CN115557836A - 一种羧酸的制备方法 - Google Patents

一种羧酸的制备方法 Download PDF

Info

Publication number
CN115557836A
CN115557836A CN202110745730.4A CN202110745730A CN115557836A CN 115557836 A CN115557836 A CN 115557836A CN 202110745730 A CN202110745730 A CN 202110745730A CN 115557836 A CN115557836 A CN 115557836A
Authority
CN
China
Prior art keywords
group
groups
hydroxide
substituted
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110745730.4A
Other languages
English (en)
Inventor
张洪彬
谭文云
卢意
何严萍
赵静峰
陈文�
羊晓东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yunnan University YNU
Original Assignee
Yunnan University YNU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yunnan University YNU filed Critical Yunnan University YNU
Priority to CN202110745730.4A priority Critical patent/CN115557836A/zh
Publication of CN115557836A publication Critical patent/CN115557836A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/08—Formation or introduction of functional groups containing oxygen of carboxyl groups or salts, halides or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种羧酸的制备方法。具体地，本发明提供的羧酸的制备方法包括如下步骤：在溶剂中，式I化合物作为氧化剂，在强碱的存在下进行氧化反应，将含有伯醇基团或醛基的反应物氧化得到相应的羧酸；所述的强碱为第一主族元素、第二主族元素、第三主族元素或过渡金属元素的氢氧化物；

Description

一种羧酸的制备方法
技术领域
本发明涉及一种羧酸的制备方法。
背景技术
羧酸是一类重要的有机化合物，广泛存在于自然界及合成化学品中，是农药和医药的重要组成部分。羧酸及其衍生化合物广泛应用在工业、农业和人们的日常生活中。在有机合成领域，从醇或醛到羧酸的氧化反应是有机化学中一种基本的、重要的官能团转化化学反应，羧酸常通过氧化的方法来获得。鉴于羧酸及其衍生物在化学工业中的重要性，发展一种高效、价格低廉、条件温和、官能团兼容性好、环境友好、具有化学选择性、氧化剂可再生的氧化体系具有重要学术价值和良好的工业化应用前景。传统上，羧酸的合成是通过利用KMnO4氧化、Jone’s氧化及其他基于CrO3的氧化方法，高价碘氧化以及利用稀贵金属及其络合物催化氧化的方法等。此类氧化方法的缺点是氧化剂含重金属，废液污染环境，或者氧化剂易爆，或者价格昂贵，部分反应还需要强酸性，条件苛刻，对设备要求高。此外传统氧化方法在选择性氧化方面表现差，氧化剂再生难度大，环境兼容性差，不利于大规模工业生产。(Oxidation of Primary Alcohols to Carboxylic Acids,Springer:Berlin,2007；Mahmood,A.；Robinson,G.E.；Powell,L.Org.Process Res.Dev.1999,3,363- 364；Thottathil,J.K.；Moniot,J.L.；Mueller,R.H.；Wong,M.K.Y.；Kissick,T.P.J.Org.Chem.1986,51,3140-3143；Tojo,G.；Fernández,M.I.Oxidation of PrimaryAlcohols to Carboxylic Acids:A Guide to Current Common Practice； Springer:NewYork,2007；Lappe,P.；Schulz,E.Aliphatic Carboxylic Acids via AldehydeOxidation.In Applied Homogeneous Catalysis with Organometallic Compounds；Cornils,B.,Herrmann,W.A.,Eds.；Wiley-VCH:Weinheim, Germany,1996，pp 424-464；Tojo,G.；Fernandez,M.Oxidation of Primary Alcohols to Carboxylic Acids.BasicReactions in Organic Synthesis，Spriner:New York,2010).
羧酸制备中常用Pinnick氧化，但该反应局限于只能从醛氧化到酸。 Pinnick氧化还要使用易燃易爆的2-甲基-2-丁烯等添加剂，而且使用氧化性很强的亚氯酸钠(NaClO2)。(Kraus,G.A.,Roth,B.J.Org.Chem.1980,45, 4825-4830)
2,2,6,6-四甲基哌啶氮氧化物TEMPO氧化是一种常用的氧化方法，能实现伯醇和仲醇的选择性氧化，常用次氯酸钠及亚氯酸钠与其联用，也有与过渡金属联用的例子。含有苯胺类以及带有叔丁基亚磺酰基官能团的底物普遍对TEMPO氧化条件不兼容(Giacomelli,G.；Masala,S.；Porcheddu,A.J.Org. Chem.2003,68,4999；Ciriminna,R.；Pagliaro,M.Industrial Oxidations with Organocatalyst TEMPO and Its Derivatives,Org.Process Res.Dev.2010,14,245– 251；Shibuya,M.Nitroxyl radical-catalyzedchemoselective alcohol oxidation for the synthesis of polyfunctionalmolecules,Tetrahedron Lett.2020,61,151515– 151525)。
Oppenauer氧化用酮和醛做氧化剂(质子转移受体)，可以把仲醇氧化为酮，伯醇氧化为醛，自身被还原为相应的醇。(Djerassi,C.Org.React.1951,6, 207-272)现有文献中仅有一例在使用芴酮做为氧化剂时，可将1,5二醇以23％收率氧化为内酯的报道。(Eignerova,L.；Kasal,A.Collect.Czech.Chem. Commun.1976,41,1065)目前未见Oppenauer氧化方法实现醇或醛氧化到酸的报道。
