Acetic Acid, Glacial

81.2%的高中生近视率，1.9亿青少年患者，其中超7000万的高度近视患者面临失明风险！  国家疾控局近期发布的报告指出，高度近视已成为我国工作年龄人群不可逆视力损伤的首要原因，在儿童与青少年群体中尤为严峻，这一问题不再是简单的视力障碍，正逐渐演变为一项影响国民健康质量的长期挑战。 然而，科学界的研究正在颠覆传统认知：近视的发生与进展，可能不仅仅是由于“用眼过度” ，还与人体另一套系统——肠道菌群的健康状态密切相关。 眼肠相通 复旦团队发现近视防控新靶点 近年来，随着“肠-脑-眼轴”通路被科学界逐步确认，肠道与眼部健康之间的内在关联正受到空前关注。而复旦大学团队在《Cell Discovery》发表的一项突破性研究，则首次系统揭示了肠道菌群与血浆代谢谱对近视进展的调控作用。[1] 研究团队对170名志愿者样本进行分析后发现，与视力健康人群相比，高度近视患者肠道中的AKK菌丰度显著降低，同时其血液中由肠道菌群衍生的代谢物3-IAA水平也明显减少。而日前实验中，AKK菌已经被证明是3-IAA的关键生产者。 这表明，肠道中的AKK菌丰度与高度近视的发生存在关联，其很可能通过调控关键代谢物3-IAA的生成，参与到近视的发生发展过程中。 那么，这条从肠道到眼睛的远程调控链路究竟是如何实现的呢？ 研究进一步揭示了其深层机制：AKK菌在肠道内产生的3-IAA进入血液循环后，随血液抵达眼部巩膜组织，提升SP1的关键转录因子的活性，使其更高效地与I型胶原蛋白的基因启动子结合，促进胶原蛋白的合成。 这一过程，如同从体内为逐渐变薄的眼球外壳持续输送“建筑材料”，可显著增强巩膜的韧性、抵抗眼轴异常拉长，从结构层面延缓近视进展。 后续开展的小鼠研究为此提供了确凿的数据支撑：每天灌胃3-IAA的近视小鼠，其屈光不正的程度减少51.9%，同时眼轴的异常伸长也被抑制35.9%。由此可清晰得知，通过补充AKK菌产生的代谢物3-IAA，能切实有效延缓高度近视恶化。 整体看来，该研究颠覆了近视只是眼睛局部问题的传统观念，揭示其与全身性的微生态平衡也息息相关。 从实验室到市场 微生物疗法的未来前景 肠道菌群对眼部健康的影响正成为一个前沿研究领域。除了AKK菌，其他益生菌在护眼方面的潜力也逐步被发掘。 研究发现，不同菌株可通过特异性机制精准调控眼部健康：植物乳杆菌LB101能调节代谢物、分泌抗炎因子，有效缓解干眼症；发酵乳杆菌HY7302在延缓年龄相关性黄斑变性方面展现出应用前景；此外，多项研究发现，特定乳酸杆菌能通过免疫调节参与眼表疾病、真菌性角膜炎等病症的辅助治疗。 图注：部分益生菌对眼部疾病的调控起积极影响 据魔镜洞察数据，我国眼健康线上市场规模已达265.4亿元，同比增长32.7%。随着“护眼+健脑+肠道健康”的复合理念在社交平台持续发酵，市场对“菌株认证”“透明工厂”等高品质标签的关注度持续攀升，成分科学化、菌株可溯源化，正成为行业竞争的新门槛 。 科学突破和市场需求协同发力，预示着微生物组疗法可能在未来的眼科医疗和保健市场中占据一席之地。 在此趋势下，具备核心菌株资源的企业正抢占先机。其中，上海原衍生物从百岁老人肠道样本中筛选出专利菌株AKK001，完成了从实验室研究到产业化落地的关键突破，并先后通过ISO22000、FSSC22000等多项国际认证。 不过，从科学研究到落地成熟护眼产品仍面临挑战。目前大多数菌株的有效剂量、作用机制及个体化差异仍需更多长期临床研究的验证。未来，随着循证科学的深入，精准菌株组合、个性化干预方案以及与传统防控手段的协同应用，将成为该领域的核心发展方向。 从“肠”计议，守护双眸，科学正为人类眼健康开辟一条前所未有的创新路径。 推荐阅读： 政策东风已至！欧盟AKK菌青少年市场开放，中国企业如何抢占先机？ 肠道里的“长寿密码”：源自百岁老人的AKK菌为何是健康优选？ [1] Li, H., Du, Y., Cheng, K., Chen, Y., Wei, L., Pei, Y., Wang, X., Wang, L., Zhang, Y., Hu, X., Lu, Y., & Zhu, X. (2024). Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis. Cell discovery, 10(1), 89. https://doi.org/10.1038/s41421-024-00709-5 更多原衍生物相关内容，扫描以上二维码进行咨询。

1. Introduction 吲哚及其衍生物是一类非常有效的药物中间体。已有不少相关综述报道其合成方法。我们将一些常用的合成方法简单的列举了出来，供大家在合成此类化合物的时候参考。 1 (a) G. W. Gribble, Contemp.Org. Synth., 1994, 145.  (b) U. Pindur and R. Adam, J. Heterocycl.Chem., 1988, 25, 1.  (c)C. J. Moody, Synlett, 1994, 681.  (d) R. J. Sundberg, Indoles,Academic Press, San Diego, CA, 1996.  (e) T. L. Gilchrist, J.Chem. Soc., Perkin Trans. 1, 1999, 2849.  (f) G. W. Gribble, J.Chem. Soc., Perkin Trans. 1, 2000, 1045.  2. Fischer 吲哚合成 Fischer 吲哚合成法是一个常见的吲哚合成方法。通过苯腙在酸催化下加热重排消除一分子氨得到2－取代或3－取代吲哚衍生物。在实际操作中，常可以用醛或酮与等当量的苯肼在酸中加热回流得到苯腙，其在酸催化下立即进行重排、消除氨而得到吲哚化合物。常用的催化剂有氯化锌、三氟化硼、多聚磷酸等，常用的酸有AcOH， HCl, 三氟乙酸等。其机理大致如下： 2.1  Fischer 吲哚合成反应示例 4-Bromophenylhydrazine hydrochloride 1 (21 g) was suspended in 150 mL of aceticacid, and the mixture was heated to reflux. Then a solution of cyclohexanone 2 (9.3 mL) in 10 mL of aceticacid was added dropwise.  