CN111748000B - 3-脱氧-5-羟基-1-氨基碳糖类化合物及其用途 - Google Patents

3-脱氧-5-羟基-1-氨基碳糖类化合物及其用途 Download PDF

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CN111748000B
CN111748000B CN201910248983.3A CN201910248983A CN111748000B CN 111748000 B CN111748000 B CN 111748000B CN 201910248983 A CN201910248983 A CN 201910248983A CN 111748000 B CN111748000 B CN 111748000B
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许佑君
姜春风
刘佳明
刘凯旋
段明飞
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Abstract

本发明属于制药领域，具体为通式如下的3‑脱氧‑5‑羟基‑1‑氨基碳糖类化合物及其用途,其中，R如权利要求书和说明书所述。本发明通过立体和位置选择性还原方法来合成保护的3‑脱氧‑5‑羟基环己酮，该化合物具有新颖的碳糖骨架。通过还原胺化方法将该化合物与小分子胺类反应，得到对应的保护基保护的目标物，最后经由脱保护基反应，获得3‑脱氧‑5‑羟基结构特征的氨基碳糖类目标物。目标物对α‑糖苷酶具有良好的抑制活性，且对正常ICR小鼠蔗糖负荷后的血糖上升有显著的抑制作用，提示其可用于降糖药物进行进一步开发。

Description

3-脱氧-5-羟基-1-氨基碳糖类化合物及其用途
技术领域
本发明属于制药领域，涉及3-脱氧-1-羟基-5-氨基碳糖类化合物及其用途。
背景技术
碳糖系分子环内氧原子(-O-)被次甲基(-CH2-)替换产物，替换之后其仍然保留原来糖的基本骨架或结构特征，具有相似的生物学活性，但具有更为稳定的化学结构和更稳定的生物学特征(McCasland G.E.,et al.,J.Org.Chem.,1966,31,1516)。作为碳糖模拟物(mimetics)一直是广泛被研究报道的化合物，具有降糖活性等；还可以作为核苷或核苷酸分子中的糖的构成骨架，呈现抗菌、抗肿瘤或抗病毒等活性(Lahiri R.,et al.,Chem.Soc.Rev.,2013,42,5102)。
市售药物阿卡波糖(acarbose,1)、伏格列波糖(voglibose,2)作为糖的模拟物，系α-糖苷酶抑制剂，因抑制小肠中的寡糖、双糖酶来减少单糖麦芽糖和果糖的产生，从而控制餐后血糖的水平，血糖的有效控制对降低高血糖患者的心血管风险、并发症等意义重大(Lefebvre P.J.,etal.,Diabetic Med.,1998,15,63)。
5α-位为-CH2-特征的碳糖苷类化合物3～5对Na+-依赖葡萄糖转运受体(SGLT2)具有很强的抑制作用，通过促进葡萄糖自尿中***来减少血液中的葡萄糖浓度(ShingT.K.M.,et al.,Angew.Chem.Int.Ed,2013,125,8559)。具有类似特征的碳糖苷类化合物7～8(SL0101即6的类似物)为P90核糖体S6激酶(p90ribosomal s6kinase,RSK)，具有较强的抗肿瘤作用(Li M.Z.,etal.,Org.Lett.,2017,19,2410)。作为EGFR抑制剂的天然物(+)-pericosine A(9)在体内也具有良好的抗肿瘤作用。神经氨酸酶抑制剂奥司米韦(10)的分子中也具有氨基碳糖的骨架，用于治疗甲型流感(Von Itzstein H.,et al.,Nat Rev DrugDiscov.,2007,6,967)。
虽然碳糖或碳糖类似物具有广泛的生物活性，但其分子中的多个手性中心、多官能团结构特征，其合成仍然为化学界的一个挑战，尤其针对新骨架类型的化合物更是如此。
Figure BDA0002011850060000011
发明内容
本发明拟报道一类构建3-脱氧即3-H型碳糖骨架的新方法，并利用该骨架化合物来设计、合成新型氨基碳糖类化合物，探讨其对α-糖苷酶的抑制作用以及体内降糖活性，以期寻找新型降糖药物。
1.本发明提供3-脱氧-5-羟基-1-氨基碳糖类化合物，具有如下的结构通式：
Figure BDA0002011850060000021
其中，R代表氢、C1～12的烃基、环烃基、环烃基烃基，或羟基烃基，或烃氧烃基，或氨基烃基，或氨基羟基烃基。
以下提供本发明化合物各种基团的定义，除另行定义外，它们在说明书和权利说明书中统一使用。
“C1～12烃基”指的是含有1～12个碳原子的直链或支链烃基，优选：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或正戊基。
“环烃基”指的是含有3～7个碳原子的单环饱和碳环基团，优选：环丙基、环丁基、环戊基、环己基和环庚基。
“环烃基烃基”指的是含有3～7个碳原子的单环碳环基团与1～6个碳原子的烃基组合，优选：环丙甲基、环丙乙基、环丁甲基、环丁乙基、环戊甲基、环戊乙基、环己甲基、环己乙基。
“羟基烃基”指含有2～12个碳原子的直链或支链的烃基被一个或多个羟基取代，优选：2-羟基乙基、2-羟基丙基、3-羟基丙基或2,3-羟基丙基。
“烃氧烃基”指含有2～12个碳原子的直链或支链的烃基被烃氧基取代，其中烃氧基指1～6个碳原子的烃氧基。优选：2-甲氧基乙基、3-甲氧基丙基或4-甲氧基丁基，2-乙氧基乙基、3-乙氧基丙基或4-乙氧基丁基，2,3-二羟基丙基。
“氨基烃基”指含有2～12个碳原子的直链或支链的烃基被氨基或取代氨基取代，优选：2-氨基乙基或3-氨基丙基。
“氨基羟基烃基”指含有3～12个碳原子的直链或支链的烃基同时被羟基和氨基或取代氨基取代，优选：2-氨基-3-羟基丙基，3-氨基-2-羟基丙基，2-氨基-4-羟基丁基，2-氨基-3-羟基丁基、3-氨基-2-羟基丁基、4-氨基-2-羟基丁基。
2.本发明提供此类氨基碳糖类化合物的生物活性，主要是α-糖苷酶抑制活性，以及动物体内的降糖活性，提示这类化合物可以作为降糖活性候选物。
3.本发明提供此类氨基碳糖类化合物的合成方法，以P保护的3-脱氧-1-羰基物为原料，经还原胺化反应，得到保护的3-脱氧-1-氨基碳糖，最后经脱保护来获得。保护基P为苄基、取代苯基甲基，优选苄基保护基。还原胺化时，所用的有机胺H2NR中的R基团同上述目标物，所用还原剂为LiBH4、NaBH4、KBH4、LiBH3CN、NaBH3CN、KBH3CN、NaBH(OAc)3；还原胺化所用溶剂为醇性溶剂，优选甲醇、乙醇、或其任意组合；或醚性溶剂如***、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷、或其任意组合；或醇性溶剂与醚性溶剂的任意组合；脱保护时，选择钯、镍、钌、铑催化氢化法脱除苄基、取代苯基甲基的保护，所用溶剂为水、醇性溶剂、或其任意组合，优选甲醇、乙醇、异丙醇；醚性溶剂或其任意组合，优选四氢呋喃、1,2-二甲氧基乙烷；为提高催化剂活性可向体系中加入盐酸、甲酸、醋酸提高脱保护反应效率。
