CN115368363A - 一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 - Google Patents
一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 Download PDFInfo
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- CN115368363A CN115368363A CN202210513147.5A CN202210513147A CN115368363A CN 115368363 A CN115368363 A CN 115368363A CN 202210513147 A CN202210513147 A CN 202210513147A CN 115368363 A CN115368363 A CN 115368363A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 diazepanone compound Chemical class 0.000 claims abstract description 186
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 24
- 239000003446 ligand Substances 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 150000008300 phosphoramidites Chemical class 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000009471 action Effects 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 150000002504 iridium compounds Chemical class 0.000 claims abstract description 8
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 7
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002611 lead compounds Chemical class 0.000 claims abstract description 4
- OHXQYFCNXHGKPJ-UHFFFAOYSA-N 1h-pyrimido[5,4-c]diazepine Chemical class N1N=CC=CC2=NC=NC=C12 OHXQYFCNXHGKPJ-UHFFFAOYSA-N 0.000 claims abstract 3
- 239000002904 solvent Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
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- 208000020401 Depressive disease Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- XQSNXLDLKOJJOU-UHFFFAOYSA-N pyrimido[5,4-c]diazepin-3-one Chemical group N1=NC(=O)C=CC2=NC=NC=C21 XQSNXLDLKOJJOU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- SRJBDGLSCPDXBL-UHFFFAOYSA-N ethyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1Cl SRJBDGLSCPDXBL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
本发明属于手性化合物合成技术领域，特别涉及一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用。本发明的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，结构式如式(I)所示，
本发明还提供上述嘧啶并二氮杂环庚酮类化合物的制备方法，具体为以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到。本发明的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐对GR、cofilin‑1和NF‑κB蛋白具有较好的抑制作用，且可逆转抑郁状态下皮质酮导致的PC12细胞的凋亡，可应用于制备预防或治疗抑郁症的药物或其先导化合物中。
Description
技术领域
本发明属于手性化合物合成技术领域，特别涉及一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用。
背景技术
苯并二氮杂环庚酮类骨架是药物分子中重要的结构单元，其衍生物通常具有广泛的药理活性，以此为关键母核针对不同的病理特征开发了一系列有前景的候选药物小分子。作为结构类似物，嘧啶并二氮杂环庚酮类化合物因其潜在的药理学活性受到合成化学家们的广泛关注，其制备方法研究在新药研发中占据着极其重要的地位。1969年，Santilli课题组首次制备了嘧啶并二氮杂环庚酮类化合物，初步的活性筛选实验表明，其具有一定程度的镇静活性同时也表现出抗痉挛作用[Kim,D.H.；Santilli,A.A.J.Med.Chem.1969,12,1121–1122.]。随后科学研究者合成了多种不同结构的嘧啶并二氮杂环庚酮类化合物，并发现具有不同的生物活性。如，2005年Seto课题组提供的化合物，对神经激肽受体NK1有较强的抑制作用(KB＝0.480nM)，可增加天竺鼠的有效膀胱容量，在治疗尿失禁方面表现出良好的前景[Seto,S.；Tanioka,A.；Ikeda,M.；Izawa,S.Bioorg.Med.Chem.2005,13,5717–5732.]。2008年，Schulz课题组研究报道了一类嘧啶并二氮杂环庚酮类化合物可有效抑制PDK1激酶，其中一些化合物对PDK1激酶的抑制作用尤为突出，IC50值可达皮摩尔级别[Schulz,M.；Burgdorf,L.T.；Finsinger,D.；Blaukat,A.；Greiner,H.；Esdar,C.；Kreysch,H.-G.；Henzler,T.PCT Int.Appl.2008,US20080318934A1,20081225.]。2012年，丁克课题组设计、合成了一系列嘧啶并二氮杂环庚酮类衍生物，发现此类化合物对EGFR蛋白及其临床相关突变体具有很好的体外抑制作用，其中一些化合物对EGFRL858R/T790M的抑制活性达纳摩尔级别(IC50＝14nM)；同时，此类化合物也能抑制非小细胞肺癌细胞H1975和HCC827的增值[Xu,S.；Zhang,L.,Chang,S.；Luo,J；Lu,X.；Tu,Z.；Liu,Y.；Zhang,Z.；Xu,Y.；Rena,X.；Ding,K.Med.Chem.Commun.2012,3,1155–1159.]。Cuevas-Cordobes和Almansa-Rosales等于2017年设计、合成的嘧啶并二氮杂环庚酮类化合物与电压门控钙离子通道(VGCC)亚结构α2δ有很强的亲和力，特别是对α2δ-1表现很强的抑制作用；此外，这类化合物也能有效抑制去氧肾上腺素转运体(NET)；双重抑制作用使此类化合物在治疗脑损伤及其相关疾病方面具有很好的应用前景[Cuevas-Cordobes,F.；Almansa-Rosales,C.PCT Int.Appl.2017,WO2017191304 A1,20171109.]。
抑郁症是现代医学面临的顽症，目前还缺少有效的治疗手段和药物。抑郁症诱发神经***功能障碍，使得调节情绪的神经回路功能和结构连接中断。糖皮质激素(GCs)及其受体(GR)是响应调节情绪重要的信号分子。慢性应激和HPA失调促进了神经炎症发生，导致促炎性细胞因子和趋化因子，如NF-κB升高。抑郁症引起的炎症和HPA轴功能障碍进一步诱导神经突触可塑性。神经可塑性发生的过程由调节蛋白控制，cofilin-1是关键调节剂之一，因此，GR、NF-κB和cofilin-1被认为是抑郁症治疗的关键靶标。
综上所述，嘧啶并二氮杂环庚酮类化合物与苯并二氮杂卓具有结构类似性，生物学活性广泛，具有潜在的研究价值。虽然目前其合成已取得一些进展，但是不对称催化构建此类化合物的方法还未见报道。因此，开发有效的不对称合成方法对于丰富此类化合物的结构及药物研发具有重要的意义。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐。本发明的嘧啶并二氮杂环庚酮类化合物为左旋体、右旋体或消旋体。所述左旋体为左旋纯品，或左旋过量的对映体混合物。所述右旋体为右旋纯品，或右旋过量的对映体混合物。所述消旋体为对映体混合物，且其ee值为0。
本发明的另一目的在于提供一种上述手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法。本发明制备方法为由嘧啶烯丙基类化合物为底物经分子内烯丙基催化胺化反应，有效合成得到嘧啶并二氮杂环庚酮类化合物及其对映体或消旋体。本发明方法可实现高效率、高对映选择性地合成光学活性的含中心手性的嘧啶并二氮杂环庚酮类化合物。
本发明的再一目的在于提供上述手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
本发明的目的通过下述方案实现：
一种手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，结构式如式(I)所示，其中，用*标注的碳原子为手性碳原子，其构型为R、S或R/S，所述嘧啶并二氮杂环庚酮类化合物为左旋体、右旋体或消旋体；
其中，R1、R2分别独立选自氢、卤素原子、羟基、羧基、氰基、硝基、C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的芳基、取代或未取代的芳基亚甲基；
其中，上述取代的取代基分别独立选自氢、卤素、羟基、氰基、硝基、C1-C20的烷基、C1-C20的氟代烷基、C1-C20的烃氧基、氨基、C1-C20的N-烷基取代胺基或C1-C20的N,N-二烷基取代胺基中的一种或一种以上的组合；
上述C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基中的一个或一个以上氢原子可被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
优选地，上述的芳基分别独立为C6-C20的芳基。
R3、R4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的杂环基亚甲基或杂环芳基亚甲基、取代或未取代C1-C20的烃氧羰基、取代或未取代的芳基酰基、取代的芳基磺酰基、取代或未取代的芳基、取代或未取代芳基亚甲基；
其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、硝基、C1-C20的烃氧基、羟基、氰基、C1-C20的N-烷基取代胺基或C1-C20的N,N-二烷基取代胺基中的一种或一种以上的组合；
上述C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基中的一个或一个以上氢原子可被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
优选地，上述的芳基分别独立为C6-C20的芳基。