After theaddition, the mixture was stirred under reflux for another 2 h.  Water (50 mL) was added dropwise slowly,cooled to room temperature, the solid was filtered, washed with water, dried,pale brown solid 3 (21.65g,91 %) was obtained. Ref: (a) B. Robinson, Chem. Rev., 1963, 373. (b) B. Robinson, Chem. Rev.,1969, 227. (c) H. Ishii, Accts. Chem. Res., 1981, 233. (d) B. Robinson, The FischerIndole Synthesis, 1982, 923. (e) D. L. Hughes, Org. Prep. Proced.Int., 1993, 607. (f) S.M. Hutchins, K. T. Chapman, Tetrahedron Letters, 1996, 4869. (g) O. Miyata et al., ibid.1999, 3601. (h) S. Wagaw et al.,J. Am. Chem. Soc., 1999, 10251.  3. 从硝基苯的衍生物出发合成吲哚 对于2，3位没有取代基的吲哚，一般工业上大多采用硝基苯的衍生物出发合成，邻甲基、邻甲酰基、邻氰乙基、邻乙烯基、及邻位有氢的硝基苯衍生物都可通过相应的方法得到吲哚。 3.1 邻甲基硝基苯衍生物合成吲哚 该方法是目前最常用的，邻甲基硝基苯衍生物与DMF-DMA反应后得到相应的烯胺，然后硝基可通过多种方法还原后加成得到吲哚。还原方法一般通过加氢，但当分子内有敏感官能团（比如：Br，I都可或烯烃等）存在时可通过化学还原如：NH2NH2-RaneyNi, 铁粉，TiCl3, 锌粉还原得到吲哚。3.1.1 邻甲基硝基苯衍生物合成吲哚示例 To a solution of 4-methoxy-2-nitrotoluene 1 (17.9 g, 0.107 mol) in 200 mL of dry DMFwas added DMFDMA (42 mL, 0.316 mol) and pyrrolidine (10 mL, 0.12 mmol).  The mixture was heated at 105 0C for 19 h under nitrogen,then cooled, diluted with water and extracted with ether (8×50 mL).  The ether layer was extracted with water (3×25 mL), dried with sodiumsulfate, and concentrated to give a deep red oil 2 which was dissolverin ethyl acetate (150 mL), and to the solution was added 10% palladium oncarbon (1.8 g).  Hydrogenation at 50 p.s.i. with shaking for 3h and then filtration through celite gave a light brown filtrate.  This filtrate is evaporated to purple oil,which was purified by chromatography on silica gel (eluent: DCM) to give6-methoxyindole Yield: 76% Ref: (a) Feldman, et al, Synthesis, 1986,735. (b) Kline.T.B. et al,  J.Med. Chem., 1982, 908. (c) Schumacher, R.W. et al, Tetrahedron,1999, 935. (d) bromidge, S.M., et al, J. Med. Chem., 1998,1598. (e) Maehr, H. et al, J. Org. Chem. 1984, 1549. (f)Nicolaou, K.C. et al, J. Am. Chem. Soc., 2004, 10162.   3.2 邻甲酰基硝基苯衍生物合成吲哚 该邻甲酰基硝基苯衍生物与硝基甲烷反应后得到相应的不饱和硝化物再还原后得到吲哚。  3.1.2邻甲酰基硝基苯衍生物合成吲哚示例 To a solution of 2-nitro-benzaldehyde 1 (3.14 g, 0.02 mol) in nitromethane (40 mL)was added ammonia acetate (0.9 g,0.012 mol) under N2 protected. Then it was heated to reflux for 1.25 h. After cooled to room temperature, it was poured into water and stirredfor 30 min.  Then it was extracted withDCM (50 mL×3), and the combined organic layer was washed with brine, dried overNa2SO4 and evaporated under vacuum.  