Hz),7.02(1H,d,J=1.5Hz),7.13(1H,d,J=1.5Hz),7.2〜7.4(15H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(76),2914(73), 2868(71), 2103(45), 1794(79), 1494(75), 1482(76),1453(67), 1362(70),1312(75), 1279(70), 1260(70), 1209(71), 1140(65),1094(53), 1025(71), 738(58),698(57)
【００６９】
（例１７）
中間化合物Ｒの合成
中間化合物Ｑ0.102g(0.206mmol)、酢酸５mlおよび10％パラジウム−炭素0.137gを、室温にて水素圧４気圧で15時間攪拌した。反応終了後、メタノールで希釈し遠心分離した後上澄み液をろ過し、さらに沈殿物をメタノールで３回洗浄し同じく上澄み液をろ過し、ろ液を減圧下に乾固し、水で２回共沸乾固し、下式で示される目的物57.9mgを得た。
【００７０】
【化２６】
中間化合物Ｒの物性
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 ）Ｒｆ＝0.00〜0.25
ＮＭＲ（４００ＭＨｚ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.70(1H,dd,J=9,8Hz),3.88(1H,dd,J=8,8Hz),3.92(1H,m),3.95(1H,dd,J=12,4Hz),4.05(1H,d,J=9Hz),4.18(1H,dd,J=12,2Hz),7.06(1H,d,J=1.5Hz),7.34(1H,d,J=1.5Hz)
【００７２】
（例１８）
中間化合物Ｓの合成
アルゴン雰囲気下、中間化合物Ｎ 0.131g(0.280mmol)およびトリn-ブチルフォスフィン83.8μl(0.336mmol)の乾燥ＴＨＦ溶液に安息香酸41.1mg(0.336mmol)
およびジエチルアゾジカルボメート53.0μl(0.336mmol)の乾燥テトラヒドロフラン溶液を加え、室温にて30分間攪拌した。反応終了後、減圧下に乾固し、シリカゲルカラムクロマトグラフィー（シリカＧ27g, ベンゼン／酢酸エチル＝３／１）に付し、下式で示される目的物 0.140g(0.243mmol, 87.3mol%)を得た。
【００７３】
【化２７】
中間化合物Ｓの物性
固体、〔α〕D ＋70.9°(c1.06,CHCl3)
ＴＬＣ（シリカＧ，ベンゼン／酢酸エチル＝３／１） Ｒｆ＝0.25〜0.37
ＮＭＲ（２７０ＭＨｚ，ＣＤＣｌ3 , ＴＭＳ）
δ
.74(1H,dd,J=10,6Hz),3.83(1H,dd,J=10,4Hz),4.03(1H,dd,J=6,6Hz),4.25(1H,dd,J=6,5Hz),4.41(1H,ddd,J=6,6,4Hz),4.44(1H,d,J=12Hz),4.49(1H,d,J=12Hz),4.50(1H,d,J=12Hz),4.71(1H,d,J=12Hz),4.77(1H,d,J=12Hz),4.88(1H,d,J=12Hz),6.39(1H,d,J=5Hz),7.08(1H,d,J=1.5Hz),7.1〜7.6(19H,m),7.9〜8.1(2H,m)
ＩＲ（ＮａＣｌ）：νcm-1（％Ｔ）
(29),3030(22), 2923(23), 2914(23), 2868(20), 1723(8), 1601(47),1492(22), 1451(12),
(20), 1338(26), 1314(17), 1266(7), 1209(27),1178(24), 1155(25), 1107(8),
(8), 1072(8), 1025(14), 743(10),712(11), 699(9)
【００７５】
（例１９）
中間化合物Ｐの合成
中間化合物Ｓ0.140g(0.243mmol)を乾燥メタノール 3.4mlに溶解し、これに28％ナトリウムメトキシドのメタノール溶液30μl(0.15mmol) を加え室温で1.5時間攪拌した。反応終了後、減圧下に乾固し、乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ 10g, クロロホルム／アセトン＝２／１）に付し、前記、化２４として示される化合物
.114g(0.242mmol, 99.4mol%)を得た。
【００７６】
（例２０）
本発明化合物イの合成中間化合物Ｈ 0.119g(0.254mmol)、酢酸５mlおよび10％パラジウム−炭素0.15ｇを、室温にて水素圧４気圧で15時間攪拌した。反応終了後、メタノールで希釈し遠心分離した後上澄み液をろ過し、さらに沈澱物をメタノールで３回洗浄し同じく上澄み液をろ過し、ろ液を減圧下に乾固し、水で２回共沸乾固した。乾固物をメタノールに溶解し強塩基性陰イオン交換樹脂(IRA400)を通過させて酢酸を除き、溶液を減圧下に乾固した。得られた乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ6g,クロロホルム／メタノール＝１／１）に付し、下式で示される目的物 0.046g(0.227mmol,89.2mol%) を得た。
【００７７】
【化２８】
本品の物性は分析の結果、次のとおりであった。
固体、mp= 〜80℃、〔α〕D＋29.2°(c1.6,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2） Ｒｆ＝0.00〜0.25
ＮＭＲ（２７０ＭＨｚ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.87(1H,dd,J=7,2Hz),4.03(2H,d,J=5Hz),4.23(1H,dt,J=5,4Hz),4.38(1H,dd,J=4,2Hz),4.76(1H.d,J=7Hz),7.05(1H,d,J=1Hz),7.36(1H,d,J=1Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(12),1638(72), 1489(59), 1450(63), 1360(73), 1305(67), 1264(71),1144(61), 1113(41),1086(45), 1065(43), 1051(41), 750(64), 686(66)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００７９】
（例２１）
本発明発明物ロの合成
中間化合物Ｐ0.102g(0.228mmol)、酢酸５mlおよび10％パラジウム−炭素0.15ｇを、室温にて水素圧４気圧で15時間攪拌した。以下、例２０と同様の後処理を行い、下式で示される目的物0.041g(0.206mmol, 95.6mol%)を得た。
【００８０】
【化２９】
本品の物性は、分析の結果次のとおりであった。
無色固体、mp=169〜174
℃、〔α〕D −8.0 °(c0.97,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2 Ｒｆ＝0.00〜0.17
ＮＭＲ（２７０ＭＨｚ，Ｄ2Ｏ）
δ
.85(1H,dd,J=10,9Hz),3.98(1H,J=10,9Hz),4.11(1H,dd,J=13,3Hz),4.12(1H,m),4.27(1H,dd,J=13,3Hz),4.72(1H,d,J=9Hz),7.30(1H,d,J=1.5Hz),7.43(1H,d,J=1.5Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(7),2913(47), 1491(52), 1448(60), 1419(59), 1319(58), 1268(67),1198(76), 1178(77),1118(42), 1089(44), 1069(48), 1057(48), 1029(46),749(62), 651(68)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００８２】
（例２２）
本発明の参考化合物ハの合成
中間化合物Ｊ0.164g(0.349mmol)、酢酸 3.2mlおよび10％パラジウム−炭素0.20ｇを、室温にて水素圧４気圧で15時間攪拌した。以下、例２０と同様の後処理を行い、下式で示される目的物53.1mg(0.266mmol,76.3mol%)を得た。
【００８３】
【化３０】
本品の物性は、分析の結果次のとおりであった。
固体、mp= 〜80℃、〔α〕D＋25.3°(c1.8,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2） Ｒｆ＝0.00〜0.25
ＮＭＲ（４００ＭＨZ，ＣＤ3ＯＤ, ＴＭＳ）
δ
.04(1H,dd,J=4,2Hz),4.07(1H,dd,J=12,6Hz),4.09(1H,dd,J=12,4Hz),4.21(1H,ddd,J=6,4,4Hz),4.34(1H,dd,J=4,2Hz),4.82(1H,d,J=4Hz),7.12(1H,d,J=1.5Hz),7.43(1H,d,J=1.5Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(26),2926(47), 1641(73), 1486(67), 1444(70), 1266(73), 1100(59),1057(58), 1048(63),768(72)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００８５】
（例２３）
本発明化合物ニの合成
中間化合物Ｎ0.107g(0.227mmol)、酢酸５mlおよび10％パラジウム−炭素0.15ｇを、室温にて水素圧４気圧で15時間攪拌した。以下、例２０と同様の後処理を行い、下式で示される目的物0.042ｇ(0.209mmol,91.9mol%)を得た。
【００８６】
【化３１】
本品の物性は、分析の結果次のとおりであった。
無色固体、mp=111〜114
℃、〔α〕D −36.2°(c1.01,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝１／１ Ｒｆ＝0.00〜0.37
ＮＭＲ（２７０ＭＨｚ，pyridine-d5 ，ＴＭＳ）
δ