发明内容
本发明为了克服现有技术中使用重金属为氧化剂、稀贵过渡金属参与反应、反应条件比较苛刻、底物适用性窄、氧化剂氧化性不易控制、氧化剂不可再生利用等缺陷，而提供了一种羧酸的制备方法。本发明的方法采用邻位具有叔羟基的酮作为氧化剂，在强碱的存在下将伯醇或醛直接氧化为羧酸。本发明原料工业上廉价易得，并且所用氧化剂在反应完成后可利用安全价廉的无机氧化剂单过硫酸氢钾复合盐(oxone)再生利用，成本低，减少反应过程中产生的废物污染，具有高效、温和、反应规模易于放大并具有官能团兼容性的优势。
本发明的羧酸的制备方法在仲醇和伯醇同时存在下，可选择性氧化伯醇生成羧酸，并且所述羧酸的制备方法普适性较广，能够适应具有广泛常见官能团的反应底物，即兼容多种官能团。
本发明提供一种羧酸的制备方法，其包括如下步骤：在溶剂中，式I化合物作为氧化剂，在强碱的存在下，将含有伯醇基团或醛基的反应物中的伯醇基团或醛基氧化成相应的羧基；所述的强碱为第一主族元素、第二主族元素、第三主族元素或过渡金属元素的氢氧化物；
Figure BDA0003144288210000031
R1和R2各自独立地为C1-C3烷基，或者R1和R2与其相连的原子共同形成5-6元碳环；n为0、1、2、3或4；R3为H、C1-C3烷基、C1-C3烷氧基或卤素。
本发明中，所述式I化合物中，R1和R2优选与其相连的原子共同形成 5-6元碳环，更优选地形成环己烷。
本发明中，所述式I化合物中，所述n优选为0或1。
本发明中，所述式I化合物中，所述R3优选为H、甲基、乙基、异丙基、甲氧基、乙氧基、丙氧基、氟、氯或溴；更优选为H。
本发明中，当n≥2时，优选地，各R3相同或不同。
本发明中，所述式I化合物最优选1-羟基环己基苯基甲酮，即
Figure BDA0003144288210000041
本发明中，当反应物含有伯醇基团时，所述氧化剂与含有伯醇基团的反应物的摩尔比优选等于或大于2:1；更优选为2:1-3:1，最优选2:1。当反应物含有醛基时，所述氧化剂与含有醛基的反应物的摩尔比优选等于或大于1:1；更优选为1:1-2:1，最优选为1:1。
本发明中，所述第一主族元素的氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯中的一种或多种；所述第二主族元素的氢氧化物选自氢氧化钙、氢氧化镁和氢氧化钡中的一种或多种；所述第三主族元素的氢氧化物选自氢氧化铝；所述过渡金属的氢氧化物选自氢氧化铜、氢氧化铁、氢氧化锌和氢氧化钯中的一种或多种。
本发明中，当反应物含有伯醇基团时，所述强碱与含有伯醇基团的反应物的摩尔比优选2:1-3:1；更优选为2:1。当反应物含有醛基时，所述强碱与含有醛基的反应物的摩尔比优选1.5:1-2:1，优选2:1。
本发明中，所述溶剂可为本领域中常用的不影响反应进行的惰性有机溶剂，优选非醇类溶剂，可以为醚类溶剂，优选乙醚、二甲醚、叔丁基甲醚、乙二醇二甲醚、乙二醇二乙醚、环戊基甲醚、二甲基亚砜、吡啶、二氯甲烷、 1,2-二氯乙烷、1,1-二氯乙烷、1,4-二氧六环、四氢呋喃、乙腈、苯和甲苯中的一种或多种，更优选甲苯、吡啶和乙二醇二甲醚中的一种或多种，最优选乙二醇二甲醚。所述溶剂的体积与含有伯醇基团或醛基的反应物的摩尔比优选为(1.5mL-2mL):1mmol，更优选为1.5mL:1mmol。
本发明中，反应的温度可为常规的保证反应正常进行所需的温度，一般不低于20℃，优选不低于60℃，更优选为60℃-80℃。
本发明中，所述含有伯醇基团的反应物、氧化剂、强碱的摩尔比优选为 1:(2-3):(2-3)，更优选为1:2:2或1:3:3。
本发明中，所述含有醛基的反应物、氧化剂、强碱摩尔比优选为1：(1- 2)：(1.5-2)，更优选为1:1:2。
本发明中，所述含有伯醇基团或醛基的反应物可以为本领域中任意含有伯醇基团或者醛基的化合物，包括含有伯醇基团或醛基的芳烃化合物、含有伯醇基团或醛基的烷烃化合物、含有伯醇基团或醛基的烯烃化合物、含有伯醇基团或醛基的炔烃化合物、含有伯醇基团或醛基的环烷烃化合物、含有伯醇基团或醛基的杂环烷基化合物，或含有伯醇基团或醛基的杂芳基化合物，例如甾类化合物、萜类化合物、长链烷烃类化合物、长链烯烃类化合物、芳烃类化合物、杂芳烃类化合物、金刚烷类化合物、杂烷烃类化合物等。
本发明中，含有伯醇基团的反应物通式优选：R1’CH2OH；其中，R1’为直链或支链C1-C17烷基、直链或支链C2-C17烯基、直链或支链C2-C17炔基、 C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类。所述直链或支链C1-C17烷基、直链或支链C2-C17烯基、直链或支链C2-C17炔基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基、萜类可任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代。所述C6-C14芳基优选取代或未取代的苯基、萘基、联苯基、蒽基等苯环衍生物。其中，取代的苯基优选为烷氧基取代的苯基(例如甲氧基苯基)、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基。所述卤代苯基可为单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基。所述萜类优选为单萜、倍半萜、二萜或三萜。
其中，所述C2-C8杂环基可为C2-C8杂环烷基或者C2-C8杂环芳基，优选为吡咯基、嘧啶基、苯并呋喃基、四氢呋喃基、四氢噻吩基、六氢吡啶基、四氢吡咯基、二氢苯并噻吩基、二氢苯并呋喃基、二氢吲哚基、噻吩基、苯并噻吩基、呋喃基、吡啶基或吲哚基。
优选地，所述R1’为直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基、C6-C14芳基或萜类可任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基或亚砜基所取代。
进一步优选地，R1’为直链或支链C2-C16烷基、C3-C8环烷基、含氧和/或硫的C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C2-C16烷基、C3-C8环烷基、含氧和/或硫的C2-C8杂环基、C6-C14芳基或萜类可任选地被苯基、噻吩基、呋喃基、酯基、醚基或硫醚基所取代。
本发明中，含有伯醇基团的反应物优选为苯丙醇、对甲氧基苄醇、1-萘甲醇、4-(三氟甲基)苄醇、肉桂醇、2-溴苯乙醇、2-(4-苯甲氧基苯基)乙醇、 2-环戊基乙醇、四氢吡喃-4-甲醇、1-Boc-3-羟甲基吡咯烷、N-Boc-4-哌啶甲醇、 1-金刚烷甲醇、(1-苯基环己基)甲醇、2-(4-乙氧基苯基)-2-甲基丙醇、2,2-二甲基-3-(间甲苯基)丙-1-醇、N-Boc-4-哌啶甲醇、呋喃-3-甲醇、2-(苄氧基)乙醇、苯并噻吩-2-甲醇、2-苯硫基乙醇、2-氨基-3-羟甲基吡啶、3-吡啶丙醇、 3-(二甲基氨基)苄醇、1-(2-喹啉基)乙-1-醇、3-吲哚乙醇、油醇、香茅醇、10- 十一烯-1-醇、5-苯基-4-戊炔-1-醇、果糖二丙酮、(2R,3R,4S,5R,6S)-4,5-双 (苄氧基)-2-(羟甲基)-6-甲氧基四氢-2H-吡喃-3-醇、3-(4-甲氧基苯基)丙烷-1,2- 二醇、石胆醇、鹅去氧胆醇、(R)-亚磺酰胺的伯醇或(S)-亚磺酰胺的伯醇等。