Figure BDA0002011850060000031
4.本发明提供重要中间体12的立体和位置选择性合成方法，该中间体为未见报道的保护多羟基的高度官能团化的中间体，特别适合于构筑新颖骨架的碳糖，或作为片段用于碳糖苷的构建块；如上所述，保护基P为苄基、取代芳基甲基，优选苄基保护基；Hydride的1,4-Micheal加成，可以选择还原剂连二亚硫酸钠，也可以选择钯、镍、钌、铑催化剂与氢气组合的双键还原方法；所用溶剂为水、醇性溶剂或其任意组合优选甲醇、乙醇、异丙醇；醚性溶剂或其任意组合，优选四氢呋喃、1,2-二甲氧基乙烷。
Figure BDA0002011850060000032
5.本发明选取鼠源寡糖酶α-蔗糖酶、α-麦芽糖酶为测试对象，***测试了主要目标物对两种酶的抑制活性，结果显示，部分目标物表现出对α-蔗糖酶良好的抑制活性，其作用与市售药物Voglibose的相当，其对α-麦芽糖酶也有抑制作用。
6.选取对酶抑制活性较好的目标物，进行小鼠体内糖耐量试验，结果显示，目标物的活性与Voglibose的相当，提示目标物可作为候选结构来进一步筛选降糖药物。
本发明属于制药领域，涉及3-脱氧-5-羟基-1-氨基碳糖类化合物、其选择性合成及应用。
本发明提供一种化学结构和生物学特征更稳定的氨基碳糖类，该类目标物具有3-脱氧即3-H-5-OH-1-氨基碳糖的结构特征，为环高度官能团化的新型化合物，该类化合物具有显著的α-糖苷酶抑制活性、体内明显的降糖活性，该研究对进一步寻找新型降糖药物具有重要意义。
附图说明
图1为样品对ICR小鼠蔗糖负荷后血糖曲线和曲线下面积的影响。
具体实施方式
说明书中，命名时将中间体和目标物的骨架均作为碳糖骨架处理，其命名编号均模仿葡萄糖的命名编号方法，替换葡萄糖环中-O-的-CH2-所处位置为5α-位，此也为文献中经常出现的编号和命名方法；但目标物为多取代的氨基醇结构，按照有机化学的***命名方法，应以环己环为骨架、醇为编号的起点，结构中的氨基处于5-位，原5α-位即为6-位。两种命名编号有所不同，特此说明，以免混淆。
下面用具体实例进一步说明本发明，但不限制本发明。
具体实施方式
1.(2S,4S,5S)-2,4-二苄氧基-5-苄氧甲基-5-羟基-环己酮(12)的制备
实施例1a：冰水浴下，化合物14计4.88g(11.0mmol)、10％Pd/C 0.20g、Na2CO30.24g和MeOH 100mL剧烈搅拌进行常压催化氢化2.0h。过滤，滤液以1.0M NaH2PO4/Na2HPO4缓冲液100mL稀释，再减压浓缩回收甲醇。剩余物以乙酸乙酯萃取，无水硫酸钠干燥。浓缩后，粗品经柱层析分离，得白色固体12计3.04g，收率62.0％。m.p 104～106℃，[α]D 20＝+82.88(c 1.0,CHCl3).
1H NMR(600MHz,CDCl3):δ7.29–7.17(m,15H),4.80(d,J＝11.9Hz,1H),4.57(d,J＝11.5Hz,1H),4.41–4.38(m,4H),3.94(dd,J＝11.6Hz,4.7Hz,1H),3.83(dd,J＝12.7Hz,6.1Hz,1H),3.56(d,J＝8.7Hz,1H),3.10(d,J＝8.7Hz,1H),2.65(d,J＝14.7,1H),2.42-2.39(m,1H),2.36(d,J＝14.6,1H),2.07(q,J＝12.2Hz,1H).
13C NMR(150MHz,CDCl3):δ206.19,137.95,137.79,137.68,128.60,128.18,128.11,128.07,128.00,127.96,77.96,77.02,74.03,73.54,73.10,72.05,71.97,45.75,32.62.
HR–MS:calcd.for C28H30O5Na+469.1985,found 469.1996.
实施例1b：类似条件下，以10％Ru/C 0.25g代替实施例1a中的Pd/C，类似后处理后得到12计2.89g，收率59.0％。
实施例1c：类似条件下，以Raney/Ni(W–2)0.40g代替实施例1a中的Pd/C，类似后处理后得到12计2.40g，收率49.0％。
实施例1d：氩气保护、电磁搅拌下，将化合物14计4.45g(10.0mmol)、NaHCO318.5g、Na2S2O4 28.0g、1,4-二氧六环100mL与100mL水的混和物于80℃反应4.0h。以1.0mole/L盐酸调pH 5～6。减压浓缩回收溶剂，残余物以EtOAc萃取，经无水硫酸钠干燥。浓缩后所得粗品经柱层析分离，得白色固体12计1.87g，收率为42.0％。
实施例1e：类似条件下，以乙醇代替实施例1a中的甲醇进行反应，类似后处理后得到12计2.70g，收率55.0％。
实施例1f：类似条件下，以四氢呋喃代替实施例1a中的甲醇进行反应，类似后处理后得到12计3.10g，收率为63.0％。
实施例1g：类似条件下，以1,2-二甲氧基乙烷代替实施例1a中的甲醇进行反应，类似后处理后得到12计2.85g，收率为58.0％。
2.关键中间体13的制备
2.1(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-苯乙基氨基-1-环己醇(13a)
实施例2a：冰水浴条件下，12计223.0mg(0.5mmol)、β-苯乙胺0.19mL(1.5mmol)于乙醇20mL中，分批加入硼氢化钠55.0mg(1.5mmol)，加毕保温反应3.0h后减压蒸出乙醇，残余物以二氯甲烷50mL稀释，饱和氯化铵50mL洗涤，有机层无水硫酸钠干燥。浓缩后，粗品经柱层析分离，得白色固体13a计142.7mg，收率51.8％。m.p 142–144℃，[α]D 20＝–16.59(c1.0,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.15(m,15H),7.17–7.02(m,5H),4.56–4.59(d,J＝12.0Hz,1H),4.26–4.45(m,2H),3.59(d,J＝8.6Hz,1H),3.40–3.46(m,1H),3.34–3.40(m,1H),3.23(d,J＝8.6Hz,1H),3.10–2.97(m,2H),2.80(dt,J＝12.4,5.9Hz,1H),2.62(dt,J＝13.6,7.6Hz,1H),2.53(dt,J＝11.0,7.4Hz,1H),2.08(dt,J＝12.4,4.7Hz,1H),1.98(t,J＝12.0Hz,1H),1.91(dd,J＝14.8,3.4Hz,1H),1.39(dd,J＝15.0,2.6Hz,1H).
13C NMR(100MHz,CDCl3):δ139.78,138.96,129.15,129.01,128.92,128.72,128.63,128.39,128.18,128.11,127.93,127.85,126.78,77.06,76.36,74.45,73.88,73.75,71.86,70.81,55.63,49.00,36.59,31.82,28.58.
HR-MS:calcd.for C36H41NO4H+552.3108,found 552.3137.