进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R1、R2分别独立选自氢、氟、氯、溴、碘、羟基、羧基、氰基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、苄基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、苄氧基、氨基、C1-C20的酰胺基、三甲基硅基、三乙基硅基、三苯基硅基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、C2-C20的酮羰基、C1-C20的磺酰基、取代或未取代的芳基；所述取代的芳基中的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中的一种或一种以上的组合；R3、R4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、杂环基亚甲基或杂环芳基亚甲基、烯丙基、炔丙基、乙酰基、苯甲酰基、C1-C20的磺酰基、叔丁氧羰基、芴甲氧羰基、2,2,2-三氯乙氧羰基、取代或未取代的芳基、取代或未取代的芳基亚甲基、取代或未取代的苯磺酰基；其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、硝基或C1-C20的烃氧基中的一种或一种以上的组合。
更进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R1、R2分别独立选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、羟基、羧基、氰基、环戊基、环己基、氨基、甲胺基、乙胺基、二乙基胺基、二异丙基胺基、三甲基硅基、三乙基硅基、三苯基硅基、乙酰胺基、乙酰基、三氟乙酰基、苯基、苯胺基、苯甲酰基、3,4,5-三甲氧基苯基、苄基、4-二甲氨基苄基、苄氧基、甲磺酰基、苯磺酰基、萘基、吗啉基、吡咯基、四氢吡咯基、1-哌嗪基、1-甲基哌嗪基、吡啶基、4-甲基吡啶基、甲氧基吡啶基、呋喃基、哌啶基、4-羟甲基-3,5-二甲基哌啶基、噻吩基、噁唑基。
更进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R3、R4分别独立选自氢、甲基、乙基、正丙基、异丙基、环己基、环戊基甲基、烯丙基、炔丙基、羰基、乙氧羰基、叔丁氧羰基、三氯乙氧甲酰基、苯甲酰基、4-溴苯甲酰基、9-亚芴基甲氧甲酰基、3-氟-4-(烯丙基酰胺基)苯基、磺酰基、甲苯磺酰基、苯基、4-甲氧基苯基、4-(三氟甲基)苯基、3,5-双(三氟甲基)苯基、苄基、对氟苄基、4-二甲氨基苄基、4-甲氧基苄基、2-四氢吡喃基、4-(三氟甲基)苄基、3,5-双(三氟甲基)苄基、嘧啶基、4-氟嘧啶基甲基、4-氯嘧啶基甲基、吡咯并嘧啶基、吗啉基、吡啶基、3-甲基吡啶基、吡啶基甲基、吡嗪基、4-三氟甲基吡嗪基、哌嗪基、3-甲基哌嗪基、哌啶基、哌啶基甲基。
本发明还提供一种上述手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法，具体为以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到所述手性或消旋的嘧啶并二氮杂环庚酮类化合物。
本发明制备方法反应式如反应式(一)所示：
其中，L为手性或非手性配体，Base为各种碱及碱和添加剂的组合，T为反应温度，Solvent为各种有机溶剂。
本发明方法中，所述嘧啶类烯丙基化合物中间体的结构式如式(S)所示，其中，LG是离去基团，为羟基、氯、溴、
或
M为NH或O；R5为卤素取代或未取代的C1-C20的烷基、卤素取代或未取代的C1-C20的烃氧基；R6为C1-C20的烷基、取代或未取代的芳基。
优选的，式(S)的R5中，卤素取代的C1-C20的烷基中的卤素为氟、氯、溴或碘。进一步的，卤素取代的C1-C20的烷基为三氯甲基。
优选的，式(S)的R6中，取代的芳基的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中一种或一种以上的组合。所述的芳基为C6-C20的芳基。
优选的，式(S)的R5和R6中，所述C1-C20的烷基分别独立选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述C1-C20的烃氧基分别独立选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基或苄氧基。
所述的取代基可以为一个或多个，当取代基为多个时，所述的取代基可以相同或不同。
进一步的，所述嘧啶类烯丙基化合物中间体(S)，可由包括以下步骤方法制备得到：2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物和胺类化合物反应生成2-氯-4-取代胺基-6-取代-嘧啶-5-羧酸甲酯类化合物，通过常规的亲核取代反应或Suzuki等偶联反应引入基团R1，然后水解生成羧基类化合物，进而与
反应得到式S化合物。化合物S作为底物进一步进行催化反应，得到产物I。反应方程式如下所示：
所述2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物可为2,4-二氯-嘧啶-5-羧酸甲酯、2,4-二氯-6-羟基-嘧啶-5-羧酸甲酯、2,4-二氯-6-氰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苯基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苯甲酰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苄基-嘧啶-5-羧酸甲酯、2,4-二氯-6-氨基-嘧啶-5-羧酸甲酯、2,4-二氯-6-乙基-嘧啶-5-羧酸甲酯、2,4-二氯-6-甲磺酰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苯甲氧基-嘧啶-5-羧酸甲酯、2,4-二氯-6-三苯基硅基-嘧啶-5-羧酸甲酯、2,4-二氯-6-二乙氨基-嘧啶-5-羧酸甲酯、2,4-二氯-6-羧基-嘧啶-5-羧酸甲酯、2,4-二氯-6-N-甲基哌嗪-嘧啶-5-羧酸甲酯等；基团R2可由市售品直接带入或由2,4,6-三氯-嘧啶-5-羧酸甲酯经常规的亲核取代反应、Suzuki等偶联反应或Grignard反应等引入，得到化合物1。
本发明方法中，所述的碱可以是有机碱，也可以是无机碱，如可为三乙胺、4-二甲氨基吡啶、1,8-二氮杂二环[5,4,0]十一碳-7-烯、1,5-二氮杂二环[4,3,0]壬-5-烯、三乙烯二胺、N,O-双(三甲基硅基)乙酰胺、碳酸铯、碳酸钾、碳酸锂、氟化钾、氢化钠、氟化铯、磷酸钾、醋酸钾、磷酸钠、醋酸钠、醋酸锂、正丁基锂、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、甲醇钠、乙醇钠、异丙醇钠、质子海绵、叔丁醇锂、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺。
进一步的，所述的碱和三氟磺酸银、氯化锂或分子筛添加剂组合加入反应体系中。
本发明方法中，所述嘧啶类烯丙基化合物中间体、铱化合物的铱原子、亚膦酰胺配体、碱的摩尔比为1：(0.005-0.1)：(0.005-0.2)：(0.05-3)。
本发明方法中，所述反应可在0-120℃下进行。所述反应的时间可为20min-24h。
本发明方法中，所述的铱化合物可为[Ir(COD)Cl]2、[Ir(dncot)Cl]2、[Ir(OMe)(COD)]2、[Ir(COD)2]BArF4、Ir(COD)2BF4、[Ir(OH)(COD)]2、Ir(ppy)3、[Ir(COD)2]SbF6等中的至少一种。
本发明中，所述的亚膦酰胺配体参照CN109336887A中的亚膦酰胺配体，详见说明书【0076】段。
本发明方法中，所述反应后产物可通过硅胶短柱纯化得到手性嘧啶并二氮杂环庚酮类化合物及其对映体或消旋体。
本发明方法中，所述反应在有机溶剂体系中进行。所述有机溶剂可以为极性溶剂或非极性溶剂。优选的，所述的有机溶剂可为芳烃类溶剂或取代芳烃类溶剂、卤代烃类溶剂、醚类溶剂、酰胺类溶剂、烷烃类溶剂、环烷烃类溶剂、腈类溶剂、二甲亚砜和醇类溶剂中的一种或一种以上的组合。进一步的，所述的芳烃类溶剂或取代芳烃类溶剂优选为甲苯、二甲苯、乙苯、异丙苯、氯苯和硝基苯中的至少一种；所述的卤代烃类溶剂优选为二氯甲烷、1,2-二氯乙烷和三氯甲烷中的至少一种；所述的醚类溶剂优选为四氢呋喃、***、乙二醇二甲醚、甲基叔丁基醚、1,4-二氧六环中的至少一种；所述的酰胺类溶剂优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙酰胺、α-吡咯烷酮、N-甲基吡咯烷酮中的至少一种；所述的烷烃类溶剂优选为正己烷、正戊烷和正庚烷中的至少一种；所述的环烷烃类溶剂优选为环戊烷、环己烷和环庚烷中的至少一种；所述的腈类溶剂优选为乙腈；所述的醇类溶剂优选为甲醇、乙醇、异丙醇、正丙醇和叔丁醇中的至少一种。
本发明制备方法可包括如下具体步骤：
(1)以2,4-二氯-5-嘧啶甲酸乙酯类化合物1和胺类化合物2为起始原料，N,N-二异丙基乙胺为碱，经亲核取代反应得到化合物3；
(2)化合物3与硼酸化合物、胺类化合物或醇钠类化合物，在无水溶剂中和碱存在条件下，经常规的Suzuki等偶联反应或亲核取代反应，得到多种不同取代的化合物4；
(3)化合物4在水中，在碱存在下，发生水解反应得到化合物5；
(4)化合物5在1-羟基苯并***(HOBt)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDCI)作用下，与化合物6缩合，得到嘧啶类烯丙基化合物中间体(S)，作为下一步烯丙基胺化催化反应的底物；
(5)在有机碱或无机碱存在的条件下、铱化合物和亚磷酰胺配体形成的金属铱配合物，在有机溶剂中催化底物S发生分子内的烯丙基胺化反应得到式(I)所示的化合物。
步骤(1)中，化合物1和化合物2的摩尔比可为1:1-1:1.2；反应温度可为50℃–100℃，反应时间可为1-6h。
步骤(2)中，化合物3与硼酸化合物、胺类化合物或醇钠类化合物、碱的摩尔比可为1:(1-2):(1-2):(1-3)；反应温度可为20℃-130℃，反应时间可为30min-4h。
步骤(3)中，化合物4与碱的摩尔比可为1:1-1:3；反应温度可为20℃-100℃，反应时间可为10min–2h；所述的碱可为氢氧化钠、氢氧化钾或氢氧化锂等。
步骤(4)中，化合物5、化合物6、HOBt、EDCI的摩尔比可为1:1:(1-2):(1-2)；反应温度可为0-80℃；反应时间可为1-10h；所述反应在溶剂中进行，如二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜。
步骤(5)中，底物S、铱、配体、碱的摩尔比可为1:(0.005-0.1):(0.005-0.2):(0.05--3)；反应温度可为0-70℃；反应时间可为3min-24h。
本发明制备方法以铱-亚磷酰胺配体配合物为催化剂，尤其是以铱-手性桥连亚膦酰胺配体配合物为催化剂时，通过嘧啶类烯丙基碳酸酯底物的精心设计、合成，经分子内烯丙基胺化反应高效率、高对映选择性地合成嘧啶并二氮杂环庚酮类化合物的方法；其对映体由相反构型的配体制备相应的催化剂，进行类似的分子内烯丙基胺化催化反应得到；其消旋体则由消旋的配体制备相应的催化剂，进行类似的分子内烯丙基胺化催化反应得到。
本发明还提供上述手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
本发明相对于现有技术，具有如下的优点及有益效果：
本发明提供了一种有效的以铱-亚磷酰胺配体配合物作为催化剂，由精心设计合成的嘧啶类烯丙基底物经分子内烯丙基催化胺化反应，高效率、高区域选择性和高对映选择性地合成新型手性嘧啶并二氮杂环庚酮类化合物的策略和方法，可制备得到多种手性嘧啶并二氮杂环庚酮类化合物。
同时，本发明还对构建的手性或消旋的嘧啶并二氮杂环庚酮类化合物进行了初步体外抗抑郁活性评价。结果显示：本发明化合物对GR、cofilin-1和NF-κB蛋白具有较好的抑制作用，且可逆转抑郁状态下皮质酮导致的PC12细胞的凋亡，表明本发明的嘧啶并二氮杂环庚酮化合物具有较好的抗抑郁活性。
与现有方法相比，本发明制备方法可适用于多种不同类型的嘧啶类烯丙基化合物，其催化活性高、反应条件温和、底物适用范围广、操作简便，且反应产率好(高达99％)，对映选择性高(高达99％ee)。这种运用催化不对称分子内烯丙基胺化反应、高效构建手性嘧啶并二氮杂环庚酮类化合物的方法和由此合成得到的相应的此类化合物目前国内外尚无文献报道。