本发明中，含有醛基的反应物通式优选R2’CHO；其中，R2’为直链或支链C1-C17烷基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类。所述直链或支链C1-C17烷基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类可任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代。所述C6-C14芳基优选取代或未取代的苯基、萘基、联苯基、蒽基等苯环衍生物。其中，取代的苯基优选为烷氧基取代的苯基(例如甲氧基苯基)、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基。所述卤代苯基可为单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基。所述萜类优选为单萜、倍半萜、二萜或三萜。
所述C2-C8杂环基可为C2-C8杂环烷基或者C2-C8杂环芳基，优选为呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、苯并噻吩基、苯并呋喃基、吲哚基、四氢呋喃基、四氢噻吩基、六氢吡啶基、四氢吡咯基、二氢苯并噻吩基、二氢苯并呋喃基或二氢吲哚基。
优选地，所述R2’为直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基。所述直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基可任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代。
本发明中，含有醛基的反应物优选为多芳基取代的甲醛、含杂环取代的甲醛、含多种取代基的不饱和醛或C2-C17烷基脂肪醛。所述含多种取代基的不饱和醛可指含有羟基、甲氧基、噻吩基、苯并噻吩基、苯硫基、呋喃基、吡啶基、吲哚基、胺基苯基或酚氧基的不饱和醛。所述C2-C17烷基脂肪醛可被羟基、甲氧基、噻吩基、苯并噻吩基、苯硫基、呋喃基、吡啶基、吲哚基、胺基苯基或酚氧基所取代。所述多芳基取代的甲醛中，芳基可以相同或不同。所述芳基优选C6-C14芳基，进一步优选取代或未取代的苯基、萘基、联苯基、蒽基等苯环衍生物；其中，取代的苯基优选为烷氧基取代的苯基(例如甲氧基苯基)、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基。所述卤代苯基可为单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基。
本发明中，所述含有伯醇基团或醛基的反应物可以带有手性，经过本发明方法制备得到相应的羧酸后，手性保留，立体产物收率很高，手性专一性强，优选地为
Figure BDA0003144288210000071
Figure BDA0003144288210000081
本发明方法优选包括如下步骤：在常压60～80℃下，有机溶剂中，1-羟基环己基苯基甲酮作为氧化剂，第一主族元素、第二主族元素、第三主族元素或过渡金属元素的氢氧化物(如氢氧化钠)作碱，将含有伯醇基团或醛基的反应物中的伯醇基团或醛基氧化成相应的羧基。
本发明方法可将同时含有碳碳单键，碳碳双键，碳碳三键、酰胺、胺、亚磺酰基、亚砜、硫醚等多种官能团的伯醇或醛基化合物中的伯醇基或醛基选择性地氧化，生成相应的羧酸，而除伯醇或醛基以外的其他基团不受氧化。
本发明中，当反应物中同时存在醛基和仲醇基团时，仅氧化醛基到羧酸基团；当反应物中同时存在伯醇基团和仲醇基团时，仅氧化伯醇到羧酸基团，而不氧化仲醇。
本发明中，当反应物中同时存在醛基和伯醇基团时，若氧化剂的当量为 1，则主要氧化醛基，若氧化剂的当量大于2，则可同时氧化醛基和伯醇基。
本发明具有反应条件温和、产率高、操作简单、分离纯化方便、底物官能团兼容性好、反应过程环境友好、氧化剂可再生利用等诸多优点，既可用于小规模实验室合成，也适合工业化生产。
本发明具有底物适用性广的优点，可用于氧化结构比较复杂的伯醇，如含有酰胺基、醚基、卤素、苯基、杂环基、炔基、双键、亚磺酰基、亚砜基等官能团的伯醇，甚至萜类、生物碱及甾体结构亦可在本发明条件下兼容。
本发明采用邻位具有叔羟基的酮，特别是廉价的1-羟基环己基苯基甲酮作为氧化剂，替代传统氧化剂体系中所使用的氧化剂。所用无机氢氧化物均为工业易得原料。在反应结束后，所用氧化剂1-羟基环己基苯基甲酮被还原为1-羟基环己基苯甲醇，该化合物可以通过单过硫酸氢钾复合盐(oxone) 和溴化钾在乙腈溶剂中氧化再生出氧化剂1-羟基环己基苯基甲酮。整个反应过程操作简便、后处理简单、产物收率高、经济环保，是一种绿色化学合成方法。
在本发明条件下，仲醇或叔醇与伯醇同时存在时可以选择性氧化伯醇成羧酸。这一优点为同时含有伯醇和仲醇的药物合成以及天然产物改造提供了一种绿色环保、低成本、高效的合成新方法。
具体实施方式
结合以下实施例，对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域内的普通知识和公共常识，本发明没有特别限制内容。
实施例1:苯丙酸的合成
Figure BDA0003144288210000101
将1-羟基环己基苯基甲酮(408.5mg,99％纯度，2mmo1)，氢氧化钠(80.0 mg,>95％纯度,2mmol)，苯丙醇(139.0mg,98％纯度，1mmol)和乙二醇二甲醚(DME,1.5mL)加入到8mL反应瓶中。80℃搅拌至薄层层析TLC监测反应完成。反应完毕后，加入水(30mL)，用乙醚萃取3次(30mL/次)，合并有机相，饱和NaCl溶液洗涤后，加无水硫酸钠干燥，过滤除去干燥剂，减压蒸馏回收乙醚，蒸馏后将得到的还原粗产物1-羟基环己基苯甲醇收集回收用于再生利用。将水相加入HCl(12M,166.7μl,2mmol)酸化，用乙醚萃取3 次(30mL/次)，合并有机相，蒸干得到粗产物。该粗产品可重结晶或通过柱层析(石油醚：乙酸乙酯：醋酸＝5:1：0.1)得到纯的苯丙酸(145.7mg,97％)。1H-NMR(600MHz,CDCl3)δ10.88(brs,1H),7.32–7.22(m,5H),2.98(t,J＝ 7.8Hz,2H),2.70(t,J＝7.8Hz,2H).13C-NMR(151MHz,CDCl3)δ179.2,140.3,130.3,128.7,128.6,128.4,126.5,35.7,30.7.
实施例2：对甲氧基苯甲酸的合成
Figure BDA0003144288210000111
其他操作参考实施例1，所用原料为对甲氧基苄醇，反应时间为6小时，得到对甲氧基苯甲酸(144.5mg,95％)。1H-NMR(400MHz,CDCl3)δ8.07(d,J ＝8.8Hz,2H),6.95(d,J＝8.8Hz,2H),3.88(s,3H).13C-NMR(100MHz,CDCl3) δ171.9,164.2,132.5,121.8,113.9,55.6.