The residue was purified by flash columnchromatography to yield 1.2 gpure 2-(2-nitro-vinyl)-nitrobenzene 2. Yield: 42% To a solution of 2-(2-nitro-vinyl)-nitrobenzene 2(1.0 g, 0.005 mol) inethanol (10 mL), glacial acetate acid (10 mL) and water (3 mL) was added ironpowder (5.7 g, 0.1 mol)portionwise.  After the addition, it washeated to 50 °C for 30 min.  After cooled to room temperature, aq. NaHSO3was added to it and extracted with ether (50 mL×3).  The combined organic layer was washed withsaturated aq. NaHCO3, dried over Na2SO4 andevaporated under vacuum.  The residue waspurified by flash column chromatography to yield 0.45 g 1H-indole 3.  Yield: 75% Ref: (a) Sinhababu, Achintya K.;Borchardt, Ronald T., J. Am. Chem. Soc., 1985, 7618, (b) He,Feng; Bo, Yunxin; Altom, Jason D.; Corey, E. J.; J. Am. Chem. Soc.,1999, 6771. 3.3 邻氰甲酰基硝基苯衍生物合成吲哚示例  To a solution of 2-nitro-1-naphthyl-acetonitrile (33g, 0.155 mol) in 630 mL of ethanol containing10% water and 6.3 mL of pure acetic acid was added 19 g of 10% palladium-on-carbon.  Then it was stirred at r.t. under 4 bars ofhydrogen.  After the reaction completed,the catalyst was filtered and the filtration was concentrated under reduced pressure.  Then residue was dissolved in 250 mL of DCM,washed with 100 mL of 0.1 N KOH solution and then dried over Na2SO4,evaporated under reduced pressure to give the crude product, which was purifiedby column chromatography using cyclohexane/EA=4:1 as eluant to yield 13 g of 3H-benzo[e]indole.  Yield: 50% Ref: (a) Makosza, M. et al., Tetrahedron, 1995,7263. (b) Bromidge, S.M. et al., J. Med. Chem., 1998, 1598.  3.4 邻乙烯基硝基苯衍生物合成吲哚示例 To a solution of 2-bromo-4-methylnitrobenzene1(1.00 g, 4.61 mmol) and vinyltri-n-butyltin(1.61 g, 5.07 mmol) intoluene (25 mL) was added, under a positive flow of argon,bis(dibenzylideneacetone) palladium (0)(265 mg, 0.46 mmol) together withtriphenylphosphine (498 mg, 1.90 mmol).  Thesolution was heated at reflux (19 h) whereupon a red solution containing a blackprecipitate was formed.  The reactionmixture was cooled to ambient temperature, and the solvent was removed to giveblack oil.  The oil was dissolved indichloromethane (50 mL), washed with NH4OH (10%, aq, 3 x30 mL), and dried(MgSO4).  Removal of solvent gave yellowoil containing a smaller amount of black viscous oil.  The crude product was purified bychromatography (hexanes-EtOAc, 19:1) to give 2-ethenyl-4-methylnitrobenzene(589 mg, 3.61mmol, 78%) as yellow oil 2. To an oven-dried, threaded ACEglass pressure tube was added 2-ethenyl-4-methylnitrobenzene 2 (152 mg,0.93 mmol), Pd(OAc)2(13 mg, 0.06mmol), triphenylphosphine (62 mg, 0.24 mmol), and 4 mL of MeCN.  