本发明既丰富了桥连亚磷酰胺配体及其它类型亚膦酰胺配体的应用，同时也拓宽了烯丙基化反应底物的适用范围，为新药研发提供了新颖的手性杂环分子结构和高效构建新方法。
附图说明
图1为实施例3中制备的化合物I-9的单晶结构图。
图2为本发明化合物抗抑郁作用浓度和时间的关系图。其中，B中采用的浓度为0.625uM，C、D中采用的浓度为1.0uM。
图3为本发明化合物对GR、cofilin-1和NF-κB蛋白过度表达的抑制作用。其中，A、B中采用的浓度为0.625uM，C、D中采用的浓度为1.0uM。
图4为不同手性构型化合物抗抑郁作用的效果。其中，A中采用的浓度为1.0uM，B、C、D中采用的浓度为0.625uM。
图5为本发明化合物对利血平诱导的小鼠抑郁模型实验。其中，A为小鼠悬尾实验；B为小鼠强迫游泳实验；C为小鼠糖水偏好实验；D为小鼠开放旷场实验；E为单次给药的小鼠悬尾实验；F为单次给药的小鼠强迫游泳实验。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。下列实施例中涉及的物料若无特殊说明均可从商业渠道获得。所述方法若无特别说明均为常规方法。各组分用量以摩尔体积份计，mol、L。
实施例1：嘧啶类烯丙基化合物(S)的制备
以2,4-二氯-5-嘧啶甲酸乙酯类化合物1(1.0当量)和胺类化合物2(1.05当量)为起始原料，N,N-二异丙基乙胺(2.0当量)为碱，乙腈为溶剂，于80℃搅拌反应，经亲核取代反应得到化合物3；化合物3与硼酸化合物(2.0当量)、胺类化合物(1.2当量)或醇钠类化合物(3.0当量)，在无水溶剂中和碱存在条件下，经常规的Suzuki等偶联反应或亲核取代反应，得到化合物4；化合物4在甲醇溶剂中，氢氧化钠(1.0mol/L)存在下，发生水解反应得到化合物5；用DMF将化合物5溶解，然后分别加入1-羟基苯并***(HOBt，1.1当量)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDCI，1.1当量)，于室温搅拌反应30min，再将化合物6(1.1当量)加入反应液中，继续室温搅拌反应，原料反应完全后，将反应液倒入冰水中，然后用乙酸乙酯萃取，有机相减压浓缩，粗品经柱层析纯化得到嘧啶类烯丙基中间体S。
产物嘧啶类烯丙基中间体S：
S1：(E)-4-(N-苄基-2-吗啉基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.93g，产率90％。1H NMR(400MHz,CDCl3)δ9.55(s,1H),8.15(s,1H),7.67–7.54(m,2H),7.40–7.28(m,5H),7.28–7.23(m,1H),7.12–7.04(m,1H),5.92–5.82(m,1H),5.78–5.68(m,1H),4.71(s,2H),4.65(dd,J＝5.8,1.2Hz,2H),4.04(d,J＝5.6Hz,2H),3.86–3.77(m,7H),3.76–3.70(m,4H).13C NMR(100MHz,CDCl3)δ170.51,160.79,159.61,156.55,155.53,138.76,136.42,129.76,128.95,128.95,128.69,128.69,128.69,127.69,127.40,127.37,123.31,121.23,121.23,100.02,67.34,66.80,66.80,54.91,50.58,48.65,44.30,44.30.HRMS(ESI)calcd for C28H31N5O5[M+H]+:518.2398,found:518.2393.
S2：(E)-4-(N-苄基-2-吗啉基-4-(4-三氟甲基苯胺基)嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，1.08g，产率93％。1H NMR(400MHz,CDCl3)δ9.89(s,1H),8.19(s,1H),7.72(d,J＝8.1Hz,2H),7.59(d,J＝8.5Hz,2H),7.41–7.34(m,2H),7.33–7.23(m,3H),5.93–5.82(m,1H),5.80–5.64(m,1H),4.71(s,2H),4.65(dd,J＝5.8,1.2Hz,2H),4.05(d,J＝5.5Hz,2H),3.85–3.80(m,4H),3.79(s,3H),3.78–3.71(m,4H).13C NMR(100MHz,CDCl3)δ169.25,159.63,158.46,155.81,154.47,140.99,135.26,128.49,127.91,127.91,126.67,126.49,126.31,126.31,124.87,124.87,123.48(q,J＝32.8Hz),121.99,119.36,119.36,99.18,66.21,65.64,65.64,53.78,49.55,47.68,43.29,43.29.19F NMR(376MHz,CDCl3)δ-61.74.HRMS(ESI)calcd for C29H30F3N5O5[M+H]+:586.2272,found:586.2265.
S3：(E)-4-(N-苄基-4-(4-甲氧基苯胺基)-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.93g，产率85％。1H NMR(400MHz,CDCl3)δ9.37(s,1H),8.12(s,1H),7.50–7.44(m,2H),7.39–7.33(m,2H),7.33–7.28(m,1H),7.28–7.23(m,2H),7.05–6.82(m,2H),5.94–5.82(m,1H),5.78–5.68(m,1H),4.70(s,2H),4.68–4.63(m,2H),4.04(d,J＝5.6Hz,2H),3.82(s,3H),3.79(s,3H),3.79–3.74(m,4H),3.74–3.68(m,4H).13C NMR(101MHz,CDCl3)δ170.58,160.79,159.70,156.41,155.86,155.52,136.47,131.79,129.82,129.82,128.92,128.92,127.65,127.39,127.31,123.09,123.09,113.85,113.85,99.71,67.34,66.79,66.79,55.48,54.89,50.63,48.65,44.23,44.23.HRMS(ESI)calcdfor C29H33N5O6[M+H]+:548.2504,found:548.2508.
S4：(E)-4-(N-苄基-4-(3,5-二三氟甲基苯胺基)-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，1.04g，产率80％.1H NMR(400MHz,CDCl3)δ10.14(s,1H),8.25(s,1H),8.18(s,2H),7.55(s,1H),7.43–7.36(m,2H),7.35–7.24(m,3H),5.98–5.85(m,1H),5.84–5.69(m,1H),4.74(s,2H),4.68(dd,J＝5.8,1.3Hz,2H),4.08(d,J＝5.6Hz,2H),3.87–3.81(m,4H),3.80(s,3H),3.79–3.71(m,4H).13C NMR(101MHz,CDCl3)δ169.95,160.36,159.37,157.15,155.45,140.36,136.25,131.62(q,J＝33.1Hz),129.31,128.85,127.65,127.29,124.75,122.04,120.61(q,J＝4.2Hz),119.33,115.75,115.71,115.68,115.64,115.60,100.09,67.10,67.10,66.48,54.62,50.10,48.70,44.31,44.31.19F NMR(376MHz,CDCl3)δ-63.09.HRMS(ESI)calcd for C30H29F6N5O5[M+H]+:654.2146,found:654.2130.
S5：(E)-4-(N-苄基-2-吗啉基-4-丙胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.79g，产率82％.1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.39–7.32(m,2H),7.32–7.20(m,4H),5.90–5.79(m,1H),5.76–5.64(m,1H),4.74–4.60(m,4H),4.01(d,J＝5.3Hz,2H),3.86–3.78(m,7H),3.76–3.70(m,4H),3.46–3.34(m,2H),1.71–1.59(m,2H),0.99(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ170.51,161.59,160.85,155.50,155.40,136.73,129.98,128.71,128.71,127.41,127.31,127.31,126.97,99.56,67.24,66.69,66.69,54.68,50.81,48.41,44.06,44.06,42.15,22.44,11.60.HRMS(ESI)calcdfor C25H33N5O5[M+H]+:484.2554,found:484.2546.
S6：(E)-4-(N-苄基-4-异丙胺基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.82g，产率85％.1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.99(s,1H),7.40–7.30(m,2H),7.26–7.16(m,2H),7.03(d,J＝7.2Hz,1H),5.83(dt,J＝16.0,5.6Hz,1H),5.69(dt,J＝15.9,6.1Hz,1H),4.69–4.55(m,4H),4.24(h,J＝6.6Hz,1H),3.99(d,J＝5.7Hz,2H),3.83–3.68(m,11H),1.24(d,J＝6.5Hz,6H).13C NMR(101MHz,CDCl3)δ170.59,160.90,160.71,155.61,155.47,136.68,130.06,128.79,128.79,127.50,127.34,127.34,127.02,99.58,67.32,66.78,66.78,54.81,54.76,50.44,48.46,44.11,44.11,42.03,22.53.HRMS(ESI)calcd for C25H33N5O5[M+H]+:484.2554,found:484.2559.
S7：(E)-4-(N-苄基-4-环己胺基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.90g，产率86％.1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.38–7.27(m,3H),7.24–7.19(m,2H),7.11(d,J＝7.5Hz,1H),5.88–5.78(m,1H),5.74–5.62(m,1H),4.71–4.56(m,4H),3.98(d,J＝5.6Hz,2H),3.96–3.88(m,1H),3.80(s,3H),3.79–3.75(m,4H),3.75–3.69(m,4H),2.09–1.89(m,2H),1.80–1.68(m,2H),1.66–1.55(m,1H),1.47–1.16(m,5H).13C NMR(101MHz,CDCl3)δ170.42,160.83,160.58,155.60,155.31,136.80,129.95,128.60,128.60,127.30,127.27,127.27,126.93,99.48,67.13,66.58,66.58,54.51,50.27,48.66,48.42,44.00,44.00,32.41,32.41,25.69,25.49,24.59.HRMS(ESI)calcdfor C28H37N5O5[M+H]+:524.2867,found:524.2853.