.39(1H,dd,J=13,4Hz),4.40(1H,dd,J=7.5,4Hz),4.41(1H,dd,J=13,4Hz),4.76(1H,ddd,J=9,4,4Hz),5.04(1H,dd,J=9,7.5Hz),5.66(1H,d,J=4Hz),7.39(1H,d,J=1.5Hz),7.78(1H,d,J=1.5Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(1),2924(29), 2862(30), 1638(55), 1490(30), 1442(34), 1422(37),1372(49), 1327(47),1281(37), 1182(58), 1133(32), 1096(12), 1067(18),1012(52), 900(33), 816(55),762(27), 720(36)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２０１（Ｍ＋１）
【００８８】
（例２４）
本発明化合物ホの合成
中間化合物Ｌ33.7mg(0.17mmol)をメタノール 0.4mlに溶解し、この溶液に無水酢酸 172μl 加え室温で１時間攪拌した。反応終了後、減圧下に乾固し、少量の水を加えさらに共沸乾固した。乾固物をメタノールに溶解し強塩基性陰イオン交換樹脂(IRA400)を通過させて酢酸を除き、溶液を減圧下に乾固した。得られた乾固物をシリカゲルカラムクロマトグラフィー（シリカＧ４ｇ、クロロホルム／メタノール＝１／１）に付し、下式で示される目的物 33.4g(0.129mmol,76.0 mol%) を得た。
【００８９】
【化３２】
本品の物性は、分析の結果次のとおりであった。
無色固体、mp=210〜212℃、（分解）、〔α〕D ＋75.8°(c1.1,CH3OH)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2） Ｒｆ＝0.32〜0.40
ＮＭＲ（２７０ＭＨｚ，ＣＤ3ＯＤ，ＴＭＳ）
δ
.07(3H,s,Ac),4.10(2H,d,J=6Hz),4.15(1H,dd,J=9,2Hz),4.34(1H,m),4.37(1H,dd,J=2,2Hz),5.08(1H,d,J=9Hz),7.39(1H,d,J=2Hz),7.78(1H,d,J=2Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(38),1639(51), 1557(63), 1487(77), 1442(78), 1374(77), 1115(72),1057(76)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２４２（Ｍ＋１）
【００９１】
（例２５）
本発明化合物ヘの合成
中間化合物Ｒ57.9mgをメタノール0.58mlに溶解し、この溶液に無水酢酸0.270mlを加え室温で１時間攪拌した。以下、例２４と同様の後処理を行い、下式で示される目的物17.6mg(0.073mmol, 35.4mol%)を得た。
【００９２】
【化３３】
本品の物性は、分析の結果次のとおりであった。
無色固体、mp=249〜251℃、(decomp.) 、〔α〕D ＋52.6°(c0.90,H2O)
ＴＬＣ（シリカＧ，クロロホルム／メタノール＝1/1, Ｉ2） Ｒｆ＝0.34〜0.43
ＮＭＲ（５００ＭＨｚ，pyridine-d5 ，ＴＭＳ）
δ
.11(3H,s,Ac),4.34(1H,ddd,J=9,5,2.5Hz),4.40(1H,dd,J=11,5Hz),4.44(1H,dd,J=9,9Hz),4.57(1H,dd,J=9,9Hz),4.66(1H,dd.J=11,2.5Hz),5.85(1H,dd,J=9,9Hz),7.35(1H,d,J=1.5Hz),7.68(1H,d,J=1.5Hz),9.17(1H,d,J=9Hz)
ＩＲ（ＫＢｒ）：νcm-1（％Ｔ）
(30),3308(21), 3072(50), 2911(61), 2854(61), 1659(12), 1565(26),1479(50), 1244(50),1135(54), 1103(45), 1052(50), 1003(51), 770(50),730(67), 690(65)
ＭＳ：（ＦＡＢ＋）ｍ／ｚ２４２（Ｍ＋１）
【００９４】
【発明の効果】
本発明化合物の酵素活性スクリーニング試験の結果は、表１に示したものであり、優れた糖加水分解酵素阻害活性が認められ、これらの化合物は抗肥満薬、抗糖尿病薬などとして有用なものである。
【００９５】
【表１】
[Industrial applications]
The present invention relates to a 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compound having excellent sugar hydrolase inhibitory activity and useful as an antiobesity agent, an antidiabetic agent and the like.
[0002]
2. Description of the Related Art As a substance having such a medicinal effect, there is known a naturally occurring Nagstatin represented by the following formula.
[Change1]
Nagstatin is a compound isolated from a culture of streptomyces amakusaensis MG846-fF3, which is superior to N-acetyl-β-D-glucosaminidase (NAG-ase). It has inhibitory activity (Journal of Antibiotics, 45, 1404, 1992). NAG-ase, an exoglycosidase that cleaves N-acetyl-β-D-glucosamine from glycoproteins and glycolipids, has been reported to be localized in lysosomes and increase in activity during diseases such as diabetes, leukemia and cancer. ing. This increase in activity is also an indicator of liver disease and pregnancy. NAG-ase
It is important to investigate the behavior of intractable diseases such as nephritis and immune deficiency in addition to the above-mentioned diseases, and in this case, the action of specific inhibitors such as nagstatin is indispensable. It is thought that it will become. In addition, no studies have been reported on the synthesis of a complex condensed bicyclic compound containing an imidazole ring, and it has been difficult to obtain an analog having a nagstatin skeleton in which an imidazole ring and a saccharide are condensed.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to mass-produce substances having a sugar hydrolase inhibitory activity at low cost by chemical synthesis.
[0005]
[Means for Solving the Problems]
The present inventors have conducted intensive studies in view of such circumstances, and as a result, using an L-ribose or L-xylose derivative as a starting material, a nucleophilic reaction of an imidazole derivative at each C-1 position was performed. By the intramolecular nucleophilic substitution reaction between the introduced imidazole moiety and the hydroxyl group of the sugar chain, it has become possible to stereoselectively synthesize the nagstatin analog which is a nitrogen-containing saccharide containing an imidazole ring, and these compounds are They have found that they have inhibitory activity against various glucosidases, and have accomplished the present invention.
[0006]
The present invention provides a 6,7,8-trihydroxy-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine compound represented by the following structural formula and 8-acetamide The present invention relates to a -6,7-dihydroxy-5-hydroxymethyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine compound.
[Change2]
Compound of the present invention(A, b, d, e, f) and the reference compound of the present invention (c)Are as follows.