The tube was fitted with a pressure head, thesolution was saturated with CO (four cycles to 4 atm of CO), and the reactionmixture was heated to 70 °C(oil bath temperature) under CO (4 atm) until all starting material wasconsumed (15 h) as judged by TLC.  Thereaction mixture was diluted with HCl (aq, 10%, 10 mL) and extracted with Et2O (3x10 mL).  The combined organic phases were washed withHCl (aq, 10%, 10 mL) and dried (MgSO4), and the solvent was removed to give the crude product. The crude product was purified bychromatography (hexanes-EtOAc, 9:1) to give 5-methylindole 3 (62 mg,0.47 mmol, 51%) as faint yellow crystals. Ref: Soederberg, B. et al, J.Org. Chem., 1997, 5838   3.5 邻位有氢的硝基苯衍生物直接用乙烯格氏试剂合成吲哚（Bartoli反应）示例 The 2-nitrotoluene (685 mg, 5mmol) was placed in a two–necked round bottomed flask fitted with a gas inlet(argon) and rubber septum. The flask was purged several times with argon beforeadding THF (35–40 ml) and cooling to between –40 and –45 °C. The Grignard reagent (3 eq.) was then addedrapidly in one portion to the THF solution and stirring continued for a further30 mins to 1 hour (exact length of time had little effect on yield). Saturatedammonium chloride solution was added to the reaction mixture (at ca. –40 °C) before allowing the mixture towarm to room temperature. The mixture was thoroughly extracted with diethylether (2 x 200 ml), the ether extracts combined and thoroughly washed withfurther ammonium chloride (300 ml), water (300 ml) and brine (300 ml) beforedrying (MgSO4) and concentrating in vacuo to give a dark brown gum, which was purifiedby flash column chromatography (hexane:ethyl acetate 9:1) to give 465 mg of7-methyl-indole. Yield: 71%. Ref: (a) Adrian P. Dobbs,Martyn Voyle, Neil Whittall, Synlett, 1999, 1594, (b) Curtin, M.L et al, J.Med.Chem.,1998, 74.  4. 从苯胺的衍生物出发合成吲哚 从苯胺的衍生物合成吲哚虽不常用，但还是有一些方法被报道。  4.1苯胺经佛克烷基化再还原关环合成吲哚 Toa stirred solution of boron trichloride (645 mg, 5.5mmol) in drybenzene (6 mL), a solution of 4-chloroaniline 1(638mg, 5 mmol) in dry benzene (6 mL) was added dropwise underice-cooling. To the resulting mixture containing 4-chloroanilineborontrichloride complex, chloroacetonitrile (0.38 mL, 6 mmol) and aluminumtrichloride (734 mg, 5.5 mmol) were added successively. The mixture was thenrefluxed for 6 h under nitrogen, becoming a solution of two layers. The evolvedhydrogen chloride was absorbed through a drying tube containing silica gel orcalcium chloride to a surface of aqueous sodium hydroxide. After cooling, ice 2N hydrochloric acid was added and a yellow precipitate was formed. To hydrolyzethe ketimine of 2 the mixturewas warmed at 80 °Cunder stirring, until the precipitate had dissolved (ca. 30 min). The cooledmixture