实施例2b：类似条件下，以NaBH3CN 94.2mg(1.5mmol)代替实施例2a中的硼氢化钠进行反应，类似后处理后得到13a计133.6mg，收率48.5％。
实施例2c：类似条件下，以NaBH(OAc)3 317.9mg(1.5mmol)代替实施例2a中的硼氢化钠进行反应，类似后处理后得到13a计137.8mg，收率50.0％。
实施例2d：类似条件下，以THF代替实施例2a中的乙醇进行反应，类似后处理后得到13a计124.1mg，收率45.0％。
实施例2e：类似条件下，以1,4-二氧六环代替实施例2a中的乙醇进行反应，类似后处理后得到13a计110.0mg，收率40.0％。
2.2(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-羟基-1-(羟甲基)乙基氨基)-1-环己醇(13b)
实施例2f：类似条件下，以丝氨醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13b，收率48.5～61.2％。[α]D 20＝+30.8(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.34–7.24(m,15H),4.61(dd,J＝11.7,1.9Hz,2H),4.50–4.42(m,4H),3.73–3.66(m,4H),3.58(d,J＝8.6Hz,1H),3.52–3.45(m,2H),3.33(d,J＝2.8,1H),3.25(d,J＝8.6Hz,1H),2.78(t,J＝3.9Hz,1H),2.20–2.17(m,1H),2.06(q,J＝12.0Hz,1H),1.91(dd,J＝15.1,2.8Hz,1H),1.49(dd,J＝15.1,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ138.67,138.45,138.08,128.62,128.42,128.35,128.02,127.94,127.81,127.78,127.67,127.62,76.18,75.77,74.32,73.42,71.42,70.35,65.01,61.17,56.60,51.91,32.21,27.93.
HR–MS:calcd.for C31H39NO6H+522.2850,found 522.2865.
2.3(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-羟基乙基)氨基-1-环己醇(13c)
实施例2g：类似条件下，以乙醇胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13c，收率55.1～86.1％。[α]D 20＝+10.5(c 1.0,CHCl3).
1H NMR(400MHz,CDCl3):δ7.24–7.18(m,15H),4.51–4.36(m,6H),3.62–3.58(m,1H),3.53–3.51(m,2H),3.42–3.37(m,2H),3.19(d,J＝8.6Hz,1H),3.05(d,J＝2.8Hz,1H),2.80–2.77(m,1H),2.53–2.51(m,1H),2.11–2.08(m,1H),1.98(q,J＝12.1Hz,1H),1.87(dd,J＝15.0,J＝2.9Hz,1H),1.38(dd,J＝15.0,J＝2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ138.74,138.46,138.13,128.57,128.34,128.26,128.01,127.88,127.74,127.72,127.58,127.52,76.31,75.80,74.22,73.33,71.37,70.47,61.25,55.05,49.20,31.26,28.06.
HR-MS:calcd.for C30H37NO5H+492.2744,found 492.2764.
2.4(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(3-羟基丙基)氨基-1-环己醇(13d)
实施例2h：类似条件下，以3-氨基-1-丙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13d，收率49.3～69.3％。[α]D 20＝–4.6(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.94(m,1H),3.76–3.69(m,3H),3.51(s,2H),3.11(d,J 2.8Hz,1H,H5),3.01–2.95(m,1H),2.83–2.78(m,1H),2.06(dd,J 15.0,J＝4.2Hz,1H),1.98–1.87(m,2H),1.46(d,J 14.8Hz,1H).
13C NMR(100MHz,D2O):δ77.32,71.45,70.34,67.76,62.46,59.59,50.59,34.90,31.18.
HR-MS:calcd.for C9H19NO5H+222.1336,found 222.1331.
2.5(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(4-羟基丁基)氨基-1-环己醇(13e)
实施例2i：类似条件下，以4-氨基丁醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13e，收率49.5～65.0％。[α]D 20＝+7.1(c 1.00,CHCl3).
1H NMR(600MHz,CDCl3):δ7.37–7.24(m,15H),4.64–4.45(m,6H),3.63–3.56(m,3H),3.50–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.08(d,J＝3.1Hz,1H),2.83–2.78(m,1H),2.40–2.36(m,1H),2.17–2.14(m,1H),2.03(q,J＝12.1Hz,1H),1.94(dd,J＝15.0,3.2Hz,1H),1.59–1.51(m,3H),1.43(dd,J＝15.0,2.6Hz,1H).
13C NMR(150MHz,CDCl3):δ138.91,138.55,138.27,128.64,128.38,128.29,128.07,127.96,127.76,127.66,127.60,127.53,76.66,75.91,74.14,73.46,73.37,71.51,70.60,62.77,55.49,47.16,31.33,30.26,28.18,26.60.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3079.
2.6(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-((R)-1-羟基丙基)氨基)-1-环己醇(13f)
实施例2j：类似条件下，以(R)-2-氨基-1-丙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13f，收率44.5～79.3％。[α]D 20＝–0.3(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.2(m,15H),4.63(d,J＝12.0Hz,1H),4.52–4.45(m,5H),3.90–3.86(m,1H),3.61(d,J＝8.6Hz,1H),3.51–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.10(d,J＝2.9Hz,1H),2.82(dd,J＝11.6,3.2Hz,1H),2.33(dd,J＝11.4,9.0Hz,1H),2.18–2.14(m,1H),2.06(q,J＝12.0Hz,1H),1.95(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.4Hz,1H),1.17(d,J＝6.2Hz,3H).
13C NMR(100MHz,CDCl3):δ138.85,138.53,138.20,128.63,128.40,128.32,128.07,127.93,127.81,127.79,127.63,127.57,76.45,75.84,74.22,73.44,73.40,71.45,70.52,67.34,55.63,55.20,31.52,28.16,21.80.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2921.
2.7(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-((S)-1-羟基丙基)氨基)-1-环己醇(13g)
实施例2k：类似条件下，以(S)-2-氨基-1-丙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13g，收率45.8～72.3％。[α]D 20＝–24.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.25(m,15H),4.64–4.44(m,6H),3.90–3.86(m,1H),3.62(d,J＝8.6Hz,1H),3.51–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.12(d,1H),2.65(dd,J＝12.3,7.3Hz,1H),2.52(dd,J＝12.3,3.3Hz,1H),2.20–2.14(m,1H),2.05(q,J＝12.0Hz,1H),1.93(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.5Hz,1H),1.15(d,J＝6.3Hz,3H).
13C NMR(100MHz,CDCl3):δ138.83,138.51,138.18,128.63,128.38,128.30,128.06,127.95,127.76,127.61,127.55,76.52,75.85,74.15,73.42,73.37,71.52,70.56,66.06,54.80,54.38,31.44,27.99,20.78.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2933.
2.8(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-((R)-1-羟基丁基)氨基)-1-环己醇(13h)
实施例2l：类似条件下，以(R)-2-氨基-1-丁醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13h，收率47.4～62.3％。[α]D 20＝+2.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.28–7.18(m,15H),4.58–4.38(m,6H),3.68(dd,J 11.5,J 3.4Hz,1H),3.56(d,J 8.7,J 3.2Hz,1H),3.45–3.33(m,3H),3.23(d,J 3.1Hz,1H),3.18(d,J 8.6Hz,1H),2.51–2.49(m,1H),2.13–2.10(m,1H),1.95(q,J＝12.1,1H),1.79(d,J14.9,J 3.0Hz,1H,),1.46–1.38(m,3H),0.85(t,J＝7.4Hz,3H).
13C NMR(100MHz,CDCl3):δ138.81,138.49,137.88,128.70,128.41,128.34,128.07,127.86,127.82,127.66,127.61,76.25,75.87,73.94,73.57,73.40,71.59,70.45,61.21,57.62,52.28,32.67,27.52,25.51,10.93.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3078.