[Change3]
[0008]
Physical properties of compound A of the present invention
Solid, mp = ~ 80 ℃, [α]D
+ 29.2 ° (c1.6, CHThreeOH)
TLC (silica G,
Chloroform / methanol = 1/1, ITwo ) Rf = 0.00 to 0.25
NMR (270 MHz, CDThreeOD, TMS)
δ
.87 (1H, dd, J = 7.2Hz), 4.03 (2H, d, J = 5Hz), 4.23 (1H, dt, J = 5,4Hz), 4.38 (1H, dd, J = 4,2Hz) , 4.76 (1H, d, J = 7Hz), 7.05 (1H, d, J = 1Hz), 7.36 (1H, d, J = 1Hz)
IR (KBr): νcm-1(% T)
(12), 1638 (72), 1489 (59), 1450 (63), 1360 (73), 1305 (67), 1264 (71), 1144 (61), 1113 (41), 1086 (45), 1065 (43), 1051 (41), 750 (64), 686 (66) MS: (FAB +) m / z 201 (M + 1)
[0009]
[Change4]
[0010]
Physical Properties of Compound B of the Present Invention
Colorless solid, mp = 169-174
° C, [α]D −8.0 ° (c0.97, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.00 to 0.17
NMR (270 MHz, DTwoO)
δ
.85 (1H, dd, J = 10,9Hz), 3.98 (1H, J = 10,9Hz), 4.11 (1H, dd, J = 13,3Hz), 4.12 (1H, m), 4.27 (1H, dd , J = 13,3Hz), 4.72 (1H, d, J = 9Hz), 7.30 (1H, d, J = 1.5Hz), 7.43 (1H, d, J = 1.5Hz) IR (KBr): νcm-1(% T)
(7), 2913 (47), 1491 (52), 1448 (60), 1419 (59), 1319 (58), 1268 (67), 1198 (76), 1178 (77), 1118 (42), 1089 (44), 1069 (48), 1057 (48), 1029 (46), 749 (62), 651 (68) MS: (FAB +) m / z 201 (M + 1)
[0011]
[Change5]
[0012]
The present inventionReferencePhysical properties of compound C
Solid, mp = ~ 80 ℃, [α]D
+ 25.3 ° (c1.8, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.00 to 0.25
NMR (400 MHz, CDThreeOD, TMS)
δ
.04 (1H, dd, J = 4,2Hz), 4.07 (1H, dd, J = 12,6Hz), 4.09 (1H, dd, J = 12,4Hz), 4.21 (1H, ddd, J = 6, 4,4Hz), 4.34 (1H, dd, J = 4,2Hz), 4.82 (1H, d, J = 4Hz), 7.12 (1H, d, J = 1.5Hz), 7.43 (1H, d, J = 1.5 Hz)
IR (KBr): νcm-1(% T)
(26), 2926 (47), 1641 (73), 1486 (67), 1444 (70), 1266 (73), 1100 (59), 1075 (58), 1048 (63), 768 (72) MS: (FAB +) m / z 201 (M + 1)
[0013]
[Change6]
[0014]
Physical properties of the compound of the present invention
Colorless solid, mp = 111-114
° C, [α]D −36.2 ° (c1.01, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1)
Rf = 0.00-0.37
NMR (270 MHz, pyridine-dFive, TMS)
δ
.39 (1H, dd, J = 13,4Hz), 4.40 (1H, dd, J = 7.5,4Hz), 4.41 (1H, dd, J = 13,4Hz), 4.76 (1H, ddd, J = 9, 4,4Hz), 5.04 (1H, dd, J = 9,75Hz), 5.66 (1H, d, J = 4Hz), 7.39 (1H, d, J = 1.5Hz), 7.78 (1H, d, J = 1.5 Hz)
IR (KBr): νcm-1(% T)
(1), 2924 (29), 2862 (30), 1638 (55), 1490 (30), 1442 (34), 1422 (37), 1372 (49), 1327 (47), 1281 (37), 1182 (58), 1133 (32), 1096 (12), 1067 (18), 1012 (52), 900 (33), 816 (55), 762 (27), 720 (36)
MS: (FAB +) m / z 201 (M + 1)
[0015]
[Change7]
[0016]
Physical properties of compound e of the present invention
Colorless solid, mp = 210-212
° C (decomposition), [α]D + 75.8 ° (c1.1, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.32 to 0.40
NMR (270 MHz, CDThreeOD, TMS)
δ
.07 (3H, s, Ac), 4.10 (2H, d, J = 6Hz), 4.15 (1H, dd, J = 9,2Hz), 4.34 (1H, m), 4.37 (1H, dd, J = 2 , 2Hz), 5.08 (1H, d, J = 9Hz), 7.39 (1H, d, J = 2Hz), 7.78 (1H, d, J = 2Hz)
IR (KBr): νcm-1(% T)
(38), 1639 (51), 1557 (63), 1487 (77), 1442 (78), 1374 (77), 1115 (72), 1057 (76)
MS: (FAB +) m / z 242 (M + 1)
[0017]
[Change8]
[0018]
Physical properties of the compound of the present invention
Colorless solid, mp = 249-251
° C, (decomp.), [Α]D + 52.6 ° (c0.90, HTwoO)
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.34 to 0.43
NMR (500 MHz, pyridine-dFive , TMS)
δ
.11 (3H, s, Ac), 4.34 (1H, ddd, J = 9,5,2.5Hz), 4.40 (1H, dd, J = 11,5Hz), 4.44 (1H, dd, J = 9,9Hz ), 4.57 (1H, dd, J = 9,9Hz), 4.66 (1H, dd.J = 11,2.5Hz), 5.85 (1H, dd, J = 9,9Hz), 7.35 (1H, d, J = 1.5Hz), 7.68 (1H, d, J = 1.5Hz), 9.17 (1H, d, J = 9Hz, NH)
IR (KBr): νcm-1(% T)
(30), 3308 (21), 3072 (50), 2911 (61), 2854 (61), 1659 (12), 1565 (26), 1479 (50), 1244 (50), 1135 (54), 1103 (45), 1052 (50), 1003 (51), 770 (50), 730 (67), 690 (65)
MS: (FAB +) m / z 242 (M + 1)
[0019]
【Example】
(Example 1)
Synthesis of intermediate compounds A and B
Under an argon atmosphere, to a solution consisting of 1.98 g (6.38 mmol) of N-trityl imidazole and 80 ml of dry tetrahydrofuran (hereinafter referred to as THF) was added 4.01 ml (6.42 mmol) of a 1.6 Mn-butyllithium-hexane solution at −5 ° C. After stirring for 10 minutes, then a solution consisting of 1.21 g (2.90 mmol) of 2,3,5-tri-O-benzyl-L-ribofuranose and 8 ml of dry THF was added at 0 ° C. and stirred for a further 30 minutes. After completion of the reaction, a small amount of dry ice was added to the system, and then 20 ml of a saturated saline solution was added thereto for liquid separation, and the organic layer was dried under reduced pressure. The dried product was subjected to silica gel column chromatography (silica G 160 g, benzene / ethyl acetate = 1/1), and 0.821 g (1.12 mmol, 38.7 L-allose derivative represented by the following formula (hereinafter referred to as intermediate compound B)) mol%)
Got.
[0020]
[Change9]
Next, the other components of the reaction mixture were again subjected to silica gel column chromatography (120 g of silica G, chloroform / ethyl acetate = 2/1) to give an L-altrose derivative represented by the following formula (hereinafter referred to as intermediate compound A). ) 0.994 g (1.36 mmol, 46.9 mol%).
[Change10]
Physical properties of the intermediate compound A
Solid, mp = 62-67 ° C, [α]D −111.8 ° (c1.0, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/1) Rf = 0.61-0.7
NMR (270 MHz, CDClThree TMS)
δ
.98 (1H, br.d, J = 6Hz), 3.54 (1H, dd, J = 10,6Hz), 3.59 (1H, dd, J = 10,4Hz), 3.83 (1H, dd, J = 8, 2Hz), 3.92 (1H, ddd, J = 8,6,4Hz), 4.00 (1H, dd, J = 8,2Hz), 4.25 (1H, d, J = 11Hz), 4.43 (1H, d, J = 11Hz), 4.45 (1H, d, J = 12Hz), 4.51 (1H, d, J = 12Hz), 4.52 (2H, s), 4.53 (dd, J = 8,6Hz), 6.83 (1H, d, J = 2Hz), 7.09 (1H, d, J = 2Hz), 7.0 ~ 7.4 (30H, m)
IR (KBr): νcm-1(% T)
(69), 3357 (72), 3059 (66), 3028 (60), 2858 (56), 1493 (35), 1448 (26), 1215 (55), 1089 (19), 1069 (18), 1029 (36), 1000 (55), 906 (69), 746 (12), 699 (7), 642 (53)
MS: (FAB +) m / z 731 (M + 1)
[0023]
Physical properties of the intermediate compound B
Colorless crystal, mp = 132.5-133.5
° C, (AcOEt), [α]D −31.0 ° (c1.05, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/1) Rf = 0.38-0.50
NMR (270 MHz, CDClThree , TMS)
δ
.86 (1H, dd, J = 8,2Hz), 3.29 (1H, dd, J = 10,2Hz), 3.39 (1H, dd, J = 10,7Hz), 3.45 (1H, d, J = 10Hz) , 3.50 (1H, dd, J = 8,4Hz), 3.82 (1H, ddd, J = 7,4,2Hz), 3.87 (1H, d, J = 10Hz), 4.05 (1H, d, J = 10Hz) , 4.17 (1H, d, J = 10Hz), 4.37 (1H, d, J = 10Hz), 4.45 (1H, d, J = 12Hz), 4.50 (1H, dd, J = 10,2Hz), 4.51 (1H , d, J = 12Hz), 6.9 ~ 6.7 (3H, m), 7.0 ~ 7.4 (29H, m)
IR (KBr): νcm-1(% T)
(75), 1493 (80), 1448 (77), 1102 (64), 1030 (76), 746 (59), 700 (51)
MS: (FAB +) m / z 731 (M + 1)
[0024]
(Example 2)
Synthesis of intermediate compounds C and D
Under an argon atmosphere, to a solution consisting of 1.53 g (4.94 mmol) of N-trityl imidazole and 70 ml of dry THF, 3.10 ml (4.96 mmol) of a 1.6 Mn-butyllithium-hexane solution was added at -10 ° C, stirred for 10 minutes, and then A solution consisting of 1.02 g (2.42 mmol) of 2,3,5-tri-O-benzyl-L-xylofuranose and 8 ml of dry THF was added at -10 ° C and stirred for another 30 minutes. After completion of the reaction, a small amount of dry ice was added to the system, and then 20 ml of a saturated saline solution was added thereto for liquid separation, and the organic layer was dried under reduced pressure. The dried product was subjected to silica gel column chromatography (Silica G 550 g, benzene / ethyl acetate = 1/2) to give 0.497 g (0.681 mmol, 28.0 g) of an L-growth derivative (hereinafter referred to as an intermediate compound C) represented by the following formula. mol%) and 0.161 g (0.22 mmol, 9.1 mol%) of an L-idose derivative (hereinafter referred to as intermediate compound D).