was extracted with chloromethane (three times) and the organic layerwas washed with water, dried (MgS04), and concentrated. The neutralfraction obtained (744 mg) was recrystallized to obtain pure 2 (674 mg). Yield: 66%. The acidiclayer was made alkaline with 2 N sodium hydroxide and extracted withdichloromethane. Washing, drying, and evaporation of the solvent gave the basicfraction (170 mg). Thin-layer chromatographic purification (silica gel,chloroform containing 10% methanol) gave recovered 1 (103 mg). To a stirred solution of 5-chloro-2-amino-α-chloroacetophenone2(204 mg, l mmol) indioxane (5mL) containing water(0.5 mL) was added sodium borohydride (1.1 mmol) and the solution was refluxedfor 5.5 h. After removal of the solvent, water was added and the mixture wasextracted with dichloromethane. The extract was dissolved in benzene and passedthrough a silica gel layer (ca. 2 g)to remove a polar fraction. The eluate with benzene was concentrated givingindole 3(one spot, on TLC,dichloromethane). Yield: 69% Ref: (a) T. Sugsawa, M. Adachi, K. Sasakura, A.Kitagawa, J. Org.Chem., 1979, 578, (b) Gonzalez, J.C. et al, Synthesis, 2002,475. 4.2 N-羟基苯胺DMAP催化下与丙炔酸酯缩合合成3-羧酸吲哚衍生物 To a solution of N-benzyl-N-phenylhydroxylamine1 (86.2 mg, 0.426 mmol) in THF (15.0 mL) was added 4A molecular sieves. DMAP (6.0 mg, 0.049 mmol) and methyl propiolate 2 (54 mg, 0.562 mmol) were addedto it at 0°C.  The reaction mixture was stirred at 0°C for 1 h, then at room temperature for48 h. Ethyl acetate (5.0 mL) was added, and after filtration, the organicsolution was washed with water (3 x 20 mL), brine, and then dried overmagnesium sulfate. Following filtration, the organics are concentrated underreduced pressure and the resultant oil purified by flash column chromatography(hexanes: ethyl acetate= 7:3) as eluent to give 1-benzyl-1H-indole-3-carboxylicacid methyl ester 3 (95.6 mg; 82% yield) as a white solid (m.p. 67.0-67.5°C). Ref: (a) R.Hwu, H.V. Patel, R.J. Lin, and M.O. Gray,J. Org. Chem., 1994, 1577  4.3 Nenitzescu吲哚合成 Nenitzescu是一类比较特殊的吲哚合成方法，它的最终产物一般都是在N原子上有芳香环的化合物。对于Nenitzescu反应而言，最后一步合环反应采用不同的溶剂会得到不同的合环产物。如下的化合物4和5所示。 To a solution of (E)3-amino-but-2-enenitrile 1 (1.0 g, 12.2 mmol) in acetic acid (1.54 g, 25 mmol) and water (5 mL) wasadded aniline 2 (1.13 g,12.2 mol) at r.t..  After stirring for 30min., the mixture was cooled in an ice bath and the product 3 was collected on a filter, dried invacuum.  (The mixture also can beextracted with acetic ether if there was no precipitate appearance.) To the solution of 1,4-benzo quinone (0.96 g, 9.0 mmol) in acetic acid (4 mL)was added acetic anhydride (0.8 mL) at r.t.. After stirring for 30 min., a solution of(E)3-Phenylamino-but-2-enenitrile3(1.18 g,7.5 mmol) in acetic acid (4 mL) was added to it and the mixture was stirredovernight.  