S8：(E)-4-(N-苄基-4-苄基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.93g，产率88％.1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.63(t,J＝5.7Hz,1H),7.38–7.28(m,5H),7.26–7.17(m,5H),5.90–5.78(m,1H),5.74–5.62(m,1H),4.69–4.54(m,4H),3.99(d,J＝5.6Hz,3H),3.80(s,2H),3.78–3.72(m,4H),3.69(q,J＝4.7Hz,4H).13C NMR(101MHz,CDCl3)δ170.29,161.52,160.82,155.77,155.42,139.45,136.90,129.98,128.73,128.43,128.43,127.42,127.39,127.35,127.35,127.33,127.33,127.05,126.94,99.84,67.23,66.57,66.57,54.62,50.33,48.47,44.24,44.11,44.11.HRMS(ESI)calcd for C29H33N5O5[M+H]+:532.2554,found:532.2544.
S9：(E)-4-(N-苄基-2-甲氧基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.87g，产率94％.1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.24(s,1H),7.70–7.60(m,2H),7.40–7.32(m,5H),7.30–7.22(m,2H),7.12(ddt,J＝8.5,7.0,1.2Hz,1H),5.92–5.81(m,1H),5.80–5.69(m,1H),4.71(s,2H),4.68–4.60(m,2H),4.06(d,J＝5.5Hz,2H),3.97(s,3H),3.79(s,3H).13C NMR(101MHz,CDCl3)δ169.49,165.46,160.80,157.09,155.51,138.09,135.99,129.20,129.05,129.05,128.87,128.87,128.41,127.89,127.74,123.99,121.33,121.33,104.39,67.20,63.88,54.99,54.94,50.46,48.85.HRMS(ESI)calcd for C25H26N4O5[M+H]+:463.1976,found:463.1964.
S10：(E)-4-(N-苄基-2-甲基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.84g，产率95％.1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.29(s,1H),7.68(d,J＝8.0Hz,2H),7.42–7.30(m,4H),7.28–7.20(m,2H),7.11(t,J＝7.4Hz,1H),5.85(dt,J＝15.9,5.5Hz,1H),5.74(dt,J＝15.6,5.7Hz,1H),4.71(s,2H),4.64(d,J＝5.4Hz,2H),4.05(d,J＝5.4Hz,2H),3.79(s,3H),2.57(s,3H).13C NMR(101MHz,CDCl3)δ168.71,168.56,162.24,158.12,155.26,153.97,138.52,136.12,128.94,128.76,128.76,128.61,128.61,127.62,127.62,123.41,120.92,120.92,108.01,66.94,54.57,35.97,31.00,26.02.HRMS(ESI)calcd for C25H26N4O4[M+H]+:447.2027,found:447.2031.
S11：(E)-4-(N-苄基-2-(4-甲基-1-哌嗪基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，1.02g，产率96％.1H NMR(400MHz,CDCl3)δ9.56(s,1H),8.14(s,1H),7.63–7.56(m,2H),7.40–7.30(m,5H),7.30–7.23(m,2H),7.11–7.04(m,1H),5.93–5.82(m,1H),5.79–5.65(m,1H),4.70(s,2H),4.65(dd,J＝5.8,1.3Hz,2H),4.04(d,J＝5.6Hz,2H),3.87(t,J＝5.1Hz,4H),3.79(s,3H),2.48(t,J＝5.0Hz,4H),2.35(s,3H).13C NMR(101MHz,CDCl3)δ170.59,160.64,159.58,156.63,155.50,138.89,136.48,129.81,128.91,128.91,128.65,128.65,127.64,127.40,127.40,127.32,127.32,123.15,121.12,121.12,99.68,67.31,54.89,54.86,50.57,48.67,46.15,43.77,43.77.HRMS(ESI)calcd for C29H34N6O4[M+H]+:531.2714,found:531.2710.
S12：(E)-4-(N-苄基-4-苯胺基-2-四氢吡咯基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.95g，产率95％.1H NMR(400MHz,CDCl3)δ9.57(s,1H),8.08(s,1H),7.76–7.62(m,2H),7.32–7.12(m,7H),6.99–6.91(m,1H),5.88–5.73(m,1H),5.71–5.55(m,1H),4.62(s,2H),4.56(dd,J＝5.9,1.3Hz,2H),3.95(d,J＝5.6Hz,2H),3.69(s,3H),3.60–3.46(m,4H),1.93–1.83(m,4H).13C NMR(101MHz,CDCl3)δ170.93,159.32,159.23,156.45,155.52,139.30,136.50,129.88,128.91,128.91,128.62,128.62,127.62,127.42,127.42,127.27,122.78,120.65,120.65,99.05,67.38,54.88,50.58,48.68,47.07,46.52,25.58,25.30.HRMS(ESI)calcd for C28H31N5O4[M+H]+:502.2449,found:502.2447.
S13：(E)-4-(N-苄基-2-苯基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.93g，产率92％.1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.48(s,1H),8.42–8.34(m,2H),7.79–7.71(m,2H),7.47(dd,J＝5.8,1.7Hz,3H),7.45–7.39(m,3H),7.39–7.34(m,2H),7.34–7.26(m,3H),7.18–7.12(m,1H),5.88(dt,J＝15.7,5.5Hz,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.76(s,2H),4.66(dd,J＝5.7,1.2Hz,2H),4.16–4.02(m,2H),3.79(s,3H).13C NMR(101MHz,CDCl3)δ169.06,164.65,158.74,155.52,154.66,138.56,137.44,136.08,131.19,129.12,129.05,129.05,128.92,128.65,128.56,127.91,127.83,123.82,121.32,121.32,108.45,77.80,77.48,77.16,67.20,67.20,60.38,54.90,54.90,53.69.HRMS(ESI)calcd for C30H28N4O4[M+H]+:509.2183,found:509.2171.
S14：(E)-4-(N-苄基-2-(1-萘基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.98g，产率88％.1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.86–8.79(m,1H),8.58(s,1H),8.13(dd,J＝7.2,1.3Hz,1H),7.96(d,J＝8.1Hz,1H),7.92–7.87(m,1H),7.77–7.71(m,2H),7.59–7.53(m,1H),7.52–7.46(m,2H),7.42–7.36(m,2H),7.36–7.28(m,5H),7.13–7.06(m,1H),5.98–5.85(m,1H),5.85–5.76(m,1H),4.80(s,2H),4.68(dd,J＝5.6,1.3Hz,2H),4.15(d,J＝5.3Hz,2H),3.80(s,3H).13C NMR(101MHz,CDCl3)δ169.14,167.21,158.66,155.54,154.22,138.44,135.57,134.12,131.05,130.92,129.59,129.12,129.12,129.04,128.94,128.94,128.70,128.44,128.00,127.96,127.53,126.67,126.36,125.87,125.12,124.19,123.85,121.23,121.23,107.94,67.19,62.54,54.97.HRMS(ESI)calcd for C34H30N4O4[M+H]+:559.2340,found:559.2337.
S15：(E)-4-(N-苄基-4-苯胺基-2-(3,4,5-三甲氧基苯基)嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡棕色油状物，1.08g，产率90％.1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.46(s,1H),8.01(s,2H),7.79–7.66(m,3H),7.38(m,3H),7.35–7.28(m,2H),7.17–7.10(m,1H),5.89(dt,J＝15.9,5.5Hz,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.76(s,2H),4.69–4.62(m,2H),4.14–4.08(m,2H),3.94(s,6H),3.91(s,3H),3.80(s,3H).13C NMR(101MHz,CDCl3)δ168.91,163.78,163.76,162.48,158.44,155.41,154.53,153.03,153.03,140.69,138.37,135.94,132.50,129.03,128.95,128.95,128.50,128.50,127.82,127.77,123.85,121.58,121.58,108.13,105.53,105.53,67.10,60.79,55.91,55.91,54.81,36.35,31.29.HRMS(ESI)calcd for C33H34N4O7[M+H]+:599.2500,found:599.2485.
S16：(E)-4-(N-苄基-2-(2-呋喃基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡棕色油状物，0.94g，产率95％.1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.43(s,1H),8.01(s,1H),7.75(m,2H),7.61(d,J＝1.8Hz,1H),7.44–7.31(m,4H),7.30–7.20(m,3H),7.14(t,J＝7.4Hz,1H),6.55(dd,J＝3.5,1.7Hz,1H),5.97–5.82(m,1H),5.81–5.66(m,1H),4.73(s,2H),4.65(d,J＝5.5Hz,2H),4.09(d,J＝5.4Hz,2H),3.79(s,3H).13C NMR(101MHz,CDCl3)δ162.50,158.47,157.29,155.46,154.58,151.98,145.45,138.36,135.85,129.03,129.03,128.94,128.83,128.83,127.89,127.84,127.33,123.80,121.01,121.01,114.59,112.27,112.27,107.87,67.11,54.88,50.48,48.60.HRMS(ESI)calcd forC28H26N4O5[M+H]+:499.1976,found:499.1965.
S17：(E)-4-(N-苄基-2-(4-甲氧基-3-吡啶基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
透明油状物，1.02g，产率95％.1H NMR(400MHz,CDCl3)δ9.18(d,J＝2.3Hz,1H),9.14(s,1H),8.50(dd,J＝8.7,2.4Hz,1H),8.43(s,1H),7.74–7.66(m,2H),7.46–7.35(m,4H),7.35–7.27(m,3H),7.19–7.10(m,1H),6.80(d,J＝8.8Hz,1H),5.93–5.84(m,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.75(s,2H),4.71–4.62(m,2H),4.10(dd,J＝6.5,2.9Hz,2H),4.01(s,3H),3.80(s,3H).13C NMR(101MHz,CDCl3)δ169.08,165.93,163.20,158.66,155.51,154.55,148.59,138.65,138.26,135.91,134.55,129.08,129.08,128.94,128.94,127.96,127.88,127.88,127.47,126.69,123.94,121.34,121.34,110.61,108.10,67.17,62.46,60.41,54.95,53.85.HRMS(ESI)calcd for C30H29N5O5[M+H]+:540.2241,found:540.2233.