2.9(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-((S)-1-羟基丁基)氨基)-1-环己醇(13i)
实施例2m：类似条件下，以(S)-2-氨基-1-丁醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13i，收率47.8～55.1％。[α]D 20＝+18.7(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.26–7.17(m,15H),4.57–4.37(m,6H),3.56–3.50(m,2H),3.45–3.38(m,3H),3.20(d,J＝8.4Hz,1H),2.55–2.54(m,1H),2.12–2.08(m,1H),2.00–1.89(m,2H),1.44–1.33(m,3H),0.83(t,J 6.0Hz,3H).
13C NMR(100MHz,CDCl3):δ138.77,138.46,137.97,128.61,128.39,128.32,127.98,127.93,127.76,127.63,127.59,127.56,76.18,75.85,74.32,73.42,73.40,71.49,70.43,64.82,58.97,52.93,32.35,27.91,23.46,10.18.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3080.
2.10(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(3-((R)-1,2-二羟基丙基)氨基)-1-环己醇(13j)
实施例2n：类似条件下，以(R)-3-氨基-1,2-二丙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13j，收率57.8～63.0％。[α]D 20＝–8.1(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.24(m,15H),4.60–4.40(m,6H),3.98(s,4H),3.75–3.73(m,1H),3.58(d,J＝8.6Hz,1H),3.53–3.41(m,4H),3.25(d,J＝8.6Hz,1H),3.08(d,J＝2.6Hz,1H),2.76(dd,J＝12.2,6.7Hz,1H),2.50(dd,J＝12.1,3.2Hz,1H),2.18–2.13(m,1H),2.04(q,J＝12.0Hz,1H),1.92(dd,J＝15.1,3.0Hz,1H),1.44(dd,J＝15.0,2.2Hz,1H).
13C NMR(100MHz,CDCl3):δ138.58,138.41,138.16,128.62,128.41,128.35,128.14,127.93,127.82,127.77,127.66,76.25,75.85,74.39,73.38,73.26,71.62,70.51,70.23,64.68,55.13,49.50,31.09,28.07.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.9078.
2.11(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(3-((S)-1,2-二羟基丙基)氨基)-1-环己醇(13k)
实施例2o：类似条件下，以(S)-3-氨基-1,2-二丙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13k，收率37.8～46.1％。[α]D 20＝–18.4(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.24(m,15H),4.62–4.43(m,6H),3.74–3.70(m,1H),3.58–3.54(m,2H),3.48–3.41(m,3H),3.27(d,J＝8.6Hz,1H),3.07(d,J＝2.9Hz,1H),2.84(dd,J＝11.5,3.7Hz,1H),2.40(dd,J＝11.4,8.4Hz,1H),2.17–2.13(m,1H),2.08–1.93(m,2H),1.42(dd,J＝15.0,2.3Hz,1H).
13C NMR(100MHz,CDCl3):δ138.61,138.40,138.10,128.63,128.41,128.36,128.10,127.93,127.83,127.78,127.67,76.17,75.83,74.43,73.38,73.34,71.47,71.20,70.49,65.21,55.60,49.98,31.11,28.11.
HR-MS:calcd.for C31H39NO6H+522.2850,found 522.2882.
2.12(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-((R)-2-羟基-2-苯乙基)氨基-1-环己醇(13l)
实施例2p：类似条件下，以(R)-2-氨基-1-苯乙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13l，收率57.8～66.8％。[α]D 20＝–21.3(c 1.00,CHCl3).
1H NMR(600MHz,CDCl3):δ7.37–7.24(m,20H),4.80(dd,J＝9.1,2.4Hz,1H),4.63(d,J＝12.0Hz,1H),4.51–4.47(m,3H),4.44(s,2H),3.61(d,J＝8.6Hz,1H),3.50–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.09(d,J＝2.9Hz,1H),3.01(dd,J＝11.8,2.8Hz,1H),2.57(dd,J＝11.6,9.4Hz,1H),2.18–2.14(m,1H),2.11–2.04(m,1H),1.92(dd,J＝15.0,3.1Hz,1H),1.45(dd,J＝15.0,2.5Hz,1H).
13C NMR(150MHz,CDCl3):δ142.72,138.86,138.50,138.23,128.63,128.58,128.39,128.32,128.07,127.89,127.85,127.77,127.62,127.56,125.97,76.51,75.88,74.23,73.56,73.41,73.35,71.43,70.47,55.39,55.32,31.54,28.19.
HR-MS:calcd.for C36H41NO5H+568.3057,found 568.3092.
2.13(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-((S)-2-羟基-2-苯乙基)氨基-1-环己醇(13m)
实施例2q：类似条件下，以(S)-2-氨基-1-苯乙醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13m，收率60.8～93.9％。[α]D 20＝+0.6(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.26(m,15H),4.70–4.45(m,6H),3.64(d,J＝8.6Hz,1H),3.52–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.12(d,J＝2.0Hz,1H),2.82–2.76(m,1H),2.40(s,1H),2.19–2.14(m,1H),2.08–1.96(m,2H),1.48–1.41(m,3H),1.37–1.26(m,3H),0.88(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3):δ139.03,138.63,138.32,128.65,128.38,128.29,128.07,127.94,127.80,127.66,127.60,127.49,127.10,75.96,74.07,73.53,73.38,71.52,70.61,55.47,54.23,38.15,31.42,31.38,31.31,28.29,26.67,26.15,25.99.
HR-MS:calcd.for C32H41NO4H+504.3108,found 504.3143.
2.14(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-((S)-1-羟基3-甲基丁基)氨基)-1-环己醇(13n)
实施例2r：类似条件下，以(S)-2-氨基-3-甲基丁醇代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13n，收率40.8～57.2％。[α]D 20＝–24.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.25(m,15H),4.64–4.44(m,6H),3.90–3.86(m,1H),3.62(d,J＝8.6Hz,1H),3.51–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.12(d,1H),2.65(dd,J＝12.3,7.3Hz,1H),2.52(dd,J＝12.3,3.3Hz,1H),2.20–2.14(m,1H),2.05(q,J＝12.0Hz,1H),1.93(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.5Hz,1H),1.15(d,J＝6.3Hz,3H).
13C NMR(100MHz,CDCl3):δ138.83,138.51,138.18,128.63,128.38,128.30,128.06,127.95,127.76,127.61,127.55,76.52,75.85,74.15,73.42,73.37,71.52,70.56,66.06,54.80,54.38,31.44,27.99,20.78.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2933.
2.15(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(环己基甲基)氨基)-1-环己醇(13o)
实施例2s：类似条件下，以环己甲胺代替实施例2中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13o，收率50.8～67.8％。[α]D 20＝–18.4(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.24(m,15H),4.62–4.43(m,6H),3.74–3.70(m,1H),3.58–3.54(m,2H),3.48–3.41(m,3H),3.27(d,J＝8.6Hz,1H),3.07(d,J＝2.9Hz,1H),2.84(dd,J＝11.5,3.7Hz,1H),2.40(dd,J＝11.4,8.4Hz,1H),2.17–2.13(m,1H),2.08–1.93(m,2H),1.42(dd,J＝15.0,2.3Hz,1H).
13C NMR(100MHz,CDCl3):δ138.61,138.40,138.10,128.63,128.41,128.36,128.10,127.93,127.83,127.78,127.67,76.17,75.83,74.43,73.38,73.34,71.47,71.20,70.49,65.21,55.60,49.98,31.11,28.11.
HR-MS:calcd.for C31H39NO6H+522.2850,found 522.2882.