[0025]
The structural formula of the intermediate compound C is as follows:
[Change11]
The structural formula of the intermediate compound D is as follows.
[Change12]
Physical properties of intermediate compound C
Colorless solid, mp = 40-44 ° C, [α]D −55.1 ° (c0.87, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/2) Rf = 0.58 to 0.73
NMR (400 MHz, CDClThree , TMS)
δ
.01 (1H, br.d, J = 4Hz, OH), 3.45 (2H, d, J = 6Hz), 3.74 (1H, dd, J = 4,3.5Hz), 3.98 (1H, dt, J = 6 , 4Hz), 4.15 (1H, dd, J = 9,3.5HzC3-H), 4.40 (2H, s), 4.43 (1H, d, J = 12Hz), 4.48 (1H, d, J = 12Hz), 4.48 (1H, d, J = 10Hz), 4.51 (1H, br.dd, J = 9,4Hz), 4.59 (1H, d, J = 10Hz), 6.85 (1H, d, J = 2Hz), 6.9 ~ 7.4 (31H, m)
IR (KBr): νcm-1(% T)
(62), 3060 (65), 3029 (64), 2864 (69), 1493 (58), 1448 (48), 1228 (68), 1121 (51), 1088 (45), 1068 (40), 1029 (55), 747 (31), 699 (18)
MS: (FAB +) m / z 731 (M + 1)
[0028]
Physical properties of intermediate compound D
Colorless solid, mp = 43-46 ° C, [α]D + 18.0 ° (c1.21, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/2) Rf = 0.65 to 0.79
NMR (400 MHz, acetone-d6, TMS)
δ
.19 (1H, dd, J = 6.5,2.5Hz), 3.25 (1H, dd, J = 6.5,2.5Hz), 3.32 (1H, dd, J = 9,6.5Hz), 3.37 (1H, dd, J = 9,6.5Hz), 3.49 (1H, d, J = 6.5Hz), 3.54 (1H, m), 3.58 (1H, d, J = 9Hz), 4.32 (1H, d, J = 11.5Hz), 4.34 (1H, dd, J = 9,2.5Hz), 4.35 (1H, J = 10.5Hz), 4.37 (1H, d, J = 12Hz), 4.41 (1H, d, J = 11.5Hz), 4.43 (1H, d, J = 12Hz), 4.52 (1H, d, J = 10.5Hz), 6.82 (1H, d, J = 1.5Hz), 7.05 (1H.d, J = 1.5Hz), 7.1 ~ 7.4 (30H, m )
IR (KBr): νcm-1(% T)
(36), 3059 (42), 3029 (41), 2918 (52), 2862 (45), 1598 (75), 1493 (28), 1449 (20), 1394 (55), 1359 (58), 1227 (41), 1177 (61), 1116 (13), 1065 (17), 1030 (27), 1003 (52), 907 (69), 748 (7), 700 (3), 641 (66)
MS: (FAB +) m / z 731 (M + 1)
[0029]
(Example 3)
Synthesis of intermediate compound E
To a solution consisting of 1.01 g (1.39 mmol) of the L-allose derivative (intermediate compound B) and 30 ml of pyridine was added 0.397 g (2.08 mmol) of benzylsulfonyl chloride at 0 ° C., followed by stirring at 0 ° C. for 1 hour. After completion of the reaction, 0.1 ml of ethanol was added, and the mixture was stirred for 10 minutes, concentrated under reduced pressure, then a small amount of toluene was added, and the mixture was azeotropically dried under reduced pressure. The dried product was subjected to silica gel column chromatography (silica G 50 g, benzene / ethyl acetate = 4/1) to obtain 1.02 g (1.14 mmol, 82.7 mol%) of the target product represented by the following formula.
[0030]
[ChangeThirteen]
Physical properties of intermediate compound E
Solid, mp = ~ 60 ° C, [α]D
−43.7 ° (c1.4, CHClThree )
TLC (silica G, benzene / ethyl acetate = 4/1) Rf = 0.53-0.60
NMR (400 MHz, CDClThree , TMS)
δ
.50 (1H, d, J = 10Hz), 3.20 (1H, dd, J = 12,2Hz), 3.54 (1H, dd, J = 12,9Hz), 3.73 (1H, dd, J = 10,2Hz) , 3.74 (1H, d, J = 10Hz), 4.03 (1H, d, J = 10Hz), 4.07 (1H, dJ = 10z), 4.31 (2H, s), 4.37 (1H, d, J = 10Hz), 4.42 (1H, J = 12Hz), 4.45 (1H, d, J = 12Hz), 4.46 (1H, s), 5.08 (1H, ddd, J = 9,2,2Hz), 6.7-6.8 & 7.0-7.5 ( 32H, m)
IR (KBr): νcm-1(% T)
(74), 3029 (71), 2922 (82), 2864 (80), 1493 (47), 1449 (43), 1361 (42), 1329 (62), 1218 (55), 1174 (35), 1098 (28), 1030 (39), 1001 (68), 909 (41), 747 (25), 699 (12)
MS: (FAB +) m / z 885 (M + 1)
[0032]
(Example 4)
Synthesis of intermediate compound F
L-growth derivative (intermediate compoundC) To a solution consisting of 1.11 g (1.52 mmol) and 34 ml of pyridine was added 0.444 g (2.33 mmol) of benzylsulfonyl chloride at -10 ° C, and the mixture was stirred at -10 ° C for 30 minutes. After completion of the reaction, 1 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 10 minutes, concentrated under reduced pressure, then a small amount of toluene was added, and the mixture was azeotropically dried under reduced pressure. After the dried product was extracted with 30 ml of ethyl acetate, the extract was dried under reduced pressure. The dried product was subjected to silica gel column chromatography (silica G 120 g, benzene / ethyl acetate = 4/1) to obtain 1.05 g (1.23 mmol, 81.1 mol%) of the target product represented by the following formula.
[0033]
[Change14]
Physical properties of intermediate compound F
Colorless solid, mp = 66-69 ° C, [α]D −66.4 ° (c1.06, CHClThree)
TLC (silica G, benzene / ethyl acetate = 3/1) Rf = 0.48-0.55
NMR (270 MHz, CDClThree , TMS)
δ
.96 (1H, br.J = 5Hz, OH), 3.65 (1H, dd, J = 12,6Hz), 3.74 (1H, dd, J = 12,3Hz), 4.04 (1H, dd, J = 8, 2Hz), 4.14 (1H, d, J = 14Hz), 4.19 (1H, dd, J = 8,2Hz), 4.28 (1H, d, J = 14Hz), 4.10 (1H, d, J = 11Hz), 4.42 (2H, d, J = 12Hz), 4.47 (1H, d, J = 12Hz), 4.49 (1H, d, J = 11Hz), 4.54 (1H, dd, J = 8,4Hz), 4.58 (1H, d , J = 12Hz), 5.04 (1H, ddd, J = 8,6,3Hz), 6.82 (1H, d, J = 2Hz), 6.9 ~ 7.4 (37H, m)
IR (KBr): νcm-1(% T)
(60), 3446 (63), 3060 (68), 3030 (67), 2925 (74), 2863 (75), 1493 (57), 1449 (50), 1361 (42), 1173 (40), 1122 (52), 1086 (45), 1071 (43), 1028 (57), 914 (50), 747 (33), 700 (15),
[0035]
(Example 5)
Synthesis of intermediate compound G
A system consisting of 0.224 g (0.25 mmol) of a benzylsulfonyl compound (intermediate compound E), 5 ml of pyridine and 0.4 ml of acetic anhydride was heated and stirred at 60 ° C. for 1.5 hours. After completion of the reaction, 0.5 ml of ethanol was added to the system, and the mixture was stirred at room temperature for 10 minutes, and then concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate and neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was concentrated under reduced pressure. The dried product is subjected to silica gel column chromatography (
The resulting product was subjected to 11 g of Rishika G, benzase / ethyl acetate = 1/1) to obtain 0.127 g (0.249 mmol, 98.3 mol%) of the target compound represented by the following formula as a syrup.