S18：(E)-4-(N-苄基-2,4-二苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.94g，产率90％.1H NMR(400MHz,CDCl3)δ9.50(s,1H),8.18(s,1H),7.67–7.57(m,2H),7.56–7.50(m,2H),7.40–7.20(m,9H),7.18–7.10(m,1H),7.08–7.00(m,1H),5.95–5.82(m,1H),5.82–5.64(m,1H),4.72(s,2H),4.64(dd,J＝5.9,1.2Hz,2H),4.06(d,J＝5.6Hz,2H),3.78(s,3H).13C NMR(101MHz,CDCl3)δ170.10,160.05,159.69,156.27,155.59,139.26,138.50,136.44,129.61,129.01,129.01,128.78,128.78,128.76,128.76,127.80,127.59,127.52,123.98,123.15,122.27,122.27,120.81,120.81,120.81,101.89,67.33,54.92,50.62,48.86.HRMS(ESI)calcd for C30H29N5O4[M+H]+:524.2292,found:524.2281.
实施例2
亚磷酰胺配体L1-L9可根据本领域常规的方法制备得到，具体可参见文献：(a)J.Am.Chem.Soc.2011,133,4785.(b)J.Am.Chem.Soc.2012,134,4812.(c)J.Am.Chem.Soc.2012,134,15022.(d)J.Org.Chem.2015,80,6968.(e)J.Am.Chem.Soc.2015,137,553.(f)Organometallics 2016,35,2467.(g)ACS Catal.2017,7,2397.(h)J.Am.Chem.Soc.2017,139,15022.(i)Org.Lett.2019,21,608.
实施例3
嘧啶类烯丙基中间体(S)作为底物在铱-亚磷酰胺络合物催化下发生分子内烯丙基胺化反应制备手性嘧啶并二氮杂环庚酮类化合物，具体步骤可如下：
在氮气保护下，依次加入铱化合物(0.004摩尔份)、亚磷酰胺配体L1-L9、正丙胺(0.5体积份)和四氢呋喃(1体积份)，50℃条件下搅拌30min，然后冷却至室温，减压除去溶剂，再依次加入底物S(0.2摩尔份)、碱(0.22摩尔份)、有机溶剂(2.0体积份)，于25-80℃下搅拌反应，反应产物经柱层析纯化得到烯丙基胺化产物I。
化合物I-1至化合物I-18的制备方法如上，具体反应条件参见表1。图1为实施例3中制备的化合物I-9的单晶结构图。表1中的摩尔比是指底物S:铱:配体:碱的摩尔比。
表1化合物I-1至化合物I-18的反应条件
其中，LG是离去基团，Bn是苄基，DIPEA是二异丙基乙基胺，DMAP是4-二甲胺基吡啶，DABCO是三乙烯二胺，DBU是1,8-二氮杂二环十一碳-7-烯，BSA是N,O-双三甲硅基乙酰胺，DBN是1,5-二氮杂双环[4.3.0]壬-5-烯，Ac代表乙酰基，Boc代表叔丁氧羰基，Piv代表2,2-二甲基丙酰基，Bz代表苯甲酰基，Troc代表2,2,2-三氯乙氧羰基，DME代表乙二醇二甲醚，MTBE代表甲基叔丁基醚。
化合物I-1：(R)-6-苄基-2-吗啉基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，84mg，产率95％；M.P.：125.4-125.5℃；98％ee；Ee值通过手性色谱柱检测(Daicel Chiralcel IA-3，流动相，n-hexane/2-propanol＝80/20，流速：1mL/min，检测温度：30℃，检测波长：254nm，保留时间：11.084min，14.645min)，[α]D 20＝-27.4°(c＝0.15,CHCl3)。1H NMR(400MHz,CDCl3)δ8.95(s,1H),7.39–7.27(m,7H),7.26–7.20(m,1H),7.14–7.06(m,2H),5.76(ddd,J＝16.9,10.4,6.4Hz,1H),5.44(d,J＝14.8Hz,1H),5.29–5.08(m,2H),4.56–4.45(m,1H),4.10(d,J＝14.9Hz,1H),3.93(d,J＝15.2Hz,1H),3.69–3.45(m,9H).13C NMR(101MHz,CDCl3)δ167.68,164.36,160.75,158.37,145.52,137.21,132.95,129.00,129.00,128.69,128.69,128.33,128.33,127.86,127.86,127.59,126.53,118.84,102.64,66.70,66.70,66.63,52.70,50.20,43.95,43.95.HRMS(ESI)calcdfor C26H27N5O2[M+H]+:442.2238,found:442.2241.
化合物I-2：(S)-6-苄基-2-吗啉基-9-(4-三氟甲基苯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，91mg，产率90％；M.P.：153.0-153.4℃；92％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.660min，20.165min)，[α]D 20＝+27.3°(c＝0.15,CHCl3)。1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.62(d,J＝8.5Hz,2H),7.40–7.26(m,5H),7.28–7.21(m,2H),5.77(ddd,J＝16.9,10.4,6.4Hz,1H),5.41(d,J＝14.8Hz,1H),5.29–5.15(m,2H),4.51(ddt,J＝6.4,5.0,1.4Hz,1H),4.17(d,J＝14.9Hz,1H),3.92(d,J＝15.2Hz,1H),3.62(dd,J＝15.2,6.1Hz,9H).13C NMR(101MHz,CDCl3)δ167.39,164.33,160.87,158.36,148.65,137.03,132.84,132.84,128.73,128.73,128.33,128.33,127.69,127.54,127.54,126.02(q,J＝3.8Hz),125.34,122.64,119.18,103.65,66.63,66.63,66.34,52.47,50.11,43.99,43.99.19F NMR(376MHz,CDCl3)δ-62.25.HRMS(ESI)calcd for C27H26F3N5O2[M+H]+:510.2111,found:510.2103.
化合物I-3：(R)-6-苄基-9-(4-甲氧基苯基)-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，67mg，产率72％；M.P.：189.6-190.4℃；83％ee；Ee值通过手性色谱柱检测(Daicel Chiralcel IF-3，流动相，n-hexane/2-propanol＝75/25，流速：1mL/min，检测温度：30℃，检测波长：254nm，保留时间：31.325min，33.575min)，[α]D 20＝-18.5°(c＝0.10,CHCl3)。1H NMR(400MHz,CDCl3)δ8.96(s,1H),7.41–7.24(m,5H),7.08–6.98(m,2H),6.93–6.79(m,2H),5.78(ddd,J＝17.0,10.3,6.5Hz,1H),5.46(d,J＝14.8Hz,1H),5.34–5.09(m,2H),4.45(t,J＝5.9Hz,1H),4.11(d,J＝14.9Hz,1H),3.94(d,J＝15.2Hz,1H),3.83(s,3H),3.68–3.41(m,9H).13C NMR(101MHz,CDCl3)δ167.73,164.32,160.83,158.53,157.82,138.39,137.24,133.04,132.05,131.93,128.90,128.67,128.67,128.45,128.32,127.57,118.76,114.12,102.56,67.04,66.72,66.72,55.44,52.68,50.16,43.98,43.98.HRMS(ESI)calcd for C27H29N5O3[M+H]+:472.2343,found:472.2347.
化合物I-4：(R)-6-苄基-9-(3,5-二三氟甲基苯基)-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，95mg，产率82％；M.P.：153.3-153.4℃；89％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：5.540min，10.430min)，[α]D 20＝-31.2°(c＝0.20,CHCl3)。1H NMR(400MHz,CDCl3)δ8.98(s,1H),7.69(s,1H),7.61(d,J＝1.6Hz,2H),7.37–7.27(m,5H),5.73(ddd,J＝16.8,10.4,6.2Hz,1H),5.38–5.14(m,3H),4.56–4.47(m,1H),4.23(d,J＝14.8Hz,1H),3.88(d,J＝15.1Hz,1H),3.71–3.44(m,9H).13C NMR(101MHz,CDCl3)δ167.04,164.68,160.68,157.88,146.54,136.89,132.64,132.06(q,J＝33.4Hz),128.77,128.77,128.42,128.42,127.80,127.80,127.30,124.39,121.68,119.54,119.54,119.14,103.87,66.57,66.11,66.11,52.41,50.08,44.00,44.00.19F NMR(376MHz,CDCl3)δ-62.93.HRMS(ESI)calcd for C28H25F6N5O2[M+H]+:578.1985,found:578.1971.
化合物I-5：(S)-6-苄基-2-吗啉基-9-丙基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，63mg，产率78％。86％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：12.215min，14.187min)，[α]D 20＝+20.5°(c＝0.10,CHCl3)。1H NMR(400MHz,CDCl3)δ8.85(s,1H),7.50–6.93(m,5H),5.64(ddd,J＝17.1,10.3,5.8Hz,1H),5.36(d,J＝14.9Hz,1H),5.22(d,J＝10.3Hz,1H),5.13(d,J＝17.0Hz,2H),4.12(t,J＝5.4Hz,1H),4.05(d,J＝14.9Hz,1H),3.91–3.77(m,4H),3.81–3.69(m,4H),3.65(d,J＝15.3Hz,1H),3.48(dd,J＝15.3,5.9Hz,1H),3.05(ddd,J＝13.6,9.8,5.6Hz,1H),1.78–1.38(m,2H),0.88(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ167.98,163.74,161.31,157.48,137.25,132.78,128.63,128.63,128.26,128.26,127.51,118.18,102.73,66.86,66.86,64.08,52.47,51.63,49.53,44.30,44.30,20.23,11.56.HRMS(ESI)calcdfor C23H29N5O2[M+H]+:408.2402,found:408.2401.