2.16(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-苄基氨基-1-环己醇(13p)
实施例2t：类似条件下，以苄胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13p，收率30.8～43.3％。[α]D 20＝–7.0(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.35–7.25(m,15H),4.65–4.46(m,6H),3.63(d,J＝8.6Hz,1H),3.50–3.44(m,2H),3.28(d,J＝8.6Hz,1H),2.98(d,J＝2.5Hz,1H),2.39(s,3H),2.18-2.13(m,1H),2.07–1.96(m,2H),1.43(dd,J＝14.9,2.1Hz,1H).
13C NMR(100MHz,CDCl3):δ138.99,138.64,138.28,128.66,128.40,128.32,128.13,127.98,127.79,127.69,127.61,127.56,76.69,76.02,74.19,73.57,73.41,71.53,70.60,57.56,34.26,30.77,28.17.
HR-MS:calcd.for C29H35NO4H+462.2639,found 462.2667.
2.17(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-甲氨基-1-环己醇(13q)
实施例2u：类似条件下，以甲胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13q，收率34.8～40.0％。[α]D 20＝+14.5(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.21(m,20H),4.64(d,J＝12.0Hz,1H),4.51–4.47(m,3H),4.35(dd,J＝25.7,12.0,2H),4.01(d,J＝13.1Hz,1H),3.68(d,J＝8.6Hz,1H),3.51(dd,J＝11.6,3.4Hz,2H),3.46–3.41(m,1H),3.32(d,J＝8.6Hz,1H),3.18(d,J＝3.0Hz,1H),2.18–2.11(m,1H),2.08–2.03(m,2H),1.48(dd,J＝15.0,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ139.15,138.98,138.62,138.17,128.65,128.60,128.48,128.40,128.30,128.07,127.89,127.79,127.60,127.52,127.44,76.54,76.00,74.16,73.55,73.43,71.51,70.42,53.80,51.07,31.18,28.23.
HR-MS:calcd.for C35H39NO4H+538.2952,found 538.2978.
2.18(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-丁基氨基-1-环己醇(13r)
实施例2v：类似条件下，以丁胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13r，收率34.3～40.9％。[α]D 20＝+0.6(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.26(m,15H),4.70–4.45(m,6H),3.64(d,J＝8.6Hz,1H),3.52–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.12(d,J＝2.0Hz,1H),2.82–2.76(m,1H),2.40(s,1H),2.19–2.14(m,1H),2.08–1.96(m,2H),1.48–1.41(m,3H),1.37–1.26(m,3H),0.88(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3):δ139.03,138.63,138.32,128.65,128.38,128.29,128.07,127.94,127.80,127.66,127.60,127.49,127.10,75.96,74.07,73.53,73.38,71.52,70.61,55.47,54.23,38.15,31.42,31.38,31.31,28.29,26.67,26.15,25.99.
HR-MS:calcd.for C32H41NO4H+504.3108,found 504.3143.
2.19(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-异丙基氨基-1-环己醇(13s)
实施例2w：类似条件下，以异丙胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13s，收率54.3～46.1％。[α]D 20＝+183.2(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.23(m,15H),4.65(d,J＝12.0Hz,1H),4.56–4.45(m,5H),3.65(d,J＝8.6Hz,1H),3.52–3.43(m,2H),3.32(d,J＝2.9Hz,1H),3.27(d,J＝8.6Hz,1H),2.94–2.91(m,J＝6.3Hz,1H),2.16–2.12(m,1H),2.04(q,J＝12.0Hz,1H),1.90(dd,J＝14.9,3.3Hz,1H),1.43(dd,J＝14.9,2.6Hz,1H),1.08(dd,J＝16.4,6.4Hz,6H).
13C NMR(100MHz,CDCl3):δ139.06,138.67,138.19,128.65,128.39,128.29,128.04,127.93,127.79,127.63,127.48,76.44,76.07,74.02,73.65,73.41,71.49,70.32,51.35,45.64,32.16,28.26,24.41,21.67.
HR-MS:calcd.for C31H39NO4H+490.2952,found 490.2978.
2.20(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(2-甲氧基乙基)氨基-1-环己醇(13t)
实施例2x：类似条件下，以2-甲氧基乙胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13t，收率44.3～53.8％。[α]D 20＝+58.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.37–7.23(m,15H),4.64(d,J＝12.1Hz,1H),4.55–4.45(m,5H),3.63(d,J＝8.6Hz,1H),3.54–3.38(m,4H),3.31(s,3H),3.28(d,J＝8.6,1H),3.15(d,J＝2.8Hz,1H),2.96–2.91(m,1H),2.68–2.62(m,1H),2.18–2.11(m,1H),2.08–2.02(m,1H)1.94(dd,J＝15.0,3.0Hz,1H),1.44(dd,J＝15.0,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ139.00,138.62,138.22,128.59,128.37,128.28,128.05,127.88,127.76,127.58,127.49,76.48,75.99,74.12,73.52,73.38,71.56,71.43,70.33,58.92,54.69,46.88,31.34,28.25.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2921.
2.21(1S,2S,4R,5S)-2,4-二苄氧基-1-苄氧甲基-5-(3-甲氧基丙基)氨基-1-环己醇(13u)
实施例2y：类似条件下，以3-甲氧基丙胺代替实施例2a中的β-苯乙胺，制备方法同实施例2a～2e，得白色固体13u，收率54.3～60.0％。[α]D 20＝+1.7(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.93–3.90(m,1H),3.68(dd,J＝9.9,5.6Hz,1H),3.55–3.51(m,2H),3.49(d,J＝2.5Hz,2H),3.33(s,3H),2.99(s,1H),2.86–2.82(m,1H),2.64–2.60(m,1H),1.99(d,J＝14.6Hz,1H),1.93–1.87(m,2H),1.82–1.74(m,2H),1.39(d,J＝14.2Hz,1H).
13C NMR(100MHz,D2O):δ76.92,73.43,70.85,68.84,67.70,60.93,60.43,47.05,34.71,30.28,28.28.
HR-MS:calcd.for C11H23NO5H+250.1649,found 250.1649.
3.目标物11的制备
3.1(1S,2S,4R,5S)-1-羟基甲基-5-(2-苯乙基)氨基-1,2,4-环己三醇(11a)
实施例3a：氢气条件下，13a计52.0mg(0.10mmol)、10％Pd/C 50.0mg于20％无水甲酸的甲醇溶液10.0mL中催化氢化24h。过滤后，减压蒸出甲酸和甲醇，残余物以少量水稀释，经阳离子树脂(Dowex 50W×8–200)柱层析分离，依次以水、氨水洗脱，氨水层减压浓缩后冻干，得白色固体11a计20.0mg，收率71.0％。m.p 145–147℃，[α]D 20＝+2.9(c 1.00,H2O).
1H NMR(600MHz,D2O):δ7.17–7.06(m,5H),3.65–3.62(m,1H),3.5(q,J＝6.4Hz,1H),3.38(d,J＝10.9Hz,1H),3.29(d,J＝10.9Hz,1H),2.95–2.92(m,1H),2.83(s,1H),2.72–2.63(m,3H),1.89(dd,J＝14.8,3.2Hz,1H),1.76–1.74(m,2H),1.23(d,J＝14.4Hz,1H).
13C NMR(100MHz,D2O):δ140.83,129.74,129.56,127.32,75.65,70.16,69.77,66.84,59.21,49.70,37.03,34.80,30.84.
HR-MS:calcd.for C10H21NO6Na+304.1519,found 304.1513.