[0036]
[ChangeFifteen]
Physical properties of intermediate compound G
Oily substance [α]D + 75.0 ° (c1.4, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/2) Rf = 0.53-0.59
NMR (270 MHz, CDClThree , TMS)
δ
.06 (3H, s, Ac), 3.81 (1H, dd, J = 10,8Hz), 3.98 (1H, dd, J = 5,2Hz), 4.00 (1H, dd, J = 10,3Hz), 4.21 (1H, dd, J = 6.2Hz), 4.45 (1H, ddd, J = 8,6.3Hz), 4.49 (2H, s), 4.57 (1H, d, J = 12Hz), 4.69 (1H, d , J = 12Hz), 4.70 (1H, d, J = 12Hz), 4.76 (1H, d, J = 12Hz), 6.22 (1H, d, J = 5Hz), 7.08 (1H, d, J = 1Hz), 7.15 (1H, d, J = 1Hz), 7.2 ~ 7.4 (15H, m)
IR (NaCl): νcm-1(% T)
(73), 3030 (66), 2922 (67), 2871 (64), 1744 (38), 1493 (64), 1452 (52), 1367 (46), 1304 (64), 1227 (34), 1093 (39), 1079 (40), 1044 (45), 1026 (45), 967 (69), 740 (43), 698 (42)
MS: (FAB +) m / z 513 (M + 1)
[0038]
(Example 6)
Synthesis of intermediate compound H
0.485 g (0.947 mmol) of the intermediate compound G was dissolved in 10 ml of dry methanol, and 29 μl (0.24 mmol) of a 28% sodium methoxide methanol solution was added thereto, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the residue was dried under reduced pressure, and the dried product was subjected to silica gel column chromatography (silica G 50 g, chloroform / acetone = 2/1) to obtain 0.427 g (0.906 mmol, 95.7 mmol) of the target product represented by the following formula. mol%).
[0039]
[Change16]
Physical properties of intermediate compound H
Colorless crystal, mp = 112-113
° C, (hexane / AcOEt = 1/1), [α]D + 38.6 ° (c1.0, CHClThree)
TLC (silica G, chloroform / acetone = 2/1) Rf = 0.26-0.35
NMR (270 MHz, CDClThree , TMS)
δ
.84 (1H, dd, J = 10,7.5Hz), 3.94 (1H, dd, J = 10,3Hz), 4.02 (1H, dd, J = 5.5,2Hz), 4.35 (1H, dd, J = 5 , 2Hz), 4.39 (1H, ddd, J = 7.5,5,3Hz), 4.49 (2H, s), 4.64 (1H, dJ = 12Hz), 4.75 (1H, d, J = 12Hz), 4.82 (1H, d, J = 12Hz), 4.87 (1H, d, J = 12Hz), 5.17 (1H, d, J = 5.5Hz), 6.98 (1H, d, J = 1.5Hz), 7.10 (1H, d, J = 1.5Hz), 7.2-7.6 (15H, m)
IR (KBr): νcm-1(% T)
(46), 2898 (48), 2862 (48), 1495 (41), 1467 (47), 1451 (33), 1366 (38), 1327 (47), 1311 (53), 1289 (58), 1234 (61), 1210 (65), 1180 (59), 1128 (12), 1101 (8), 1052 (34), 1023 (29), 1006 (40), 966 (67), 934 (65), 907 (69), 733 (6), 694 (14)
MS: (FAB +) m / z 471 (M + 1)
[0041]
(Example 7)
Synthesis of intermediate compound I
To a solution consisting of 0.535 g (0.733 mmol) of the L-altrose derivative (intermediate compound A) and 15 ml of pyridine was added 0.279 g (1.46 mmol) of benzylsulfonyl chloride at -15 ° C, and the mixture was stirred at -15 ° C for 1 hour. Then, 0.5 ml of acetic anhydride was added to the system, and the mixture was stirred at 0 ° C for 1 hour, and further heated and stirred at 60 ° C for 1.5 hours. Next, the same post-treatment as in Example 5 was performed to obtain 0.179 g (0.350 mmol, 47.9 mol%) of the target product represented by the following formula.
[0042]
[Change17]
Physical properties of intermediate compound I
Oily substance [α]D −3.0 ° (c1.05, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/2) Rf = 0.40-0.46
NMR (270 MHz, CDClThree , TMS)
δ
.93 (1H, dd, J = 10,8Hz), 3.97 (1H, dd, J = 10,4Hz), 4.09 (1H, dd, J = 5,2Hz), 4.21 (1H, dd, J = 4, 2Hz), 4.35 (1H, ddd, J = 8, 4, 4Hz), 4.65 (1H, d, J = 12Hz), 4.66 (1H, d, J = 12Hz), 4.76 (1H, d, J = 12Hz) , 4.80 (1H, d, J = 12Hz), 6.25 (1H, d, J = 5Hz), 7.18 (1H, s), 7.20 (1H, s),
.2 to 7.4 (15H, m) IR (NaCl): νcm-1(% T)
(72), 3061 (59), 3030 (55), 2918 (56), 2870 (53), 1735 (44), 1494 (60), 1482 (62), 1452 (53),
(51), 1306 (62), 1233 (46), 1136 (55), 1117 (50), 1098 (50), 1073 (48), 1023 (52),
(52), 698 (52) MS: (FAB +) m / z 513 (M + 1).
[0044]
(Example 8)
Synthesis of intermediate compound J
Intermediate compound I
.181 g (0.353 mmol) was dissolved in 10 ml of methanol, and 15 μl (0.07 mmol) of a 28% methanol solution of sodium methoxide was added thereto, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the residue was dried under reduced pressure, and the dried product was subjected to silica gel column chromatography (silica G 10 g, chloroform / acetone = 2/1) to obtain 0.139 g (0.296 mmol, 83.6 mmol) of the target product represented by the following formula. mol%).
[0045]
[Change18]
Physical properties of intermediate compound J
Colorless crystals, mp = 77-78 ° C, (heaxane / AcOEt = 3/1), (a) D -78 ° (cl.O, CHClThree)
TLC (silica G, chloroform / acetone = 2/1) Rf = 0.25-0.36
NMR (270 MHz, CDClThree , TMS)
δ
.90 (2H, d, J = 6Hz), 3.97 (1H, dd, J = 4,2Hz), 4.24 (1H, dd, J = 5,2Hz), 4.30 (1H, dt, J = 6,5Hz) , 4.51 (1H, d, J = 12Hz), 4.54 (1H, d, J = 12Hz), 4.67 (1H, d, J = 12Hz), 4.72 (1H, d, J = 12Hz), 4.90 (1h, d , J = 12Hz), 4.92 (1H, d, J = 12Hz), 5.02 (1H, d, J = 4Hz), 7.07 (1H, d, J = 2Hz), 7.11 (1H, d, J = 2Hz), 7.2 to 7.4 (15H, m)
IR (KBr): νcm-1(% T)
(17), 3029 (14), 2880 (16), 2864 (15), 1493 (18), 1452 (14), 1406 (51), 1356 (22), 1334 (33), 1302 (35), 1265 (34), 1208 (41), 1139 (15), 1120 (5), 1077 (1), 1026 (13), 933 (64), 733 (1), 697 (4)
MS: (FAB +) m / z 471 (M + 1)
[0047]
(Example 9)
Synthesis of intermediate compound K
Under an argon atmosphere, a solution of 60.5 mg (0.127 mmol) of the intermediate compound J and 38.1 μl (0.152 mmol) of tri-n-butylphosphine in 6 ml of dry THF was mixed with 189 μg (0.153 mmol) of a 4% hydroazideic acid-toluene solution and diethylazodicarboate. 24.1 μl (0.152 mmol) of mate was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the residue was dried under reduced pressure and subjected to silica gel column chromatography (silica G 5 g, benzene / ethyl acetate = 5/1) to give 37.4 mg (0.076 mmol, 59.1 mol%) of the desired product represented by the following formula. Obtained.