化合物I-6：(R)-6-苄基-9-异丙基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，46mg，产率56％。80％ee；(流动相，n-hexane/2-propanol＝85/15，其他参数同化合物I-1，保留时间：12.218min，19.029min)，[α]D 20＝-13.4°(c＝0.12,CHCl3)。1H NMR(400MHz,CDCl3)δ8.92(s,1H),7.52–6.94(m,5H),5.73–5.60(m,1H),4.88–4.35(m,4H),3.89–3.68(m,4H),3.62–3.53(m,4H),3.32–3.24(m,1H),3.10–3.03(m,1H),2.02–1.94(m,2H),1.36(d,J＝6.7Hz,6H).13C NMR(101MHz,CDCl3)δ169.30,160.04,159.13,156.68,136.77,128.75,128.75,128.60,128.51,127.48,127.32,127.32,99.70,67.08,66.84,66.84,53.88,53.83,48.92,44.08,44.08,22.50,22.50.HRMS(ESI)calcd for C23H29N5O2[M+H]+:408.2394,found:408.2387.
化合物I-7：(S)-6-苄基-9-环己基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，74mg，产率83％。84％ee；(其他参数同化合物I-1，保留时间：13.320min，16.457min)，[α]D 20＝-12.6°(c＝0.10,CHCl3)。1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.43–6.87(m,5H),5.87–5.56(m,1H),4.93–4.47(m,4H),4.02–3.86(m,3H),3.81–3.59(m,8H),3.21–3.06(m,1H),2.07–1.96(m,2H),1.83–1.48(m,3H),1.46–1.14(m,5H).13C NMR(101MHz,CDCl3)δ170.64,161.00,160.68,155.69,136.80,128.79,128.79,128.63,128.55,127.50,127.45,127.45,99.74,66.87,66.87,66.87,64.25,48.95,44.14,44.14,42.80,32.64,32.64,25.81,24.81,24.81.HRMS(ESI)calcdfor C26H33N5O2[M+H]+:448.2716,found:448.2714.
化合物I-8：(R)-6,9-二苄基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，90mg，产率88％。90％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-3，保留时间：15.127min，22.066min)，[α]D 20＝-21.2°(c＝0.12,CHCl3)。1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.39–7.14(m,10H),5.77–5.62(m,2H),5.40(d,J＝14.9Hz,1H),5.29(d,J＝10.2Hz,1H),5.18(d,J＝17.1Hz,1H),4.09–4.03(m,1H),4.02(d,J＝4.2Hz,1H),3.98(d,J＝4.9Hz,1H),3.80–3.69(m,4H),3.68–3.58(m,5H),3.41(dd,J＝15.4,5.8Hz,1H).13C NMR(101MHz,CDCl3)δ167.79,163.68,161.08,157.97,137.76,137.14,132.39,128.65,128.65,128.65,128.64,128.64,128.30,128.30,127.56,127.26,127.26,118.73,102.66,66.74,66.74,62.82,52.43,51.35,49.34,44.36,44.36.HRMS(ESI)calcd for C27H29N5O2[M+H]+:456.2394,found:456.2394.
化合物I-9：(R)-6-苄基-2-甲氧基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率92％；M.P.：136.7-136.9℃.96％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝75/25，检测温度：25℃，其他参数同化合物I-1，保留时间：10.080min，12.555min)，[α]D 20＝-22.1°(c＝0.12,CHCl3)。1H NMR(400MHz,CDCl3)δ9.08(s,1H),7.44–7.34(m,4H),7.34–7.27(m,4H),7.17–7.11(m,2H),5.77(ddd,J＝16.9,10.3,6.4Hz,1H),5.46(d,J＝14.8Hz,1H),5.31–5.12(m,2H),4.60–4.53(m,1H),4.14(d,J＝14.8Hz,1H),3.96(d,J＝15.4Hz,1H),3.65(dd,J＝15.4,6.0Hz,1H),3.57(s,3H).13C NMR(101MHz,CDCl3)δ166.99,166.05,165.45,159.25,144.81,136.81,132.23,129.31,129.31,128.77,128.77,128.40,128.40,127.77,127.71,127.71,127.07,119.26,106.48,67.06,54.40,52.88,49.97.HRMS(ESI)calcd for C23H22N4O2[M+H]+:387.1816,found:387.1805.
化合物I-10：(S)-6-苄基-2-甲基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，58mg，产率78％。M.P.：152.8-153.0℃。84％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.343min，15.262min)，[α]D 20＝+18.4°(c＝0.12,CHCl3).1H NMR(400MHz,CDCl3)δ9.08(s,1H),7.42–7.23(m,8H),7.13–7.06(m,2H),5.72(ddd,J＝16.8,10.4,6.2Hz,1H),5.43(d,J＝14.8Hz,1H),5.28–5.09(m,2H),4.62–4.56(m,1H),4.13(d,J＝14.8Hz,1H),3.91(d,J＝15.4Hz,1H),3.62(dd,J＝15.4,6.1Hz,1H),2.35(s,3H).13C NMR(101MHz,CDCl3)δ169.05,167.27,162.40,157.62,145.00,136.67,132.34,129.25,129.25,128.79,128.79,128.42,128.42,127.83,127.44,127.44,126.68,119.20,109.72,67.05,52.89,49.91,25.94.HRMS(ESI)calcd forC23H22N4O[M+H]+:371.1866,found:371.1861.
化合物I-11：(S)-6-苄基-2-(4-甲基-1-哌嗪基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率78％；M.P.：187.3-188.1℃。79％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝70/30，检测温度：25℃，其他参数同化合物I-1，保留时间：10.481min，14.420min)，[α]D 20＝+21.2°(c＝0.12,CHCl3).1H NMR(400MHz,CDCl3)δ8.94(s,1H),7.38–7.27(m,7H),7.25–7.20(m,1H),7.13–7.07(m,2H),5.76(ddd,J＝16.9,10.4,6.4Hz,1H),5.44(d,J＝14.9Hz,1H),5.25–5.11(m,2H),4.55–4.46(m,1H),4.10(d,J＝14.9Hz,1H),3.93(d,J＝15.2Hz,1H),3.80–3.15(m,5H),2.35–2.10(s,7H).13C NMR(101MHz,CDCl3)δ167.75,164.36,160.62,158.38,145.60,137.26,133.04,128.95,128.95,128.67,128.67,128.31,128.31,127.86,127.86,127.56,126.41,118.78,102.32,66.57,54.81,54.81,52.65,50.21,46.17,43.38,43.38.HRMS(ESI)calcd for C27H30N6O[M+H]+:455.2554,found:455.2562.
化合物I-12：(S)-6-苄基-9-苯基-2-(1-四氢吡咯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，70mg，产率82％；M.P.：153.8-154.3℃。90％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.038min，15.181min)，[α]D 20＝-20.4°(c＝0.16,CHCl3).1H NMR(400MHz,CDCl3)δ8.98(s,1H),7.40–7.29(m,7H),7.27–7.22(m,1H),7.15–7.09(m,2H),5.78(ddd,J＝16.9,10.3,6.4Hz,1H),5.46(d,J＝14.8Hz,1H),5.27–5.14(m,2H),4.56–4.47(m,1H),4.13(d,J＝14.9Hz,1H),3.96(d,J＝15.2Hz,1H),3.69–3.36(m,9H).13C NMR(101MHz,CDCl3)δ166.57,163.19,159.59,157.29,144.45,136.15,131.86,127.94,127.94,127.61,127.61,127.25,127.25,126.77,126.52,125.48,117.73,101.58,65.59,65.53,51.64,49.14,42.89,42.89,28.62,28.62.HRMS(ESI)calcd for C26H27N5O[M+H]+:426.2288,found:426.2272.
化合物I-13：(R)-6-苄基-2,9-二苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，53mg，产率62％；M.P.：212.7-213.6℃。76％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-6，保留时间：25.880min，28.153min)，[α]D 20＝-25.4°(c＝0.12,CHCl3).1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.10–7.96(m,2H),7.50–7.43(m,2H),7.43–7.30(m,9H),7.25–7.18(m,2H),5.80(ddd,J＝16.8,10.4,6.2Hz,1H),5.49(d,J＝14.8Hz,1H),5.35–5.20(m,2H),4.68(td,J＝6.1,1.2Hz,1H),4.20(d,J＝14.9Hz,1H),4.02(d,J＝15.4Hz,1H),3.70(dd,J＝15.5,6.0Hz,1H).13C NMR(101MHz,CDCl3)δ167.19,164.35,163.03,157.71,145.05,137.08,136.70,132.42,130.90,129.35,129.35,128.83,128.83,128.47,128.47,128.47,128.29,128.29,127.86,127.74,127.74,126.93,119.25,119.25,110.05,66.96,52.98,49.99.HRMS(ESI)calcd for C28H24N4O[M+H]+:433.2023,found:433.2022.
化合物I-14：(S)-6-苄基-2-(1-萘基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，84mg，产率88％；M.P.：227.2-227.4℃。86％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-3，保留时间：21.740min，25.554min)，[α]D 20＝+24.4°(c＝0.15,CHCl3).1H NMR(400MHz,CDCl3)δ9.35(s,1H),8.56–8.46(m,1H),8.23(dd,J＝7.4,1.3Hz,1H),7.85(d,J＝8.1Hz,1H),7.76(d,J＝8.3,1H),7.50–7.40(m,3H),7.40–7.27(m,7H),7.24–7.19(m,2H),7.18–7.10(m,1H),5.81(ddd,J＝16.9,10.3,6.5Hz,1H),5.51(d,J＝14.7Hz,1H),5.33–5.17(m,2H),4.70–4.51(m,1H),4.17(d,J＝14.8Hz,1H),4.04(d,J＝15.4Hz,1H),3.67(dd,J＝15.4,5.8Hz,1H).13C NMR(101MHz,CDCl3)δ167.24,166.78,162.59,157.94,145.21,136.69,134.11,134.03,132.44,131.37,131.18,130.47,129.67,129.67,128.86,128.86,128.47,128.47,128.22,128.12,128.12,127.89,127.18,126.42,126.31,125.45,125.00,119.42,109.66,67.42,52.97,49.94.HRMS(ESI)calcd for C32H26N4O[M+H]+:483.2179,found:483.2174.