实施例3：1-萘甲酸的合成
Figure BDA0003144288210000112
其他操作参考实施例1，所用原料为1-萘甲醇，反应时间为5小时，得到1-萘甲酸(142.4mg,90％)。1H-NMR(600MHz,DMSO-d6)δ13.13(s,1H), 8.87(d,J＝8.4Hz,1H),8.16–8.14(m,2H),8.01(d,J＝8.4Hz,1H),7.65–7.57 (m,3H).13C-NMR(150MHz,DMSO-d6)δ168.7,133.5,132.9,130.7,129.8, 128.6,127.5,126.1,125.5,124.8.
实施例4：4-(三氟甲基)苯甲酸的合成
Figure BDA0003144288210000113
其他操作参考实施例1，所用原料为4-(三氟甲基)苄醇，反应时间为3小时，得到4-(三氟甲基)苯甲酸(186.2mg,98％)。1H-NMR(600MHz,DMSO- d6)δ13.42(brs,1H),8.12(d,J＝8.4Hz,2H),7.83(d,J＝7.8Hz,2H).13C-NMR (150MHz,DMSO)δ166.2,134.7,132.2-132.8(m),130.1,125.5,122.9,121.1.
实施例5：肉桂酸的合成
Figure BDA0003144288210000121
其他操作参考实施例1，所用原料为肉桂醇，反应时间为30分钟，得到肉桂酸(120.8mg,90％)。1H-NMR(400MHz,CDCl3)δ7.81(d,J＝16.0Hz,1H), 7.57(m,2H),7.44-7.37(m,3H),6.47(d,J＝16.0Hz,1H).13C-NMR(100MHz, CDCl3)δ172.7,147.3,134.2,130.9,129.1,128.5,117.5.
实施例6：2-溴苯乙酸的合成
Figure BDA0003144288210000122
其他操作参考实施例1，所用原料为2-溴苯乙醇，反应时间为30小时，得到2-溴苯乙酸(150.5mg,70％)。1H-NMR(600MHz,CDCl3)δ7.59(d,J＝7.8 Hz,1H),7.32-7.27(m,2H),7.18-7.13(m,1H),3.86(s,2H).13C-NMR(150MHz, CDCl3)δ176.9,133.7,133.0,131.7,129.3,127.7,125.2,41.5.
实施例7：4-苄氧基苯乙酸的合成
Figure BDA0003144288210000131
其他操作参考实施例1，所用原料为2-(4-苯甲氧基苯基)乙醇，反应时间为30小时，得到4-苄氧基苯乙酸(169.6mg,70％)。1H-NMR(400MHz,CDCl3) δ7.35-7.33(m,2H),7.31-7.27(m,2H),7.25-7.25(m,1H),7.11(d,J＝8.8Hz, 2H),6.85(d,J＝8.8Hz,2H),4.96(s,2H),3.50(s,2H).13C-NMR(100MHz, CDCl3)δ178.3,158.15,137.0,130.49,128.6,128.0,127.5,125.7,115.1,70.1, 40.2.
实施例8：2-环戊基乙酸的合成
Figure BDA0003144288210000132
其他操作参考实施例1，所用原料为2-环戊基乙醇，反应时间为30小时，得到2-环戊基乙酸(103.9mg,91％)。1H-NMR(400MHz,CDCl3)δ2.36(d, J＝7.4Hz,2H),2.23-2.17(m,1H),1.89-1.81(m,2H),1.67-1.50(m,4H),1.22- 1.13(m,2H).13C-NMR(100MHz,CDCl3)δ180.2,40.3,36.4,32.5,25.1.
实施例9：四氢吡喃-4-甲酸的合成
Figure BDA0003144288210000133
其他操作参考实施例1，所用原料为四氢吡喃-4-甲醇，反应时间为30小时，得到四氢吡喃-4-甲酸(123.6mg,95％).1H-NMR(400MHz,CDCl3)δ9.52 (s,1H),3.98(dt,J＝11.6,3.6Hz,2H),3.45(td,J＝11.2,2.8Hz,2H),2.61-2.54 (m,1H),1.89-1.74(m,4H).13C-NMR(100MHz,CDCl3)δ180.4,67.1,39.9, 28.5.
实施例10：1-Boc-吡咯烷-3-甲酸的合成
Figure BDA0003144288210000141
其他操作参考实施例1，所用原料为1-Boc-3-羟甲基吡咯烷，反应时间为30小时，得到1-Boc-吡咯烷-3-甲酸(140mg,65％).1H-NMR(400MHz, CDCl3)δ10.57(s,1H),3.64-3.37(m,3H),3.32(s,1H),3.11-2.96(m,1H),2.11 (s,2H),1.41(s,9H).13C-NMR(100MHz,CDCl3)δ177.7,177.5,80.0,48.1,47.9, 45.5,45.1,43.2,42.4,28.8,28.5,28.2.
实施例11：1-(叔丁氧羰基)哌啶-4-羧酸的合成
Figure BDA0003144288210000142
其他操作参考实施例1，所用原料为N-Boc-4-哌啶甲醇，反应时间为30 小时，得到1-(叔丁氧羰基)哌啶-4-羧酸(201.8mg,88％)。1H-NMR(400MHz, CDCl3)δ10.56(brs,1H),4.00(brs,2H),2.83(t,J＝11.6Hz,2H),2.49-2.42(m, 1H),1.87(d,J＝10.4Hz,2H),1.65-1.57(m,2H),1.43(s,9H).13C-NMR(100 MHz,CDCl3)δ180.1,154.9,80.0,43.0,40.9,28.5,27.8.
实施例12：1-金刚烷羧酸的合成
Figure BDA0003144288210000151
其他操作参考实施例1，所用原料为1-金刚烷甲醇，反应时间为4天，得到1-金刚烷羧酸(165.8mg,92％)。1H-NMR(600MHz,CDCl3)δ2.02(brs, 3H),1.91(d,J＝3Hz,6H),1.74–1.65(m,6H).13C-NMR(150MHz,CDCl3)δ 184.3,40.6,38.7,36.6,28.0.
实施例13：1-苯基-1-环己羧酸的合成
Figure BDA0003144288210000152
其他操作参考实施例1，所用原料为(1-苯基环己基)甲醇，反应24小时，得到1-苯基-1-环己羧酸(183.8mg,90％)。1H-NMR(600MHz,CDCl3)δ11.47 (s,1H),7.48–7.42(m,2H),7.36–7.28(m,2H),7.27–7.19(m,1H),2.58–2.39 (m,2H),1.84–1.72(m,2H),1.71–1.64(m,2H),1.64–1.58(s,1H),1.57–1.48 (m,2H)1.34–1.22(m,1H).13C-NMR(150MHz,CDCl3)δ182.0,143.1,128.7, 127.1,126.3,50.6,34.4,25.7,23.7.