[0048]
[Change19]
Physical properties of intermediate compound K
Oily substance [α]D + 98.1 ° (c1.2, CHClThree)
TLC (silica G, benzene / ethyl acetate = 5/1) Rf = 0.38-0.50
NMR (270 MHz, CDClThree , TMS)
δ
.81 (1H, dd, J = 7,1.5Hz), 3.83 (2H, d, J = 6Hz), 4.24 (1H, dd, J = 4,1.5Hz), 4.28 (1H, dt, J = 6, 4Hz), 4.49 (1H, d, J = 12Hz), 4.52 (1H, d, J = 12Hz), 4.62 (1H, d, J = 12Hz), 4.74 (1H, d, J = 12Hz), 4.77 (1H , d, J = 12Hz), 4.84 (1H, d, J = 12Hz), 5.00 (1H, d, J = 7Hz), 7.07 (1H, d, J = 1Hz), 7.11 (1H, d, J = 1Hz) ), 7.2-7.4 (15H, m)
IR (NaCl): νcm-1(% T)
(71), 3030 (61), 2910 (56), 2870 (52), 2105 (22), 1792 (47), 1727 (67), 1495 (55), 1481 (57), 1453 (46), 1359 (48), 1300 (48), 1259 (41), 1209 (45), 1117 (35), 1094 (30), 1026 (48), 738 (35), 698 (36)
MS: (FAB +) m / z 496 (M + 1)
[0050]
(Example 10)
Synthesis of intermediate compound K
Under an atmosphere of argon, a solution of 0.120 g (0.255 mmol) of the intermediate compound H and 78.0 μl (0.306 mmol) of tri-n-butylphosphine in 12 ml of dry THF was added with 473 μg (0.506 mmol) of a 4% hydroazide acid-toluene solution and diethylazodicarbohydrate. 49 μl (0.306 mmol) of mate was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was dried under reduced pressure and subjected to silica gel column chromatography (silica G 5 g, benzene / ethyl acetate = 5/1) to obtain 88 mg (0.178 mmol, 69.2 mol%) of the desired product.
[0051]
(Example 11)
Synthesis of intermediate compound L
0.171 g (0.345 mmol) of the intermediate compound K, 4 ml of acetic acid and 0.22 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. After completion of the reaction, the reaction mixture was diluted with methanol and centrifuged, and the supernatant was filtered. The precipitate was further washed with methanol three times, and the supernatant was filtered again. The filtrate was dried under reduced pressure, and washed twice with water. The residue was evaporated to dryness to obtain 67.0 mg of the desired product represented by the following formula.
[0052]
[Change20]
Physical properties of intermediate compound L
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.00-0.27
NMR (270 MHz, CDThreeOD, TMS)
δ
.09 (1H, dd, J = 12,7Hz), 4.13 (1H, dd, J = 12,4.5Hz), 4.29 (1H, dd, J = 9.5,2Hz), 4.42 (1H, dd, J = 2 , 2Hz), 4.52 (1H, m), 4.83 (1H, d, J = 9.5Hz), 7.74 (1H, d, J = 1.5Hz), 8.06 (1H, d, J = 1.5Hz)
[0054]
(Example 12)
Synthesis of Intermediate Compound M
A system consisting of 0.997 g (1.16 mmol) of a benzylsulfonyl compound (intermediate compound F), 20 ml of pyridine and 2 ml of acetic anhydride was heated and stirred at 50 ° C. for 8 hours. Subsequently, the same post-treatment as in Example 5 was performed to obtain 0.501 g (0.980 mmol, 84.0 mol%) of the target product represented by the following formula as a syrup.
[0055]
[Change21]
Physical properties of intermediate compound M
Oily substance, [α]D −50.2 ° (c0.96, CHClThree)
TLC (silica G, benzene / ethyl acetate = 1/1) Rf = 0.42-0.48
NMR (270 MHz, acetone-d6, TMS)
δ
.84 (3H, s, Ac), 3.83 (1H, dd, J = 10,5Hz), 4.04 (1H, dd, J = 10,3Hz), 4.16 (1H, dd, J = 8.5,4Hz), 4.24 (1H, ddd, J = 7,5,3Hz), 4.29 (1H, dd, J = 8.5,7Hz), 4.51 (1H, d, J = 11Hz), 4.57 (1H, d, J = 11Hz), 4.63 (1H, d, J = 11Hz), 4.66 (1H, d, J = 11Hz), 4.87 (1H, d, J = 11Hz), 4.92 (1H, d, J = 11Hz), 6.50 (1H, d, J = 4Hz), 6.98 (1H, d, J = 1.5Hz), 7.2 ~ 7.5 (16H, m)
IR (NaCl): νcm-1(% T)
(64),
(55), 2922 (57), 2868 (50), 1742 (22), 1493 (49), 1452 (42), 1367 (34), 1311 (59), 1228 (22), 1106 (25), 1080 (30), 1029 (33), 947 (50), 738 (30), 699 (30)
MS: (FAB +) m / z 513 (M + 1)
[0057]
(Example 13)
Synthesis of intermediate compound N
0.157 g (0.307 mmol) of the intermediate compound M was dissolved in 4 ml of dry methanol, and 15 μl (0.07 mmol) of a 28% methanol solution of sodium methoxide was added thereto, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the residue was dried under reduced pressure. The dried product was subjected to silica gel column chromatography (silica G 10 g, chloroform / acetone = 2/1) to obtain 0.134 g (0.285 mmol,
.0 mol%).
[0058]
[Change22]
Physical properties of intermediate compound N
Colorless crystal, mp = 116.5-117.5
° C, (hexane / EtOAc = 2/1), [α]D −4.0 ° (c0.95, CHClThree)
TLC (silica G, chloroform / acetone = 2/1) Rf = 0.14 to 0.30
NMR (270 MHz, CDClThree , TMS)
δ
.69 (1H, dd, J = 10,6Hz), 3.79 (1H, dd, J = 10,3.5Hz), 3.96 (1H, dd, J = 8,4Hz), 4.15 (1H, ddd, J = 6 , 6,3.5Hz), 4.20 (1H, dd, J = 8,6Hz), 4.44 (1H, d, J = 12Hz), 4.49 (1H, d, J = 12Hz), 4.60 (1H, d, J = 11Hz), 4.72 (1H, d, J = 12Hz), 4.83 (1H, d, J = 12Hz), 4.92 (1H, d, J = 11Hz), 5.13 (1H, d, J = 4Hz), 7.01 (1H , d, J = 1.5Hz), 7.10 (1H, d, J = 1.5Hz), 7.2 ~ 7.4 (15H, m)
IR (KBr): νcm-1(% T)
(75), 2890 (73), 2861 (71), 1453 (79), 1143 (70), 1117 (54), 1084 (55), 1051 (66), 736 (51), 697 (60)
MS: (FAB +) m / z 471 (M + 1)
[0060]
(Example 14)
Synthesis of intermediate compound O
To a solution consisting of 0.106 g (0.146 mmol) of the L-idose derivative (intermediate compound D) and 3 ml of pyridine was added 0.052 g (0.274 mmol) of benzylsulfonyl chloride at -15 ° C, followed by stirring at -15 ° C for 1 hour. Next, 0.2 ml of acetic anhydride was added to the system, and the mixture was stirred at 0 ° C for 1 hour, and further heated and stirred at 60 ° C for 1.5 hours. Thereafter, the same post-treatment as in Example 5 was performed, and the target product represented by the following formula
.016 g (0.031 mmol, 21.4 mol%) was obtained.
[0061]
[Change23]
Physical properties of intermediate compound O
Oily substance
TLC (silica G, benzene / ethyl acetate = 1/1) Rf = 0.35-0.38
NMR (400 MHz, CDClThree , TMS)
δ
.08 (3H, s, Ac), 3.70 (1H, dd, J = 10,6Hz), 3.79 (1H, dd, J = 10,4Hz), 3.96 (1H, dd, J = 7,7Hz), 4.08 (1H, dd, J = 7,6Hz), 4.27 (1H, ddd, J = 7,6,4Hz), 4.43 (1H, d, J = 12Hz), 4.46 (1H, d, J = 12Hz), 4.52 (1H, d, J = 11.5Hz), 4.76 (1H, d, J = 11.5Hz), 4.77 (1H, d, J = 11.5Hz), 4.81 (1H, d, J = 11.5Hz), 6.11 (1H , d, J = 6Hz), 7.04 (1H, d, J = 1Hz), 7.11 (1H, d, J = 1Hz), 7.15 ~ 7.4 (15H, m)
[0063]
(Example 15)
Synthesis of intermediate compound P
7.2 mg (0.014 mmol) of the intermediate compound O was dissolved in 0.2 ml of dry methanol, and 2 μl (0.01 mmol) of a 28% methanol solution of sodium methoxide was added thereto, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the residue is dried under reduced pressure, and the dried product is subjected to silica gel column chromatography (silica G 0.5 g, chloroform / acetone = 2/1) to give the target compound represented by the following formula
.1 mg (0.009 mmol, 62.0 mol%) were obtained.