化合物I-15：(S)-6-苄基-9-苯基-2-(3,4,5-三甲氧基苯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，85mg，产率82％；M.P.:115.0–115.4℃。87％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝65/35，其他参数同化合物I-3，保留时间：14.863min，17.718min)，[α]D 20＝+31.3°(c＝0.20,CHCl3).1HNMR(400MHz,CDCl3)δ9.24(s,1H),7.43(m,2H),7.39–7.28(m,8H),7.24–7.17(m,2H),5.79(ddd,J＝16.8,10.3,6.3Hz,1H),5.47(d,J＝14.7Hz,1H),5.34–5.15(m,2H),4.65(t,J＝5.9Hz,1H),4.17(d,J＝14.8Hz,1H),4.01(d,J＝15.4Hz,1H),3.84(s,3H),3.73(s,6H),3.71–3.64(m,1H).13C NMR(101MHz,CDCl3)δ167.14,163.54,163.03,157.53,152.91,152.91,145.31,140.49,136.67,132.42,132.22,129.31,129.31,128.82,128.82,128.47,128.47,128.23,128.23,127.86,126.71,119.30,109.46,105.32,105.32,66.86,60.85,55.93,55.93,53.00,49.99.HRMS(ESI)calcd for C31H30N4O4[M+H]+:523.2340,found:523.2326.
化合物I-16：(R)-6-苄基-2-(2-呋喃基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率84％；M.P.：178.5-178.6℃。92％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-8，保留时间：26.611min，29.809min)，[α]D 20＝-42.3°(c＝0.20,CHCl3).1H NMR(400MHz,CDCl3)δ9.25(s,1H),7.53(m,1H),7.44(m,2H),7.41–7.31(m,6H),7.22–7.15(m,2H),6.71(dd,J＝3.4,0.9Hz,1H),6.41(dd,J＝3.5,1.7Hz,1H),5.78(ddd,J＝16.8,10.4,6.2Hz,1H),5.46(d,J＝14.8Hz,1H),5.31–5.17(m,2H),4.70–4.61(m,1H),4.19(d,J＝14.8Hz,1H),4.00(d,J＝15.4Hz,1H),3.69(dd,J＝15.4,5.9Hz,1H).13C NMR(101MHz,CDCl3)δ166.90,163.10,157.71,157.34,151.87,145.20,144.80,136.63,132.34,129.25,129.25,128.82,128.82,128.49,128.49,127.87,127.64,127.64,126.91,119.31,114.34,112.04,109.95,66.96,52.99,49.91.HRMS(ESI)calcd for C26H22N4O2[M+H]+:423.1816,found:423.1814.
化合物I-17：(S)-6-苄基-2-(4-甲氧基-3-吡啶基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，74mg，产率80％；M.P.：158.5-159.3℃。85％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝80/20，其他参数同化合物I-3，保留时间：10.868min，13.600min)，[α]D 20＝+23.4°(c＝0.12,CHCl3).1HNMR(400MHz,CDCl3)δ9.22(s,1H),8.74(d,J＝2.3Hz,1H),8.18(dd,J＝8.7,2.4Hz,1H),7.43(t,J＝7.7Hz,2H),7.38–7.27(m,6H),7.21–7.10(m,2H),6.66(d,J＝8.7Hz,1H),5.77(ddd,J＝16.8,10.4,6.3Hz,1H),5.46(d,J＝14.8Hz,1H),5.36–5.12(m,2H),4.73–4.56(m,1H),4.16(d,J＝14.8Hz,1H),3.99(d,J＝15.4Hz,1H),3.93(s,3H),3.67(dd,J＝15.4,6.0Hz,1H).13C NMR(101MHz,CDCl3)δ167.12,165.77,162.98,157.63,148.50,144.91,138.59,136.65,132.33,129.45,129.45,128.82,128.82,128.45,128.45,127.86,127.65,127.65,127.13,126.46,119.32,110.32,109.90,67.07,53.75,52.96,49.95,29.72.HRMS(ESI)calcd for C28H25N5O2[M+H]+:464.2081,found:464.2072.
化合物I-18：(R)-6-苄基-9-苯基-2-苯胺基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，76mg，产率86％；M.P.：232.1-232.3℃。88％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝70/30，其他参数同化合物I-1，保留时间：7.127min，12.460min)，[α]D 20＝-36.4°(c＝0.10,CHCl3).1H NMR(400MHz,CDCl3)δ8.99(s,1H),7.52–7.46(m,2H),7.44–7.38(m,1H),7.38–7.28(m,5H),7.22–7.10(m,3H),7.01–6.89(m,4H),6.86–6.79(m,1H),5.81(ddd,J＝17.0,10.3,6.6Hz,1H),5.48(d,J＝14.8Hz,1H),5.30–5.07(m,2H),4.53(t,J＝6.2Hz,1H),4.10(d,J＝14.8Hz,1H),4.00(d,J＝15.3Hz,1H),3.63(dd,J＝15.3,5.8Hz,1H).13C NMR(101MHz,CDCl3)δ167.38,164.09,159.04,159.01,145.72,139.26,137.09,132.56,129.85,129.85,128.75,128.75,128.50,128.50,128.46,128.46,128.39,128.39,127.69,127.05,121.86,119.18,118.26,118.26,103.79,67.13,52.86,50.09.HRMS(ESI)calcd for C28H25N5O[M+H]+:448.2132,found:448.2120.
实施例4：根据前述底物合成方法、实施例3及合成化合物I-1的反应条件，制备具体化合物I-19至化合物I-38，结果如表2所示：
表2化合物I-19至化合物I-38的收率及对映体过量值
实施例5：嘧啶并二氮杂环庚酮类化合物的抗抑郁活性评价
(1)细胞培养及抑郁模型的建立
PC12细胞购于Procell Life Science&Technology Co.，Ltd.(武汉，中国)。所有细胞培养试剂均购于Life Technologies(Grand Island，Nebraska,USA)。细胞在含有10％胎牛血清(Gibco，USA)的Dulbecco’s modified Eagle’s medium(Gibco，USA)中，并在37℃，含有5％CO2培养箱中培养。
皮质酮(corticosterone，CORT)诱导PC12细胞通常用于在体外建立抑郁模型。PC12细胞用600μM皮质酮处理24小时，在此皮质酮浓度下，细胞活力降低至60％，进而可用于随后的体外实验。
(2)细胞活力(Cell Viability)测定
使用MTT[3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴化四唑]测定细胞活力。具体步骤：将1×105个细胞接种到96孔板的每个孔中，培养24小时以稳定化后，加入600μM皮质酮处理24小时，再将含皮质酮的培养基倒掉，分别加入含不同浓度药物(本发明化合物/氟西汀)的培养基，分别处理12、24和48小时，再加入MTT在37℃下孵育4小时，在酶标仪(BIO-RAD，USA)中测量570nm处的吸光度，结果见图2和表3。表3为药物浓度为0.625uM时培养24h的细胞活力结果。
(3)蛋白质印迹法
将PC12细胞在含有1％苯基甲基磺酰氟(PMSF)的RIPA裂解液中，在冰上裂解30分钟后后，收取上清溶液后离心，并使用BCA测定试剂盒(Beyotime，碧云天，上海)测定上清液蛋白质浓度。将蛋白质样品上样至10％SDS-聚丙烯酰胺凝胶电泳，然后进一步转移至PVDF膜上(Millipore,MA,USA)。将膜用5％脱脂奶封闭，然后与单独的一抗在4℃下孵育过夜。用Tris-buffered saline-tween 20(TBST)洗涤后，在室温下将PVDF膜与二抗孵育。用ECL试剂(Beyotime，上海)并使用BIO-RAD ChemiDoc XRS***进行了分析。利用好Image J软件(The National Institutes of Health,Bethesda,MD,USA)进行光密度分析。结果见图3。
(4)Hoechst和PI染色
Hoechst和PI染色法检测PC12细胞凋亡。Hoechst可与活细胞的细胞核结合，而PI(碘化丙啶)可以与死细胞的细胞核结合。将它们铺在12孔板中，药物处理48小时后，用核染料Hoechst对细胞进行染色。简而言之，将细胞用PBS洗2遍后，并继续在培养箱中与10mg/L的Hoechst孵育20分钟。对PI染色，在4℃下与含有PI(终浓度1μg/mL)工作溶液在室温下孵育10分钟。使用荧光显微镜(Zeiss,Germany)观察细胞并拍照，结果见图2和图3。蓝色荧光表示为活细胞，红色荧光表述为死细胞。
(5)结果分析：
表3嘧啶并二氮杂环庚酮类化合物抗抑郁活性的测定结果
备注：a采用浓度为0.625uM，数值为三次独立实验的平均值；b为皮质酮；c为阳性对照药。
本发明采用MTT法测定了不同药物浓度(20uM、10uM、5uM、2.5uM、1.25uM和0.625uM)在不同时间(12h、24h和48h)时的细胞存活率，结果见图2。其中，正常细胞作为空白对照(Control)，皮质酮处理组(CORT)为对照组，DMSO+control为溶剂对照组。图2A为培养12h后不同浓度药物作用的结果；图2B为药物浓度为0.625uM时不同培养时间下作用的结果。由图可见，皮质酮导致PC12细胞存活率降低至60％左右，而添加本发明化合物(S)-I-11和阳性药物氟西汀均可有效降低CORT导致细胞的死亡率，且本发明化合物作用效果相对于阳性药物氟西汀更显著，趋向于正常细胞。此外，由图2B可见，阳性药物氟西汀需要48h才发挥其作用，而本发明化合物(S)-I-11在12h就显示了优异的作用效果(图2A和图2B)。