实施例14：2-(4-乙氧基苯基)-2-甲基丙酸
Figure BDA0003144288210000153
其他操作参考实施例1，所用原料为2-(4-乙氧基苯基)-2-甲基丙醇，反应时间为3天，得到2-(4-乙氧基苯基)-2-甲基丙酸(187.4mg,90％)。1H-NMR (400MHz,CDCl3)δ7.23(d,J＝7.2Hz,2H),6.77(d,J＝8.4Hz,2H),3.93(q,J ＝6.8Hz,2H),1.48(s,6H),1.31(t,J＝6.8Hz,3H).13C-NMR(100MHz,CDCl3) δ183.6,158.0,135.9,127.1,114.5,63.6,45.7,26.4,15.0.HRMS(ESI-TOF)m/z [M+Na]+calcd for C12H16O3 231.0991,found 231.0992.
实施例15：2,2-二甲基-3-(间甲苯基)丙酸的合成
Figure BDA0003144288210000161
其他操作参考实施例1，所用原料为2,2-二甲基-3-(间甲苯基)丙-1-醇，反应时间为3天，得到2,2-二甲基-3-(间甲苯基)丙酸(165.3mg,86％)。1H- NMR(400MHz,CDCl3)δ7.15(t,J＝8.0Hz,1H),7.03(d,J＝7.2Hz,1H),6.97 (s,1H),6.96(d,J＝7.2Hz,2H),2.85(s,2H),2.30(s,3H),1.19(s,6H).13C-NMR (100MHz,CDCl3)δ184.9,137.6,137.6,131.2,128.0,127.4,45.9,43.6,24.77, 21.5.HRMS(ESI-TOF)m/z[M+Na]+calcd for C12H16O2215.1044,found 215.1043.
实施例16：1-Boc-4-甲基-4-哌啶甲酸的合成
Figure BDA0003144288210000162
其他操作参考实施例1，所用原料为N-Boc-4-哌啶甲醇，反应时间为42 小时，得到1-Boc-4-甲基-4-哌啶甲酸(231.1mg,95％)。1H-NMR(400MHz, CDCl3)δ10.01(brs.1H),3.75(brs,2H),3.04(t,J＝11.6Hz,2H),2.05(d,J＝13.6 Hz,2H),1.43(s,9H),1.41–1.32(m,2H),1.25(s,3H).13C-NMR(100MHz, CDCl3)δ182.8,155.1,79.8,41.7,41.2,34.4,28.6,25.9.
实施例17：3-糠酸的合成
Figure BDA0003144288210000171
其他操作参考实施例1，所用原料为呋喃-3-甲醇，反应时间为5小时，得到3-糠酸(93.4mg,86％)。1H-NMR(600MHz,CDCl3)δ10.24(brs,1H),8.12 (d,J＝0.6Hz,1H),7.46(t,J＝1.8Hz,1H),6.78(dd,J＝1.8,0.6Hz,1H).13C- NMR(150MHz,CDCl3)δ168.9,149.3,144.2,119.0,110.0.
实施例18：2-(苄氧基)乙酸的合成
Figure BDA0003144288210000172
其他操作参考实施例1，所用原料为2-(苄氧基)乙醇，反应时间为30小时，得到2-(苄氧基)乙酸(141.3mg,85％)。1H-NMR(600MHz,CDCl3)δ9.92 (s,1H),7.38–7.32(m,5H),4.65(s,2H),4.16(s,2H).13C-NMR(150MHz,CDCl3) δ175.5,136.7,128.6,128.3,128.2,73.5,66.6.
实施例19：苯并噻吩-2-羧酸的合成
Figure BDA0003144288210000173
其他操作参考实施例1，所用原料为苯并噻吩-2甲醇，反应时间为5小时，得到苯并噻吩-2-羧酸(171.1mg,96％)。1H-NMR(400MHz,DMSO-d6)δ 13.45(brs,1H),8.11(s,1H),8.05–7.99(m,2H),7.53–7.43(m,2H).13C-NMR (100MHz,DMSO-d6)δ163.5,141.3,138.7,134.7,130.2,127.0,125.7,125.0, 123.0.
实施例20：苯硫基乙酸的合成
Figure BDA0003144288210000181
其他操作参考实施例1，所用原料为2-苯硫基乙醇，反应时间为30小时，得到苯硫基乙酸(153.2mg,91％)。1H-NMR(400MHz,CDCl3)δ9.87(s, 1H),7.31(m,J＝7.4Hz,2H),7.23–7.16(m,2H),7.13(m,1H),3.55(s,2H).13C- NMR(100MHz,CDCl3)δ175.9,134.6,130.0,129.2,127.2,36.6.
实施例21：2-氨基烟酸的合成
Figure BDA0003144288210000182
其他操作参考实施例1，所用原料为2-氨基-3-羟甲基吡啶，反应时间为 3.5小时，得到2-氨基烟酸(134.0mg,97％)。1H-NMR(600MHz,DMSO-d6)δ 8.16(dd,J＝4.2,1.2Hz,1H),8.03(dd,J＝7.8,1.2Hz,1H),6.59(dd,J＝7.2,4.8 Hz,1H).13C-NMR(150MHz,DMSO-d6)δ168.7,159.8,153.3,140.1,111.8, 105.8.
实施例22：3-(3-吡啶基)丙酸的合成
Figure BDA0003144288210000191
其他操作参考实施例1，所用原料为3-吡啶丙醇，反应时间为30小时，得到3-(3-吡啶基)丙酸(143.6mg,95％)。1H-NMR(400MHz,DMSO-d6)δ8.47 (s,1H),8.41(d,J＝3.6Hz,1H),7.67(d,J＝8.0Hz,1H),7.31(dd,J＝7.6,4.8Hz, 1H),2.84(t,J＝7.6Hz,2H),2.55(t,J＝7.6Hz,2H).13C-NMR(100MHz,DMSO- d6)δ174.0,149.6,147.2,136.7,135.9,123.4,35.4,27.8.
实施例23：间二甲氨基苯甲酸的合成
Figure BDA0003144288210000192
其他操作参考实施例1，所用原料为3-(二甲基氨基)苄醇，反应时间为 5小时，得到间二甲氨基苯甲酸(148.7mg,90％)。1H-NMR(400MHz,DMSO- d6)δ12.76(brs,1H),7.31–7.16(m,3H),6.95(d,J＝8.0Hz,1H),2.93(s,6H). 13C-NMR(100MHz,DMSO-d6)δ167.9,150.28,131.3,129.0,116.9,116.5, 112.4,40.0.
实施例24：喹啉-2-羧酸的合成
Figure BDA0003144288210000193
其他操作参考实施例1，所用原料为1-(2-喹啉基)乙-1-醇，反应时间为5 小时，得到喹啉-2-羧酸(169.7mg,83％)。1H-NMR(400MHz,DMSO-d6)δ8.48 (d,J＝8.5Hz,1H),8.19(d,J＝8.4Hz,1H),8.13(d,J＝8.5Hz,1H),8.04(d,J＝8.1Hz,1H),7.82(t,J＝7.6Hz,1H),7.68(t,J＝7.4Hz,1H).13C-NMR(100MHz, DMSO-d6)δ167.2,151.5,146.8,137.2,130.1,129.8,128.5,128.0,127.9,121.0.