[0064]
[Change24]
Physical properties of intermediate compound P
Colorless solid, [α]D + 10.3 ° (c0.95, CHClThree)
TLC (silica G, chloroform / acetone = 2/1) Rf = 0.20-0.28
NMR (400MHz, acetone-d6, TMS)
δ 3.84 (1H, dd, J = 10,5Hz), 3.97 (1H, dd, J = 7.5,6Hz), 4.01 (1H, dd, J = 10,3.5Hz), 4.06 (1H, dd, J = 7.5 , 7.5Hz), 4.30 (1H, m), 4.52 (1H, d, J = 12Hz), 4.54 (1H, d, J = 12Hz), 4.63 (1H, d, J = 11Hz), 4.79 (1H, d , J = 6Hz), 4.85 (1H, d, J = 11Hz), 4.92 (1H, d, J = 11Hz), 5.01 (1H, d, J = 11Hz), 6.95 (1H, s), 7.19 (1H, s), 7.2-7.5 (15H, m)
IR (NaCl): νcm-1(% T)
(56), 3030 (54), 2908 (56), 2869 (53), 1493 (58), 1452 (57), 1361 (62), 1311 (65), 1282 (69), 1207 (69), 1144 (54), 1114 (50), 1084 (49), 1053 (53), 1028 (55), 736 (50), 698 (51)
MS: (FAB +) m / z 471 (M + 1)
[0066]
(Example 16)
Synthesis of intermediate compound Q
Under an argon atmosphere, a solution of 0.14 g (0.30 mmol) of (intermediate compound N) and 112 μl (0.45 mmol) of tri-n-butylphosphine in 1.5 ml of dry tetrahydrofuran was treated with 558 μg (0.45 mmol) of a 4% hydroazide acid-toluene solution and diethyl ether. 71 μl (0.45 mmol) of azodicarbonate was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction product was dried under reduced pressure and subjected to silica gel column chromatography (silica G 35 g, benzene / ethyl acetate = 3/1) to give 0.104 g (0.210 mmol, 70.0 mol%) of the target product represented by the following formula. Obtained.
[0067]
[Change25]
Physical properties of intermediate compound Q
Oily substance, [α]D + 58.8 ° (c1.06, CHClThree)
TLC (silica G, benzene / ethyl acetate = 3/1) Rf = 0.32-0.40
NMR (270 MHz, CDClThree TMS)
δ
.68 (1H, dd, J = 10,5Hz), 3.79 (1H, dd, J = 10,3.5Hz), 3.88 (1H, dd, J = 8,7Hz), 3.96 (1H, dd, J = 7 , 7Hz), 4.15 (1H, ddd, J = 8,5,3.5Hz), 4.39 (1H, d, J = 12Hz), 4.45 (1H, d, J = 12Hz), 4.55 (1H, d, J = 12Hz), 4.73 (1H, d, J = 7Hz), 4.80 (1H, d, J = 11Hz), 4.88 (1H, d, J = 11Hz), 4.89 (1H, d, J = 12Hz), 7.02 (1H , d, J = 1.5Hz), 7.13 (1H, d, J = 1.5Hz), 7.2-7.4 (15H, m)
IR (NaCl): νcm-1(% T)
(76), 2914 (73), 2868 (71), 2103 (45), 1794 (79), 1494 (75), 1482 (76), 1453 (67), 1362 (70), 1312 (75), 1279 (70), 1260 (70), 1209 (71), 1140 (65), 1094 (53), 1025 (71), 738 (58), 698 (57)
[0069]
(Example 17)
Synthesis of intermediate compound R
0.102 g (0.206 mmol) of the intermediate compound Q, 5 ml of acetic acid and 0.137 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. After completion of the reaction, the reaction mixture was diluted with methanol and centrifuged, and the supernatant was filtered. The precipitate was further washed with methanol three times, and the supernatant was filtered again. The filtrate was dried under reduced pressure, and washed twice with water. The residue was evaporated to dryness to obtain 57.9 mg of the desired product represented by the following formula.
[0070]
[Change26]
Physical properties of intermediate compound R
TLC (silica G, chloroform / methanol = 1/1, ITwo ) Rf = 0.00-0.25
NMR (400 MHz, CDThreeOD, TMS)
δ
.70 (1H, dd, J = 9,8Hz), 3.88 (1H, dd, J = 8,8Hz), 3.92 (1H, m), 3.95 (1H, dd, J = 12,4Hz), 4.05 (1H , d, J = 9Hz), 4.18 (1H, dd, J = 12,2Hz), 7.06 (1H, d, J = 1.5Hz), 7.34 (1H, d, J = 1.5Hz)
[0072]
(Example 18)
Synthesis of intermediate compound S
Under an argon atmosphere, 41.1 mg (0.336 mmol) of benzoic acid was added to a dry THF solution of 0.131 g (0.280 mmol) of the intermediate compound N and 83.8 μl (0.336 mmol) of tri-n-butylphosphine.
Then, a solution of 53.0 μl (0.336 mmol) of diethylazodicarbamate in dry tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction product was dried under reduced pressure and subjected to silica gel column chromatography (silica G 27 g, benzene / ethyl acetate = 3/1) to give 0.140 g (0.243 mmol, 87.3 mol%) of the target product represented by the following formula. Obtained.
[0073]
[Change27]
Physical properties of intermediate compound S
Solid, [α]D + 70.9 ° (c1.06, CHClThree)
TLC (silica G, benzene / ethyl acetate = 3/1) Rf = 0.25-0.37
NMR (270 MHz, CDClThree , TMS)
δ
.74 (1H, dd, J = 10,6Hz), 3.83 (1H, dd, J = 10,4Hz), 4.03 (1H, dd, J = 6,6Hz), 4.25 (1H, dd, J = 6, 5Hz), 4.41 (1H, ddd, J = 6,6,4Hz), 4.44 (1H, d, J = 12Hz), 4.49 (1H, d, J = 12Hz), 4.50 (1H, d, J = 12Hz) , 4.71 (1H, d, J = 12Hz), 4.77 (1H, d, J = 12Hz), 4.88 (1H, d, J = 12Hz), 6.39 (1H, d, J = 5Hz), 7.08 (1H, d , J = 1.5Hz), 7.1 ~ 7.6 (19H, m), 7.9 ~ 8.1 (2H, m)
IR (NaCl): νcm-1(% T)
(29), 3030 (22), 2923 (23), 2914 (23), 2868 (20), 1723 (8), 1601 (47), 1492 (22), 1451 (12),
(20), 1338 (26), 1314 (17), 1266 (7), 1209 (27), 1178 (24), 1155 (25), 1107 (8),
(8), 1072 (8), 1025 (14), 743 (10), 712 (11), 699 (9)
[0075]
(Example 19)
Synthesis of intermediate compound P
0.140 g (0.243 mmol) of the intermediate compound S was dissolved in 3.4 ml of dry methanol, and 30 μl (0.15 mmol) of a 28% methanol solution of sodium methoxide was added thereto, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the residue was dried under reduced pressure, and the dried product was subjected to silica gel column chromatography (silica G 10 g, chloroform / acetone = 2/1) to obtain the above compound.24Compound shown as
.114 g (0.242 mmol, 99.4 mol%) were obtained.
[0076]
(Example 20)
0.119 g (0.254 mmol) of Intermediate Compound H, 5 ml of acetic acid and 0.15 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. After completion of the reaction, the mixture was diluted with methanol, centrifuged, and the supernatant was filtered. The precipitate was further washed with methanol three times, and the supernatant was filtered again. The filtrate was dried under reduced pressure, and then washed twice with water. Boil to dryness. The dried product was dissolved in methanol and passed through a strongly basic anion exchange resin (IRA400) to remove acetic acid, and the solution was dried under reduced pressure. The resulting dried product was subjected to silica gel column chromatography (silica G: 6 g, chloroform / methanol = 1/1) to obtain 0.046 g (0.227 mmol, 89.2 mol%) of the target compound represented by the following formula.
[0077]
[Change28]
As a result of analysis, the physical properties of this product were as follows.
Solid, mp = ~ 80 ° C, [α]D+ 29.2 ° (c1.6, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo) Rf = 0.00 to 0.25
NMR (270 MHz, CDThreeOD, TMS)
δ
.87 (1H, dd, J = 7.2Hz), 4.03 (2H, d, J = 5Hz), 4.23 (1H, dt, J = 5,4Hz), 4.38 (1H, dd, J = 4,2Hz) , 4.76 (1H.d, J = 7Hz), 7.05 (1H, d, J = 1Hz), 7.36 (1H, d, J = 1Hz)
IR (KBr): νcm-1(% T)
(12), 1638 (72), 1489 (59), 1450 (63), 1360 (73), 1305 (67), 1264 (71), 1144 (61), 1113 (41), 1086 (45), 1065 (43), 1051 (41), 750 (64), 686 (66)
MS: (FAB +) m / z 201 (M + 1)
[0079]
(Example 21)
Synthesis of compound b of the present invention
0.102 g (0.228 mmol) of the intermediate compound P, 5 ml of acetic acid and 0.15 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. Thereafter, the same post-treatment as in Example 20 was performed to obtain 0.041 g (0.206 mmol, 95.6 mol%) of the target product represented by the following formula.