Hoechst和PI法结果表明，皮质酮导致PC12细胞死亡，从而表现为蓝色荧光数减少和红色荧光数增加，而化合物(S)-I-11与氟西汀作用相似可减少细胞的死亡，表现为可使蓝色荧光数增加并且使红色荧光数减少(图2C和图2D，采用的浓度为1.0uM)。
抑郁症发病机制与HPA轴亢进、突触重塑和炎症有关。其中，GR、cofilin-1和NF-κB在抑郁症发病中起着关键作用。结果表明，实施例中化合物(S)-I-17和(R)-I-9表现出与氟西汀相同的作用，可促进抑郁时GR的表达，抑制cofilin-1和NF-κB蛋白的过度表达(图3A和图3B)；而且化合物(S)-I-17和(R)-I-9可逆转皮质酮导致的PC12细胞的大量凋亡(图3C和图3D)。这些结果进一步证明了化合物(S)-I-17和(R)-I-9在体外具有良好的抗抑郁活性。
此外由图4可见，化合物(S)-I-10结构蓝色荧光数量高于(R)-I-9，红色荧光数量低于(R)-I-9(图4A)；并且与(R)-I-9相比，(S)-I-9可更好地增加PC12存活率(图4B)。(S)-I-14和(S)-I-13与其对应的消旋体比可更好地增加存活率(图4C和图4D)。这些结果表明，(S)-构型化合物嘧啶并氮杂酮类化合物比(R)-构型及其对应的外消旋体可能具有更好的抗抑郁作用。
结合表3及附图表明，本发明的嘧啶并二氮杂环庚酮化合物具有较好的抗抑郁作用，甚至部分化合物抗抑郁活性优于阳性对照药氟西汀的效果；并且本发明中引入烯丙基片段的化合物抗抑郁活性明显优于不含烯丙基片段的化合物。
实施例6：嘧啶并二氮杂环庚酮类化合物的小鼠抑郁模型实验
采用利血平0.4mg/kg腹腔注射小鼠14天诱导慢性抑郁模型。采用悬尾实验(TST)、强迫游泳实验(FST)、糖水偏好实验(SWP)和开放旷场实验(OFT)来作为抑郁程度的评判标准。慢性抑郁模型建立后，以氟西汀(Fluoxetine)为阳性对照药，采用本发明的化合物治疗14天，确定本发明化合物的抗抑郁效果；采用单次给药探究化合物的起效时间。
实验步骤
悬尾实验(TST)：用胶带固定小鼠尾部末端约1cm处，将其悬挂。用摄像机记录小鼠6min内的活动情况，统计分析后4min内小鼠不动时间。
强迫游泳实验(FST)；将小鼠单独置于水深15cm的玻璃缸内(高20cm，直径14cm)，水温(25±1)℃，游泳6min，观察记录后4min内小鼠在水中累计不动时间。
糖水偏好实验(SWP)：啮齿类动物天生对甜食有强烈的喜好，给小鼠提供可自由选择蔗糖溶液和普通水的两个饮水装置时，计算24h糖水消耗。糖水偏好指数％＝糖水消耗量/(糖水消耗量+纯水消耗量)×100％。
开放旷场实验(OFT)：实验在安静的环境下进行。将动物放入40×40cm的箱内底面中心，视频行为分析***观察和记录受试小鼠在旷场试验箱内15min活动情况。
图5为本发明化合物对利血平诱导的小鼠抑郁模型实验。其中，A为小鼠悬尾实验；B为小鼠强迫游泳实验；C为小鼠糖水偏好实验；D为小鼠开放旷场实验；E为单次给药的小鼠悬尾实验；F为单次给药的小鼠强迫游泳实验。
其中，以正常无抑郁症小鼠为空白对比(control)，抑郁症无给药小鼠为对照组(图5A-图5D中表述为“-”；图5E和图5F中表述为“depression”)。
结果表明：相比于患病对照组，本发明的嘧啶并二氮杂环庚酮类化合物可显著降低抑郁小鼠悬尾的不动时间(图5A)和强迫游泳的不动时间(图5B)，并恢复小鼠对糖的喜好(图5C)，增加小鼠在中央区的移动距离(图5D)，从而趋向于正常小鼠，与阳性药物氟西汀的影响趋势一致，且效果比阳性药物氟西汀的更显著，表明本发明化合物较阳性药物氟西汀具有更优异的抗抑郁效果。
再，由图5E和图5F可见，本发明的嘧啶并二氮杂环庚酮类化合物在给药24h后即可产生明显的抗抑郁作用，使小鼠行为趋向于正常小鼠(图5E)，明显优于氟西汀的起效时间；且效果可持续144h(图5F)，表明本发明化合物的抗抑郁作用药效迅速且持久。
综合以上结果表明：本发明的嘧啶并二氮杂环庚酮类化合物具有优异、快速起效的抗抑郁作用且药效持久。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式如式(I)所示，其中，用*标注的碳原子为手性碳原子，其构型为R、S或R/S，所述嘧啶并二氮杂环庚酮类化合物为左旋体、右旋体或消旋体；
其中，R1、R2分别独立选自氢、卤素原子、羟基、羧基、氰基、硝基、C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的芳基亚甲基、取代或未取代的芳基；
R3、R4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的杂环基亚甲基或杂环芳基亚甲基、取代或未取代C1-C20的烃氧羰基、取代或未取代的芳基酰基、取代的芳基磺酰基、取代或未取代的芳基、取代或未取代芳基亚甲基。
2.根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于：R1、R2中，所述C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基中的一个或一个以上氢原子被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代；
R3、R4中，所述C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基中的一个或一个以上氢原子被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
3.根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；
其中，R1、R2分别独立选自氢、氟、氯、溴、碘、羟基、羧基、氰基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、苄基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、苄氧基、氨基、C1-C20的酰胺基、三甲基硅基、三乙基硅基、三苯基硅基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、C2-C20的酮羰基、C1-C20的磺酰基、取代或未取代的芳基；所述取代的芳基中的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中的一种或一种以上的组合；
R3、R4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、杂环基亚甲基或杂环芳基亚甲基、烯丙基、炔丙基、乙酰基、苯甲酰基、C1-C20的磺酰基、叔丁氧羰基、芴甲氧羰基、2,2,2-三氯乙氧羰基、取代或未取代的芳基、取代或未取代的芳基亚甲基、取代或未取代的苯磺酰基；其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、硝基或C1-C20的烃氧基中的一种或一种以上的组合。
4.根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)：
其中，R1、R2分别独立选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、羟基、羧基、氰基、环戊基、环己基、氨基、甲胺基、乙胺基、二乙基胺基、二异丙基胺基、三甲基硅基、三乙基硅基、三苯基硅基、乙酰胺基、乙酰基、三氟乙酰基、苯基、苯胺基、苯甲酰基、3,4,5-三甲氧基苯基、苄基、4-二甲氨基苄基、苄氧基、甲磺酰基、苯磺酰基、萘基、吗啉基、吡咯基、四氢吡咯基、1-哌嗪基、1-甲基哌嗪基、吡啶基、4-甲基吡啶基、甲氧基吡啶基、呋喃基、哌啶基、4-羟甲基-3,5-二甲基哌啶基、噻吩基、噁唑基。
5.根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)：
其中，R3、R4分别独立选自氢、甲基、乙基、正丙基、异丙基、环己基、环戊基甲基、烯丙基、炔丙基、羰基、乙氧羰基、叔丁氧羰基、三氯乙氧甲酰基、苯甲酰基、4-溴苯甲酰基、9-亚芴基甲氧甲酰基、3-氟-4-(烯丙基酰胺基)苯基、磺酰基、甲苯磺酰基、苯基、4-甲氧基苯基、4-(三氟甲基)苯基、3,5-双(三氟甲基)苯基、苄基、对氟苄基、4-二甲氨基苄基、4-甲氧基苄基、2-四氢吡喃基、4-(三氟甲基)苄基、3,5-双(三氟甲基)苄基、嘧啶基、4-氟嘧啶基甲基、4-氯嘧啶基甲基、吡咯并嘧啶基、吗啉基、吡啶基、3-甲基吡啶基、吡啶基甲基、吡嗪基、4-三氟甲基吡嗪基、哌嗪基、3-甲基哌嗪基、哌啶基、哌啶基甲基。
6.一种权利要求1-5任一项所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法，其特征在于具体为以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到所述手性或消旋的嘧啶并二氮杂环庚酮类化合物。
7.根据权利要求6所述的制备方法，其特征在于：所述嘧啶类烯丙基化合物中间体的结构式如式(S)所示，
其中，LG是离去基团，为羟基、氯、溴、
M为NH或O；R5为卤素取代或未取代的C1-C20的烷基、卤素取代或未取代的C1-C20的烃氧基；R6为C1-C20的烷基、取代或未取代的芳基。
8.根据权利要求7所述的制备方法，其特征在于：所述嘧啶类烯丙基化合物中间体，由包括以下步骤方法制备得到：2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物和胺类化合物反应生成2-氯-4-取代胺基-6-取代-嘧啶-5-羧酸甲酯类化合物，通过常规的亲核取代反应或偶联反应引入基团R1，然后水解生成羧基类化合物，进而与
反应得到式S化合物。
9.根据权利要求5所述的制备方法，其特征在于具体包括以下步骤：
(1)以2,4-二氯-5-嘧啶甲酸乙酯类化合物1和胺类化合物2为起始原料，N,N-二异丙基乙胺为碱，经亲核取代反应得到化合物3；
(2)化合物3与硼酸化合物、胺类化合物或醇钠类化合物，在无水溶剂中和碱存在条件下，经常规的偶联反应或亲核取代反应，得到多种不同取代的化合物4；
(3)化合物4在水中，在碱存在下，发生水解反应得到化合物5；
(4)化合物5在1-羟基苯并***和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐作用下，与化合物6缩合，得到嘧啶类烯丙基化合物中间体，作为下一步烯丙基胺化催化反应的底物；
(5)在有机碱或无机碱存在的条件下、铱化合物和亚磷酰胺配体形成的金属铱配合物，在有机溶剂中催化底物发生分子内的烯丙基胺化反应得到式(I)所示的化合物。
10.权利要求1-5任一项所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
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