实施例25：3-吲哚乙酸的合成
Figure BDA0003144288210000201
其他操作参考实施例1，所用原料为3-吲哚乙醇，反应时间为24小时，得到3-吲哚乙酸(105.1mg,60％)。1H-NMR(600MHz,CD3OD)δ7.56(d,J＝ 8.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.13–7.10(m,1H),7.10(s,1H)7.05–7.02 (m,1H),4.98(s,1H),3.74(s,2H).13C-NMR(150MHz,CD3OD)δ176.5,137.8, 128.5,124.6,122.5,119.9,119.4,112.2,108.8,31.9
实施例26：油酸的合成
Figure BDA0003144288210000202
其他操作参考实施例1，所用原料为油醇，反应时间为30小时，得到油酸(257mg,91％)。1H-NMR(400MHz,CDCl3)δ5.36(m,2H),2.35(t,J＝7.6 Hz,2H),2.01–1.97(m,4H),1.65–1.55(m,2H),1.31–1.26(d,20H),0.88(t,J ＝6.4Hz,3H).13C-NMR(100MHz,CDCl3)δ179.7,130.2,129.9,34.1,32.1, 29.9,29.8,29.8,29.5,29.3,29.22,29.19,27.4,27.3,24.8,22.8,14.3.
实施例27：香茅酸的合成
Figure BDA0003144288210000211
其他操作参考实施例1，所用原料为香茅醇，反应时间为30小时，得到香茅酸(136.2,mg,80％)。1H-NMR(400MHz,DMSO-d6)δ12.13(brs,1H),5.06 (t,J＝7.2Hz,1H),2.20(dd,J＝15.2,6.0Hz,1H),2.02–1.90(m,3H),1.86– 1.78(m,1H),1.64(s,3H),1.56(s,3H),1.34–1.27(m,1H),1.20–1.10(m,1H), 0.88(d,J＝6.8Hz,3H).13C-NMR(100MHz,DMSO-d6)δ173.9,130.7,124.3, 41.3,36.2,29.3,25.5,25.0,19.4,17.5.
实施例28：10-十一烯酸的合成
Figure BDA0003144288210000212
其他操作参考实施例1，所用原料为10-十一烯-1-醇，反应时间为30小时，得到10-十一烯酸(147.4mg,80％)。1H-NMR(400MHz,CDCl3)δ5.91– 5.75(m,2H),5.01–4.90(m,2H),2.35(t,J＝7.2Hz 2H),2.05–1.97(m,2H), 1.66–1.61(m,2H),1.36–1.30(m,10H).13C-NMR(100MHz,CDCl3)δ180.78, 139.20,114.26,34.25,33.89,29.37,29.29,29.15,29.00,24.76.
实施例29：5-苯基戊-4-炔酸的合成
Figure BDA0003144288210000221
其他操作参考实施例1，所用原料为5-苯基-4-戊炔-1-醇，反应时间为30 小时，得到5-苯基戊-4-炔酸(149.8mg,86％)。1H-NMR(400MHz,CDCl3)δ 7.41–7.39(m,2H),7.29–7.28(m,3H),2.78–2.69(m,4H).13C-NMR(100MHz, CDCl3)δ178.4,131.8,128.4,128.0,123.5,87.7,81.5,33.6,15.2.
实施例30：果糖二丙酮酸的合成
Figure BDA0003144288210000222
其他操作参考实施例1，所用原料为果糖二丙酮，反应时间为4天，得到果糖二丙酮酸(219.6mg,80％，ee值大于98％)。1H-NMR(600MHz,CDCl3) δ4.66(d,J＝3.0Hz,1H),4.61(dd,J＝7.8,3.0Hz,1H),4.24(d,J＝7.8Hz,1H), 3.92–3.86(m,2H),1.53(s,3H),1.46(s,3H),1.42(s,3H),1.31(s,3H).13C-NMR (150MHz,CDCl3)δ169.3,111.2,109.60,99.1,77.4,77.2,76.9,72.8,61.8,26.2, 25.8,24.5,24.1.
实施例31：甲基2,3-二-O-苄基-α-D-吡喃葡萄糖苷的合成
Figure BDA0003144288210000223
其他操作参考实施例1，所用原料为(2R,3R,4S,5R,6S)-4,5-双(苄氧基)- 2-(羟甲基)-6-甲氧基四氢-2H-吡喃-3-醇,反应时间为12小时，得到甲基2,3- 二-O-苄基-α-D-吡喃葡萄糖苷(310.7mg,80％，ee值大于98％)。
Figure BDA0003144288210000233
(c 0.66,MeOH).1H-NMR(600MHz,CD3OD)δ7.38–7.26(m,10H),4.88(d,J ＝10.8Hz,1H),4.81(d,J＝11.4Hz,1H),4.77(d,J＝3.6Hz,1H),4.73–4.60(m, 2H),4.01(d,J＝9.6Hz,1H),3.75–3.68(m,2H),3.52(dd,J＝9.0,3.0Hz,1H), 3.41(s,3H).13C-NMR(150MHz,CD3OD)δ173.2,140.2,139.6,129.4,129.2, 129.0,128.9,128.5,99.8,82.3,80.6,76.5,74.2,73.4,72.5,55.9.
实施例32：2-羟基-3-(4-甲氧基苯基)丙酸的合成
Figure BDA0003144288210000231
其他操作参考实施例1，所用原料为3-(4-甲氧基苯基)丙烷-1,2-二醇，反应时间为12小时，得到2-羟基-3-(4-甲氧基苯基)丙酸(180.5mg,92％)。1H- NMR(600MHz,DMSO-d6)δ12.49(brs,1H),7.14(d,J＝8.4Hz,2H),6.82(d, J＝8.4Hz,2H),5.26(brs,1H),4.10(dd,J＝7.8,4.2Hz,1H),3.71(s,3H),2.89 (dd,J＝13.8,4.2Hz,1H),2.72(dd,J＝13.7,8.4Hz,1H).13C-NMR(100MHz, DMSO-d6)δ175.2,157.7,130.34,129.9,113.4,71.2,55.0,39.1.