实施例3b：类似条件下，以10％Ru/C 50.0mg代替实施例3a中的Pd/C，制备方法同实施例3a，得白色固体11a计18.3mg，收率65.0％。
实施例3c：类似条件下，以Raney Ni(W–2)60.0mg代替实施例3a中的Pd/C，制备方法同实施例3a，得白色固体11a计14.1mg，收率50.0％。
实施例3d：类似条件下，以20％无水醋酸的甲醇溶液代替实施例3a中的20％无水甲酸的甲醇溶液，制备方法同实施例3a，得白色固体11a计20.0mg，收率71.0％。
实施例3e：类似条件下，以20％无水甲酸的THF溶液代替实施例3a中的20％无水甲酸的甲醇溶液，制备方法同实施例3a，得白色固体11a计18.3mg，收率65.0％。
3.2(1S,2S,4R,5S)-1-(羟甲基)-5-(2-羟基-1-(羟甲基)乙基氨基)-1,2,4-环己三醇(11b)
实施例3f：13b计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率61.0～81.0％。[α]D 20＝+11.8(c 1.00,H2O).
1H NMR(600MHz,D2O):δ1.40(d,J＝22.1,1H),1.94–1.90(m,2H),2.00(dd,J＝22.3,5.6Hz,1H),2.90–2.87(m,1H),3.19(s,1H),3.49(s,2H),3.71–3.57(m,5H),3.94–3.89(m,1H).
13C NMR(100MHz,D2O):δ74.47,68.90,68.03,65.11,61.84,58.68,56.28,53.64,32.04,29.47.
HR-MS:calcd.for C10H21NO6H+252.1442,found 252.1436.
3.3(1S,2S,4R,5S)-1-羟基甲基-5-(2-羟基乙基)氨基-1,2,4-环己三醇(11c)
实施例3g：13c计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率71.0～85.8％。[α]D 20＝–4.6(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.94(m,1H),3.76–3.69(m,3H,H2),3.51(s,2H),3.11(d,J＝2.8Hz,1H),3.01–2.95(m,1H),2.83–2.78(m,1H),2.06(dd,J＝15.0,J＝4.2Hz,1H),1.98–1.87(m,2H),1.46(d,J＝14.8Hz,1H).
13C NMR(100MHz,D2O):δ77.32,71.45,70.34,67.76,62.46,59.59,50.59,34.90,31.18.
HR-MS:calcd.for C9H19NO5H+222.1336；found 222.1331.
3.4(1S,2S,4R,5S)-1-羟基甲基-5-(3-羟基丙基)氨基-1,2,4-环己三醇(11d)
实施例3h：13d计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率51.0～69.8％。[α]D 20＝–3.0(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.99(m,1H),3.76–3.69(m,3H),3.54(s,2H),3.18(s,1H),3.06–3.02(m,1H),2.87–2.81(m,1H),2.10(dd,J＝15.1,J＝4.6Hz,1H),1.98–1.90(m,2H),1.85–1.82(m,2H),1.53(d,J＝15.2Hz,1H).
13C NMR(100MHz,D2O):δ74.44,68.54,67.06,65.00,59.70,57.16,43.70,32.13,29.88,28.14.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1486.
3.5(1S,2S,4R,5S)-1-羟基甲基-5-(4-羟基丁基)氨基-1,2,4-环己三醇(11e)
实施例3i：13e计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率55.0～76.7％。[α]D 20＝–0.1(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.02–3.98(m,1H),3.74(dd,J＝9.9,4.8Hz,1H),3.61(t,J＝6.2Hz,2H),3.52(s,2H),3.22(d,J＝3.5Hz,1H),3.03–2.97(m,1H),2.86–2.80(m,1H),2.10(dd,J＝15.1,4.8Hz,1H),2.00–1.86(m,2H),1.68–1.60(m,5H).
13C NMR(100MHz,D2O):δ77.11,71.12,69.47,67.64,63.96,59.80,48.57,34.80,31.47,30.66,26.52.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1476.
3.6(1S,2S,4R,5S)-1-羟基甲基-5-(((R)-2-羟基丙基)氨基)-1,2,4-环己三醇(11f)
实施例3j：13f计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率45.0～55.0％。[α]D 20＝–0.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.02–3.95(m,2H),3.72(dd,J＝10.0,5.0Hz,1H),3.51(s,2H),3.16(d,J＝3.1Hz,1H),2.99(dd,J＝12.3,3.6Hz,1H),2.66(dd,J＝12.1,8.7Hz,1H),2.08(dd,J＝15.1,4.6Hz,1H),1.99–1.87(m,2H),1.52(d,J＝14.4Hz,1H),1.20(d,J＝6.4Hz,3H).
13C NMR(400MHz,D2O):δ77.27,71.27,69.87,68.52,67.67,60.29,55.81,34.83,31.04,22.76.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1484.
3.7(1S,2S,4R,5S)-1-羟基甲基-5-(((S)-1-羟基丙基)氨基)-1,2,4-环己三醇(11g)
实施例3k：13g计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率55.0～79.2％。[α]D 20＝+11.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.06–3.98(m,2H),3.73(dd,J＝10.8,4.7Hz,1H),3.53(s,J＝1.2Hz,2H),3.24(d.J＝3.28Hz,1H),2.92–2.90(m,2H),2.12(dd,J＝15.4,4.1Hz,1H),2.03–1.98(m,1H),1.93–1.84(m,1H),1.54(d,J＝13.4Hz,1H),1.21(d,J＝6.4Hz,3H).
13C NMR(100MHz,D2O):δ77.26,71.22,69.72,67.85,67.35,60.11,55.39,34.87,30.68,22.58.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1478.
3.8(1S,2S,4R,5S)-1-羟基甲基-5-(2-((R)-1-羟基丁基)氨基)-1,2,4-环己三醇(11h)
实施例3l：13h计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率45.0～53.2％。[α]D 20＝+2.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.98(s,1H),3.74(s,2H),3.62(d,J＝10.4,1H),3.52(s,2H),3.35(s,1H),2.96(s,1H),2.05(d,J＝13.4Hz,1H),1.96–1.52(m,5H),0.95(t,J＝6.9Hz,3H).
13C NMR(100MHz,D2O):δ77.32,71.27,69.79,67.79,62.02,60.19,57.20,34.80,31.59,26.23,12.34.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1480.
3.9(1S,2S,4R,5S)-1-羟基甲基-5-(2-((S)-1-羟基丁基)氨基)-1,2,4-环己三醇(11i)
实施例3m：13i计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率45.8～59.3％。[α]D 20＝+15.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.96(m,1H),3.73–3.71(m,2H),3.58(dd,J＝11.6,7.1Hz,1H),3.51(s,2H),3.32(s,1H),2.95(s,1H),2.06–1.96(m,2H),1.91–1.83(m,1H),1.64–1.63(m,1H),1.53–1.48(m,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(100MHz,D2O):δ74.32,68.51,67.14,65.00,61.99,57.23,54.27,31.96,28.69,20.68,8.56.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1474
3.10(1S,2S,4R,5S)-1-羟基甲基-5-(((R)-2,3-二羟基丙基)氨基)-1,2,4-环己三醇(11j)
实施例3n：13j计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率47.8～59.4％。[α]D 20＝+15.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.96(m,1H),3.73–3.71(m,2H),3.58(dd,J＝11.6,7.1Hz,1H),3.51(s,2H),3.32(s,1H),2.95(s,1H),2.06–1.96(m,2H),1.91–1.83(m,1H),1.64–1.63(m,1H),1.53–1.48(m,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(100MHz,D2O):δ74.32,68.51,67.14,65.00,61.99,57.23,54.27,31.96,28.69,20.68,8.56.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1474.