[0080]
[Change29]
Physical properties of this product were as follows as a result of the analysis.
Colorless solid, mp = 169-174
° C, [α]D −8.0 ° (c0.97, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo Rf = 0.00-0.17
NMR (270 MHz, DTwoO)
δ
.85 (1H, dd, J = 10,9Hz), 3.98 (1H, J = 10,9Hz), 4.11 (1H, dd, J = 13,3Hz), 4.12 (1H, m), 4.27 (1H, dd , J = 13,3Hz), 4.72 (1H, d, J = 9Hz), 7.30 (1H, d, J = 1.5Hz), 7.43 (1H, d, J = 1.5Hz)
IR (KBr): νcm-1(% T)
(7), 2913 (47), 1491 (52), 1448 (60), 1419 (59), 1319 (58), 1268 (67), 1198 (76), 1178 (77), 1118 (42), 1089 (44), 1069 (48), 1057 (48), 1029 (46), 749 (62), 651 (68)
MS: (FAB +) m / z 201 (M + 1)
[0082]
(Example 22)
The present inventionReferenceSynthesis of compound C
0.164 g (0.349 mmol) of the intermediate compound J, 3.2 ml of acetic acid and 0.20 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. Thereafter, the same post-treatment as in Example 20 was carried out to obtain 53.1 mg (0.266 mmol, 76.3 mol%) of the target product represented by the following formula.
[0083]
[Change30]
The physical properties of this product were as follows as a result of the analysis.
Solid, mp = ~ 80 ° C, [α]D+ 25.3 ° (c1.8, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo) Rf = 0.00 to 0.25
NMR (400 MHz, CDThreeOD, TMS)
δ
.04 (1H, dd, J = 4,2Hz), 4.07 (1H, dd, J = 12,6Hz), 4.09 (1H, dd, J = 12,4Hz), 4.21 (1H, ddd, J = 6, 4,4Hz), 4.34 (1H, dd, J = 4,2Hz), 4.82 (1H, d, J = 4Hz), 7.12 (1H, d, J = 1.5Hz), 7.43 (1H, d, J = 1.5 Hz)
IR (KBr): νcm-1(% T)
(26), 2926 (47), 1641 (73), 1486 (67), 1444 (70), 1266 (73), 1100 (59), 1057 (58), 1048 (63), 768 (72)
MS: (FAB +) m / z 201 (M + 1)
[0085]
(Example 23)
Synthesis of compound d of the present invention
0.107 g (0.227 mmol) of the intermediate compound N, 5 ml of acetic acid and 0.15 g of 10% palladium-carbon were stirred at room temperature under a hydrogen pressure of 4 atm for 15 hours. Thereafter, the same post-treatment as in Example 20 was performed to obtain 0.042 g (0.209 mmol, 91.9 mol%) of the target product represented by the following formula.
[0086]
[Change31]
The physical properties of this product were as follows as a result of the analysis.
Colorless solid, mp = 111-114
° C, [α]D −36.2 ° (c1.01, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1 Rf = 0.00-0.37
NMR (270 MHz, pyridine-dFive , TMS)
δ
.39 (1H, dd, J = 13,4Hz), 4.40 (1H, dd, J = 7.5,4Hz), 4.41 (1H, dd, J = 13,4Hz), 4.76 (1H, ddd, J = 9, 4,4Hz), 5.04 (1H, dd, J = 9,7.5Hz), 5.66 (1H, d, J = 4Hz), 7.39 (1H, d, J = 1.5Hz), 7.78 (1H, d, J = 1.5Hz)
IR (KBr): νcm-1(% T)
(1), 2924 (29), 2862 (30), 1638 (55), 1490 (30), 1442 (34), 1422 (37), 1372 (49), 1327 (47), 1281 (37), 1182 (58), 1133 (32), 1096 (12), 1067 (18), 1012 (52), 900 (33), 816 (55), 762 (27), 720 (36)
MS: (FAB +) m / z 201 (M + 1)
[0088]
(Example 24)
Synthesis of compound e of the present invention
33.7 mg (0.17 mmol) of the intermediate compound L was dissolved in 0.4 ml of methanol, and 172 μl of acetic anhydride was added to this solution, followed by stirring at room temperature for 1 hour. After completion of the reaction, the mixture was dried under reduced pressure, a small amount of water was added, and the mixture was further azeotropically dried. The dried product was dissolved in methanol and passed through a strongly basic anion exchange resin (IRA400) to remove acetic acid, and the solution was dried under reduced pressure. The resulting dried product was subjected to silica gel column chromatography (4 g of silica G, chloroform / methanol = 1/1) to obtain 33.4 g (0.129 mmol, 76.0 mol%) of a target product represented by the following formula.
[0089]
[Change32]
The physical properties of this product were as follows as a result of the analysis.
Colorless solid, mp = 210-212 ° C, (decomposition), [α]D + 75.8 ° (c1.1, CHThreeOH)
TLC (silica G, chloroform / methanol = 1/1, ITwo) Rf = 0.32 to 0.40
NMR (270 MHz, CDThreeOD, TMS)
δ
.07 (3H, s, Ac), 4.10 (2H, d, J = 6Hz), 4.15 (1H, dd, J = 9,2Hz), 4.34 (1H, m), 4.37 (1H, dd, J = 2 , 2Hz), 5.08 (1H, d, J = 9Hz), 7.39 (1H, d, J = 2Hz), 7.78 (1H, d, J = 2Hz)
IR (KBr): νcm-1(% T)
(38), 1639 (51), 1557 (63), 1487 (77), 1442 (78), 1374 (77), 1115 (72), 1057 (76)
MS: (FAB +) m / z 242 (M + 1)
[0091]
(Example 25)
Synthesis of the compound of the present invention
57.9 mg of the intermediate compound R was dissolved in 0.58 ml of methanol, and 0.270 ml of acetic anhydride was added to this solution, followed by stirring at room temperature for 1 hour. Thereafter, the same post-treatments as in Example 24 were performed to obtain 17.6 mg (0.073 mmol, 35.4 mol%) of the target product represented by the following formula.
[0092]
[Change33]
The physical properties of this product were as follows as a result of the analysis.
Colorless solid, mp = 249-251 ° C, (decomp.), (Α)D + 52.6 ° (c0.90, HTwoO)
TLC (silica G, chloroform / methanol = 1/1, ITwo) Rf = 0.34 to 0.43
NMR (500 MHz, pyridine-dFive , TMS)
δ
.11 (3H, s, Ac), 4.34 (1H, ddd, J = 9,5,2.5Hz), 4.40 (1H, dd, J = 11,5Hz), 4.44 (1H, dd, J = 9,9Hz ), 4.57 (1H, dd, J = 9,9Hz), 4.66 (1H, dd.J = 11,2.5Hz), 5.85 (1H, dd, J = 9,9Hz), 7.35 (1H, d, J = 1.5Hz), 7.68 (1H, d, J = 1.5Hz), 9.17 (1H, d, J = 9Hz)
IR (KBr): νcm-1(% T)
(30), 3308 (21), 3072 (50), 2911 (61), 2854 (61), 1659 (12), 1565 (26), 1479 (50), 1244 (50), 1135 (54), 1103 (45), 1052 (50), 1003 (51), 770 (50), 730 (67), 690 (65)
MS: (FAB +) m / z 242 (M + 1)
[0094]
【The invention's effect】
The results of the enzyme activity screening test of the compounds of the present invention are shown in Table 1, and excellent sugar hydrolase inhibitory activity was confirmed. These compounds are useful as antiobesity agents, antidiabetic agents and the like. is there.
[0095]
[Table 1]
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP01643095A JP3561546B2 (en) | 1995-01-06 | 1995-01-06 | New 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP01643095A JP3561546B2 (en) | 1995-01-06 | 1995-01-06 | New 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08188579A JPH08188579A (en) | 1996-07-23 |
| JP3561546B2 true JP3561546B2 (en) | 2004-09-02 |
Family
ID=11916031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP01643095A Expired - Fee Related JP3561546B2 (en) | 1995-01-06 | 1995-01-06 | New 5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3561546B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7741340B2 (en) * | 2003-11-12 | 2010-06-22 | Amicus Therapeutics, Inc. | Hydroxy piperidine derivatives to treat gaucher disease |
-
1995
- 1995-01-06 JP JP01643095A patent/JP3561546B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08188579A (en) | 1996-07-23 |
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