实施例33：石胆酸的合成
Figure BDA0003144288210000232
将1-羟基环己基苯基甲酮(408.5mg,99.95％纯度，2mmo1)，氢氧化钠(80.0mg,99.99％纯度，2mmol，ee值大于98％)，石胆醇(360.57mg，1mmol) 和吡啶(1.5mL)加入到8mL反应瓶中。80℃搅拌30小时，TLC监测直至反应完成。反应完毕后，将小瓶冷却至室温，用2NHCl酸化至pH＝2，然后用乙醚(3×30mL)萃取。合并的有机层用盐水(30mL)洗涤，经无水Na2SO4干燥，过滤，并真空浓缩。残余物通过快速色谱纯化(石油醚：乙酸乙酯：乙酸)，得到纯的石胆酸(338.00mg,90％，为白色固体)。1H-NMR(600MHz, CD3OD)δ3.57–3.47(m,1H),2.32(m,1H),2.22–2.11(m,1H),2.01(m,1H), 1.94–1.83(m,2H),1.78(m,3H),1.66–1.54(m,2H),1.50–1.34(m,7H),1.28 (m,5H),1.22–1.04(m,5H),0.99(dd,J＝14.2,3.3Hz,1H),0.96–0.90(m,6H), 0.69(s,3H).13C-NMR(150MHz,CD3OD)δ178.1,72.4,57.9,57.5,43.9,43.6, 41.9,41.5,37.3,37.2,36.69,36.5,35.7,32.3,32.0,31.2,29.2,28.4,27.7,25.3,24.0,22.0,18.8,12.5.
实施例34：鹅去氧胆酸的合成
Figure BDA0003144288210000241
其他操作参考实施例1，所用原料为鹅去氧胆醇，反应时间为3天，得到鹅去氧胆酸(353.3mg,90％，ee值大于98％)。1H-NMR(600MHz,CD3OD) δ3.80–3.78(m,1H),3.40–3.34(m,1H),2.35–2.17(m,3H),2.00–0.97(m, 30H),0.95(d,J＝6.6Hz,3H),0.90(s,3H),0.69(s,3H).13C-NMR(150MHz, CD3OD)δ178.1,72.8,69.0,57.3,51.5,43.7,43.2,41.0,40.8,40.4,36.7,36.6, 36.2,35.9,34.0,32.3,32.0,31.4,29.2,24.6,23.4,21.8,18.8,12.2。
实施例35：(R)-4-(((R)-叔丁基亚磺酰基)(甲基)氨基)-4-苯基丁酸的合成
Figure BDA0003144288210000251
将1-羟基环己基苯基甲酮(408.5mg,99％纯度，2mmo1),氢氧化钠(80.0 mg,>95％纯度，2mmol，ee值大于98％),(R)-N-((R)-4-羟基-1-苯基丁基)-N， 2-二甲基丙烷-2-亚磺酰胺(283.4mg，1mmol)和乙二醇二甲醚(DME,1.5mL) 加入到8mL反应瓶中。80℃搅拌18小时，TLC监测直至反应完成。反应完毕后，加入水(30mL)，用乙醚萃取3次(30mL/次)，合并有机相，饱和NaCl 溶液洗涤后，加无水硫酸钠干燥，过滤除去干燥剂，减压蒸馏回收乙醚。蒸馏后将得到的还原粗产物1-羟基环己基苯甲醇收集回收。将水相用弱酸性离子交换树脂酸化至弱酸性后过滤树脂，减压蒸馏除去溶剂后，残余物通过快速色谱纯化(石油醚：乙酸乙酯：甲醇)，得到(R)-4-(((R)-叔丁基亚磺酰基)(甲基)氨基)-4-苯基丁酸(270.6mg,91％)。
Figure BDA0003144288210000253
(c 0.87,CHCl3).1H-NMR (400MHz,CDCl3)δ9.76(brs,1H),7.29–7.25(m,4H),7.24–7.18(m,1H),4.29 (t,J＝8.0Hz,1H),2.40(s,3H),2.36–2.29(m,1H),2.27–2.23(m,2H),2.20– 2.12(m,1H),1.11(s,9H).13C-NMR(100MHz,CDCl3)δ177.1,138.9, 128.7,128.1,66.0,58.9,31.4,28.1,27.5,24.0.HRMS(ESI-TOF)m/z[M+Na]+ calcd forC15H23NO3S 320.1286,found 320.1291。
实施例36：噻吩-2-甲酸的合成
Figure BDA0003144288210000252
将1-羟基环己基苯基甲酮(204.3mg,99％纯度，1mmo1)，氢氧化钠(80.0 mg,>95％纯度，2mmol)，2-噻吩甲醛(112.15mg,1mmol)和乙二醇二甲醚 (DME,1.5mL)加入到8mL反应瓶中。80℃搅拌0.5h，TLC监测直至反应完成。反应完毕后，加入水(30mL)，用乙醚萃取3次(30mL/次)，合并有机相，饱和NaCl溶液洗涤后，加无水硫酸钠干燥，过滤除去干燥剂，减压蒸馏回收乙醚，蒸馏后将得到的还原粗产物1-羟基环己基苯甲醇收集回收。将水相加HCl(12M,166.7ul,2mmol)酸化，用乙醚萃取3次(30mL/次)，合并有机相，蒸干得到粗产物。该粗产物通过硅胶柱层析(石油醚：乙酸乙酯：醋酸＝5:1:0.1)得到相应的噻吩-2-甲酸(106.4mg,83％)。1H-NMR(400MHz, CDCl3)δ9.40(brs,1H),7.91(dd,J＝3.6,1.2Hz,1H),7.66(dd,J＝5.2,1.2Hz, 1H),7.15(dd,J＝4.8,3.6Hz,1H).13C-NMR(100MHz,CDCl3)δ167.9,135.2, 134.2,133.0,128.2。
实施例38：异烟酸的合成
Figure BDA0003144288210000261
其他操作参考实施例36，所用原料为4-吡啶甲醛，反应时间为3小时，得到异烟酸(110.8mg,90％)。1H-NMR(400MHz,DMSO-d6)δ8.70(d,J＝4.5 Hz,2H),7.79(d,J＝4.5Hz,2H).13C-NMR(100MHz,DMSO-d6)δ167.02, 150.21,140.88,122.90。
实施例39：4-(1H-咪唑-1-基)苯甲酸的合成
Figure BDA0003144288210000262
其他操作参考实施例36，所用原料为4-(咪唑-1-基)苯甲醛，反应时间为 2小时，得到4-(1H-咪唑-1-基)苯甲酸(171.3mg,91％)。1H-NMR(400MHz, DMSO-d6)δ8.39(brs,1H),8.06(d,J＝8.4Hz,2H),7.85(brs,1H),7.76(d,J＝ 8.4Hz,2H),7.13(brs,1H).13C-NMR(100MHz,DMSO-d6)δ167.8,139.5,135.7, 131.0,130.2,119.6,117.9。
实施例40：环戊酸的合成
Figure BDA0003144288210000271
其他操作参考实施例36，所用原料为环戊基甲醛，反应时间为18小时，得到环戊酸(113mg,99％)。1H-NMR(400MHz,CDCl3)δ10.56(s,1H),2.80– 2.72(m,1H),1.95–1.78(m,4H),1.74–1.66(m,2H),1.60–1.57(m,2H).13C- NMR(100MHz,CDCl3)δ183.6,43.8,30.1,25.9。
实施例41：4-二甲氨基苯甲酸的合成
Figure BDA0003144288210000272
其他操作参考实施例36，所用原料为对二甲胺基苯甲醛，反应时间为5 小时，得到4-二甲氨基苯甲酸(148.7mg,90％)。1H-NMR(400MHz,CDCl3)δ 7.97(d,J＝9.2Hz,2H),6.66(d,J＝8.8Hz,2H),3.06(s,6H).13C-NMR(100 MHz,CDCl3)δ172.2,154.0,132.2,116.0,110.8,40.2.