3.11(1S,2S,4R,5S)-1-羟基甲基-5-((S)-2,3-二羟基丙基)氨基)-1,2,4-环己三醇(11k)
实施例3o：13k计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率37.8～41.7％。[α]D 20＝–11.2(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.04–3.99(m,1H),3.94–3.89(m,1H),3.73(dd,J＝10.3,4.8Hz,1H),3.68–3.64(m,2H),3.61–3.56(m,2H),3.52(s,2H),3.23(d,J＝2.48Hz,1H),3.15(dd,J＝11.9,2.8Hz,1H),2.80(dd,J＝11.9,8.5Hz,1H),2.11(dd,J＝15.2,4.5Hz,1H),2.02–1.92(m,2H),1.88(d,J＝11.0Hz,1H).
13C NMR(100MHz,D2O):δ77.32,72.15,71.28,69.70,67.79,66.73,60.65,51.70,34.88,30.94.
HR-MS:calcd.for C10H21NO6H+252.1442,found 252.1444.
3.12(1S,2S,4R,5S)-1-羟基甲基-5-((R)-2-羟基-2-苯乙基)氨基-1,2,4-环己三醇(11l)
实施例3p：13l计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率39.8～50.4％。[α]D 20＝–15.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ7.45–7.39(m,5H),4.93(dd,J＝8.4,4.4Hz,1H),3.99–3.97(m,1H),3.70(dd,J＝10.4,4.7Hz,1H),3.49(s,2H),3.22(d,J＝13.2Hz,2H),3.01(t,J＝9.4Hz,1H),2.06(dd,J＝15.0,4.3Hz,1H),1.98–1.83(m,2H),1.51(d,J＝15.0Hz,1H).
13C NMR(100MHz,D2O):δ143.64,131.64,131.19,128.87,77.19,74.24,71.24,69.82,67.66,60.38,55.51,34.80,31.12.
HR-MS:calcd.for C15H23NO5H+298.1649,found 298.1647.
3.13(1S,2S,4R,5S)-1-羟基甲基-5-((S)-2-羟基-2-苯乙基)氨基-1,2,4-环己三醇(11m)
实施例3q：13m计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率61.8～71.2％。[α]D 20＝+24.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ7.47–7.39(m,5H),4.94(dd,J＝8.1,4.2Hz,1H),3.98–3.94(m,1H),3.71–3.67(m,1H),3.50(s,2H),3.21–3.16(m,2H),3.02(dd,J＝12.4,3.8Hz,1H),2.08(dd,J＝15.0,3.1Hz,1H),1.98–1.81(m,2H),1.48(d,J＝14.7Hz,1H).
13C NMR(100MHz,D2O):δ143.56,131.48,130.98,128.78,77.09,73.68,71.18,69.95,67.65,59.64,55.14,34.69,30.88.
HR-MS:calcd.for C15H23NO5H+298.1649,found 298.1643.
3.14(1S,2S,4R,5S)-1-羟基甲基-5-(2-((S)-1-羟基-3-甲基丁基)氨基)-1,2,4-环己三醇(11n)
实施例3r：13n计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率51.8～77.7％。[α]D 20＝–5.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.97(m,1H),3.77(dd,J＝11.8,4.0Hz,1H),3.70(dd,J＝10.4,4.9Hz,1H),3.58(dd,J＝11.7,7.9Hz,1H),3.51(s,2H),3.31(s,1H),2.85–2.83(m,1H),2.05–1.89(m,4H),1.46(d,J＝14.5Hz,1H),0.97(d,J＝6.9Hz,3H).0.88(d,J＝6.9Hz,3H).
13C NMR(100MHz,D2O):δ77.24,71.54,70.29,67.96,64.27,63.11,57.53,34.85,31.84,29.00,21.11,18.70.
HR–MS:calcd.for C12H25NO5H+264.1805,found 264.1814.
3.15(1S,2S,4R,5S)-1-羟基甲基-5-(环己基甲基)氨基-1,2,4-环己三醇(11o)
实施例3s：13o计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率21.8％～31.7％。[α]D 20＝–3.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.00–3.97(m,1H),3.74(dd,J＝10.3,4.6Hz,1H),3.52(d,J＝5.0Hz,2H),3.16(d,J＝2.8Hz,1H),2.76(dd,J＝11.8,8.3Hz,1H),2.61(dd,J＝11.7,5.4Hz,1H),2.08(dd,J＝14.9,4.0Hz,1H),2.00–1.89(m,2H),1.77–1.53(m,7H),1.49–1.14(m,3H),1.02–0.94(m,2H).
13C NMR(100MHz,D2O):δ77.42,71.28,70.03,67.75,60.26,55.47,38.82,34.98,33.38,30.92,28.77,28.25,28.13.
HR-MS:calcd.for C14H27NO4H+274.2013,found 274.2023.
3.16(1S,2S,4R,5S)-1-羟基甲基-5-氨基-1,2,4-环己三醇(11p)
实施例3t：13p计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率61.8～81.8％。[α]D 20＝+3.0(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.97(m,1H),3.73(dd,J＝10.1,4.8Hz,1H),3.52(s,2H),3.05(d,J＝4.3Hz,1H),2.54(s,3H),2.10(dd,J＝19.6,4.4Hz,1H),2.00–1.84(m,2H),1.52(dd,J＝15.2,2.4Hz,1H).
13C NMR(100MHz,D2O):δ77.20,71.32,69.74,67.82,61.64,34.91,30.45,22.88.
HR-MS:calcd.for C8H17NO4H+192.1230,found 192.1231.
3.17(1S,2S,4R,5S)-1-羟基甲基-5-甲氨基-1,2,4-环己三醇(11q)
实施例3u：13q计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率21.8～31.0％。[α]D 20＝–2.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.97(m,1H),3.73(dd,J＝10.1,4.8Hz,1H),3.52(s,2H),3.05(d,J＝4.3Hz,1H),2.54(s,3H),2.10(dd,J＝19.6,4.4Hz,1H),2.00–1.84(m,2H),1.52(dd,J＝15.2,2.4Hz,1H).
13C NMR(100MHz,D2O):δ77.20,71.32,69.74,67.82,61.64,34.91,30.45,22.88.
HR-MS:calcd.for C8H17NO4H+192.1230,found 192.1231.
3.18(1S,2S,4R,5S)-1-羟基甲基-5-丁基氨基-1,2,4-环己三醇(11r)
实施例3v：13r计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率29.8％～49.7％。[α]D 20＝–1.1(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.05–4.00(m,1H),3.75(dd,J＝10.0,4.7Hz,1H),3.53(d,J＝1.0Hz，2H),3.28(d,J＝3.9Hz,1H),3.08–2.01(m,1H),2.90–2.84(m,1H),2.12(dd,J＝15.2,4.7Hz,1H),2.01–1.89(m,2H),1.62–1.51(m,3H),1..39–1.31(m,2H),0.90(t,J＝7.4Hz,3H).
13C NMR(100MHz,D2O):δ77.08,71.02,69.02,67.67,59.98,48.56,34.18,31.35,30.41,22.18,15.74.
HR-MS:calcd.for C11H23NO4H+234.1700,found 234.1703.