Crude solid was collectedafter filtered, washed with a little acetic acid and water, dried invacuum.  The solid was purified by columnchromatography on silica gel using EtOAc/petro ether (1:2) as eluent to yield 6-hydroxy-3-cynao-2-methyl-1-phenyl-indole 4. (30%) Ref: (a) R. K. Brown, The Chemistry of HeterocyclicCompounds, (b) W. J. Houlihan, Ed., 1972, 413, (c) G. R. Allen, Jr.,Org. React.1973, 337, (d) Synthetic applications: U.Kuecklander, W. Huehnermann, Arch. Pharm.1979, 515, (e) J. L. Bernier, J. P.,Henichart, J. Org. Chem.1981, 4197, (f) M. Kinugawa et al.,J. Chem. Soc. Perkin Trans. I, 1995, 2677; (g) J. M. Pawlak et al., J.Org. Chem.1996, 9055. 5. 2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物 通过叠氮基丙烯酸酯与芳香醛缩合可以得到2-叠氮基-3-芳基丙烯酸酯，其加热环合生成吲哚2-羧酸酯衍生物，一般而言只有富电子的芳环（带推电子苯环，呋喃，噻吩，吡咯）可通过该方法环合。由于反应放出氮气，在环合时一定要严格控制2-叠氮基-3-芳基丙烯酸酯滴加速度及反应瓶敞口，否则很容易喷发出来。5.1 2-叠氮基-3-芳基丙烯酸酯环合合成2-羧酸吲哚衍生物示例 To a solution of NaN3 (60 g, 0.92 mol) in 240 mL of DMF wasadded dropwise chloro-acetic acid methyl ester 1 (75 mL, 0.86 mol) at 0 °C.  After the addition, it wasallowed to warm to r.t. and overnight. The reaction mixture was poured into 1.5 L of water and extracted with ether (500mL×3).  The combined organic layer waswashed with brine, dried over Na2SO4 and evaporated underreduced pressure to yield 78.4 gyellow oil azido-acetic acid methylester 2.  Yield: 90% To 500 mL of methanol was added portionwise sodium (15.7 g, 0.68 mol).  After the addition, it was heated to refluxfor 30 min.  Then a solution of4-methoxy-benzaldehyde 3 (46.2 g, 0.34 mol) and azido-aceticacid methyl ester 2 (78 g,0.68 g) in 100 mL ofmethanol was added dropwise to it.  Afterthe addition, it was stirred at 5 °C for 2 h and overnight at r.t..  Then the reaction mixture was poured into icewater and stirred for 10 min. Deposited and filtered.  The solid was washed with water (50 mL×3),dried under vacuum to yield 54.3 g yellow solid 2-azido-3-(4-methoxy-phenyl)-acrylicacid methyl ester 4.  Yield: 69% To 600 mL of xylene was slowly added dropwise asolution of compound 4 (54 g, 0.23 mol) in 400 mL of xylene atreflux.  After the addition, it wasreflux for 1 h and cooled to room temperature and stirred overnight.  The solvent was removed under reducedpressure and the residue was recrystallized with xylene to yield 28 g white solid 6-methoxy-1H-indole-2-carboxylic acid methyl ester 5. Yield: 59% Reference: (a) Coowar, D. et al, J.Med. Chem., 2004, 6270, (b) Blair, J. B., et al, J. Med. Chem.,2000, 4701 觉得不错，请点这里！！