3.19(1S,2S,4R,5S)-1-羟基甲基-5-异丙基氨基-1,2,4-环己三醇(11s)
实施例3w：13s计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率59.8～71.0％。[α]D 20＝+2.5(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.07–4.03(m,1H),3.78(dd,J＝9.8,4.6Hz,1H),3.55(s,2H),3.52–3.47(m,2H),2.13(dd,J＝15.2,4.9Hz,1H),2.02–1.98(m,1H),1.93–1.85(m,1H),1.68(dd,J＝15.1,2.4Hz,1H),1.28(dd,J＝17.7,6.5Hz,6H).
13C NMR(100MHz,D2O):δ77.12,70.85,68.41,67.62,57.44,50.84,34.07,30.45,22.72,20.76.
HR-MS:calcd.for C10H21NO6H+220.1543,found 220.1539.
3.20(1S,2S,4R,5S)-1-羟基甲基-5-(2-甲氧基乙基)氨基-1,2,4-环己三醇(11t)
实施例3x：13t计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率49.8～59.1％。[α]D 20＝–6.6(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.98–3.94(m,1H),3.70(dd,J＝15.2,7.7Hz,1H),3.64–3.60(m,2H),3.51(s,2H),3.37(s,3H),3.11(d,J＝4.4Hz,1H),3.08–2.84(m,2H),2.05(dd,J＝22.5,6.5Hz,1H),1.97–1.88(m,2H),1.47(d,J＝22.0Hz,1H).
13C NMR(100MHz,D2O):δ77.53,73.03,71.64,70.44,67.97,61.02,59.90,48.30,35.11,31.38.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1491.
3.21(1S,2S,4R,5S)-1-羟基甲基-5-(3-甲氧基丙基)氨基-1,2,4-环己三醇(11u)
实施例3y：13u计52.0mg(0.10mmol)，制备方法同实施例3a～3e，收率55.8～60.9％。[α]D 20＝+1.7(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.93–3.90(m,1H),3.68(dd,J＝9.9,5.6Hz,1H),3.55–3.51(m,2H),3.49(d,J＝2.5Hz,2H),3.33(s,3H),2.99(s,1H),2.86–2.82(m,1H),2.64–2.60(m,1H),1.99(d,J＝14.6Hz,1H),1.93–1.87(m,2H),1.82–1.74(m,2H),1.39(d,J＝14.2Hz,1H).
13C NMR(100MHz,D2O):δ76.92,73.43,70.85,68.84,67.70,60.93,60.43,47.05,34.71,30.28,28.28.
HR-MS:calcd.for C11H23NO5H+250.1649,found 250.1649.
4.α-糖苷酶抑制剂活性测试：
实施例4a：α-糖苷酶抑制剂活性检测方法：
鼠小肠α-糖苷酶被制备。反应混合物由100μL的α-糖苷酶和80μL的化合物(在50mM磷酸盐缓冲剂pH值6.8)。在37℃孵化10分钟后，20μL蔗糖(100毫克/毫升)被加入，溶液进一步孵化30分钟37℃。通过80～85℃孵化3分钟来终止反应。用葡萄糖氧化酶法测定游离葡萄糖量。阳性对照为voglibose、miglitol和acarbose。
表1.α-糖苷酶抑制剂活性测试结果
Figure BDA0002011850060000181
a：无抑制活性
实施例4b：选取的5个样品对正常ICR小鼠蔗糖耐量的影响.
健康雄性ICR小鼠(20～22g)购自北京维通利华实验动物技术有限公司(北京，中国)。所有小鼠均在光照和温控室内适应3天，随机给予食物和水。将小鼠分为9组。每组由8只动物组成。每只小鼠口服单次剂量(2.0mg/kg)试验化合物。阳性对照为voglibose、miglitol、acarbose(2.0mg/kg)。每只小鼠给予4.0g/kg蔗糖溶液(表示为0min)。对照组小鼠给予等量蒸馏水和蔗糖溶液。从尾静脉收集大约20μL血液，时间分别为0、30、60和120分钟，血糖水平测量采用葡萄糖氧化酶法。数据表示为均值±SD(mg/dL)。
表2.样品对ICR小鼠蔗糖负荷后血糖及血糖曲线下面积的影响
Figure BDA0002011850060000191
Note:*P<0.05,**P<0.01,***P<0.001vs Nor group,n＝8,means±SD.
图1.样品对ICR小鼠蔗糖负荷后血糖曲线和曲线下面积的影响(见附图)

Claims (7)

1.3-脱氧-5-羟基-1-氨基碳糖类化合物，所述化合物具有如下的结构通式：
Figure DEST_PATH_IMAGE002
其中，所述的化合物的特征在于R为乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、环丙基、环丁基、环戊基、环己基、环庚基、环丙甲基、环丙乙基、环丁甲基、环丁乙基、环戊甲基、环戊乙基、环己甲基、环己乙基、2-羟基乙基、2-羟基丙基、3-羟基丙基、2-甲氧基乙基、3-甲氧基丙基、4-甲氧基丁基、2-乙氧基乙基、3-乙氧基丙基、4-乙氧基丁基、2,3-二羟基丙基、2-氨基乙基、3-氨基丙基、2-氨基-3-羟基丙基、3-氨基-2-羟基丙基、2-氨基-4-羟基丁基、2-氨基-3-羟基丁基、3-氨基-2-羟基丁基、4-氨基-2-羟基丁基。
2.一种药物组合物，其特征在于，包含权利要求1中所述的3-脱氧-5-羟基-1-氨基碳糖类化合物和药学上可接受的载体。
3.权利要求1所述的3-脱氧-5-羟基-1-氨基碳糖类化合物的合成方法，其特征在于以P保护的3-脱氧-1-羰基物为原料，经还原胺化反应，得到保护的3-脱氧-1-氨基碳糖，最后经脱保护来获得，保护基P为苄基，R如权利要求1所述：
Figure DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE008
。
4.权利要求3所述的合成方法，其特征在于，还原胺化时，所用的有机胺H2NR中的R基团同上述目标物，所用还原剂为LiBH4、NaBH4、KBH4、LiBH3CN、NaBH3CN、KBH3CN、NaBH(OAc)3；还原胺化所用溶剂为醇性溶剂，或醚性溶剂，或醇性溶剂与醚性溶剂的任意组合，所述醇性溶剂为甲醇、乙醇、或其任意组合，所述醚性溶剂为***、四氢呋喃、1,4-二氧六环、1,2-二甲氧基乙烷、或其任意组合；脱保护时，选择钯、镍、钌、铑催化氢化法脱除苄基的保护，所用溶剂为水、醇性溶剂、或其任意组合，醚性溶剂或其任意组合；为提高催化剂活性可向体系中加入盐酸、甲酸、醋酸提高脱保护反应效率。
5.权利要求3所述的合成方法，其特征在于，其中化合物12经由化合物14的合成路线来合成，保护基P为苄基；1,4-Micheal加成选择还原剂连二亚硫酸钠，或选择钯、镍、钌、铑催化剂与氢气组合的双键还原方法，所用溶剂为水，甲醇、乙醇、异丙醇或其任意组合，四氢呋喃、1,2-二甲氧基乙烷或其任意组合：
Figure DEST_PATH_IMAGE009
。
6.权利要求1所述的3-脱氧-5-羟基-1-氨基碳糖类化合物或权利要求2所述的药物组合物在制备降血糖药物中的应用。
7.权利要求5所述的化合物12在制备权利要求1所述的3-脱氧-5-羟基-1-氨基碳糖类化合物中的应用。
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