实施例42：(R)-(+)-香茅酸的合成
Figure BDA0003144288210000281
其他操作参考实施例36，所用原料为(R)-(+)-香茅醛，反应时间为2天，得到(R)-(+)-香茅酸(119.2mg,70％,ee值98％)。1H-NMR(400MHz,DMSO- d6)δ12.18(s,1H),5.07(t,J＝7.2Hz,1H),2.20(dd,J＝15.2,6.0Hz,1H),2.02 –1.90(m,3H),1.84–1.79(m,1H),1.64(s,3H),1.56(s,3H),1.41–1.21(m,2H), 1.17–1.11(m1H),0.88(d,J＝6.8Hz,3H).13C-NMR(100MHz,DMSO-d6)δ 173.9,130.7,124.3,41.2,36.2,29.3,25.5,24.91,19.4,17.5。

Claims (19)

1.一种羧酸的制备方法，其特征在于，包括如下步骤：在溶剂中，式I化合物作为氧化剂，在强碱的存在下，将含有伯醇基团或醛基的反应物中的伯醇基团或醛基氧化成相应的羧基；
Figure FDA0003144288200000011
其中，
所述的强碱为第一主族元素、第二主族元素、第三主族元素或过渡金属元素的氢氧化物；
R1和R2各自独立地为C1-C3烷基，或者R1和R2与其相连的原子共同形成5-6元碳环；
n为0、1、2、3或4；
R3为H、C1-C3烷基、C1-C3烷氧基或卤素。
2.如权利要求1所述的制备方法，其特征在于，所述式I化合物中，R1和R2与其相连的原子共同形成5-6元碳环；优选地形成环己烷；
和/或，所述n为0或1；
和/或，所述R3为H、甲基、乙基、异丙基、甲氧基、乙氧基、丙氧基、氟、氯或溴；优选为H；
当n≥2时，各R3相同或不同。
3.如权利要求2所述的制备方法，其特征在于，所述式I化合物为1-羟基环己基苯基甲酮，即
Figure FDA0003144288200000012
4.如权利要求1-3中任一项所述的制备方法，其特征在于，
当反应物含有伯醇基团时，所述氧化剂与含有伯醇基团的反应物的摩尔比等于或大于2:1；优选为2:1-3:1，更优选2:1；
当反应物含有醛基时，所述氧化剂与含有醛基的反应物的摩尔比等于或大于1:1；优选为1:1-2:1，更优选为1:1。
5.如权利要求1-3中任一项所述的制备方法，其特征在于，所述第一主族元素的氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯中的一种或多种；所述第二主族元素的氢氧化物选自氢氧化钙、氢氧化镁和氢氧化钡中的一种或多种；所述第三主族元素的氢氧化物选自氢氧化铝；所述过渡金属的氢氧化物选自氢氧化铜、氢氧化铁、氢氧化锌和氢氧化钯中的一种或多种。
6.如权利要求5所述的制备方法，其特征在于，所述强碱为氢氧化钠和/或氢氧化钾。
7.如权利要求1-3中任一项所述的制备方法，其特征在于，
当反应物含有伯醇基团时，所述强碱与含有伯醇基团的反应物的摩尔比优选2:1-3:1；更优选为2:1；
当反应物含有醛基时，所述强碱与含有醛基的反应物的摩尔比优选1.5:1-2:1，优选2:1。
8.如权利要求1-3中任一项所述的制备方法，其特征在于，所述溶剂为非醇类溶剂，优选为醚类溶剂，更优选为乙醚、二甲醚、叔丁基甲醚、乙二醇二甲醚、乙二醇二乙醚、环戊基甲醚、二甲基亚砜、吡啶、二氯甲烷、1,2-二氯乙烷、1,1-二氯乙烷、1,4-二氧六环、四氢呋喃、乙腈、苯和甲苯中的一种或多种，进一步优选为甲苯、吡啶和乙二醇二甲醚中的一种或多种，最优选为乙二醇二甲醚。
9.如权利要求1所述的制备方法，其特征在于，所述溶剂的体积与含有伯醇基团或醛基的反应物的摩尔比为(1.5mL-2mL):1mmol，优选为1.5mL:1mmol。
10.如权利要求1-3中任一项所述的制备方法，其特征在于，氧化反应的温度不低于20℃，优选不低于60℃，较佳地为60℃～80℃。
11.如权利要求1-3中任一项所述的制备方法，其特征在于，含有伯醇基团的反应物、氧化剂与强碱的摩尔比为1:(2-3):(2-3)，优选为1:2:2或1:3:3。
12.如权利要求1-3中任一项所述的制备方法，其特征在于，含有伯醇基团的反应物通式为：R1’CH2OH；
其中，R1’为直链或支链C1-C17烷基、直链或支链C2-C17烯基、直链或支链C2-C17炔基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C1-C17烷基、直链或支链C2-C17烯基、直链或支链C2-C17炔基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基、萜类任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代；所述C6-C14芳基优选取代或未取代的苯基、萘基、联苯基、蒽基等苯环衍生物；所述取代的苯基优选烷氧基取代的苯基、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基；所述卤代苯基优选单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基；
优选地，所述萜类为单萜、倍半萜、二萜或三萜；
优选地，所述C2-C8杂环基为C2-C8杂环烷基或者C2-C8杂环芳基；更优选为吡咯基、嘧啶基、苯并呋喃基、四氢呋喃基、四氢噻吩基、六氢吡啶基、四氢吡咯基、二氢苯并噻吩基、二氢苯并呋喃基、二氢吲哚基、噻吩基、苯并噻吩基、呋喃基、吡啶基或吲哚基。
13.如权利要求12所述的制备方法，其特征在于，所述R1’为直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基、C6-C14芳基或萜类任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基或亚砜基所取代；
优选地，所述R1’为直链或支链C2-C16烷基、C3-C8环烷基、含氧和/或硫的C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C2-C16烷基、C3-C8环烷基、含氧和/或硫的C2-C8杂环基、C6-C14芳基或萜类可任选地被苯基、噻吩基、呋喃基、酯基、醚基或硫醚基所取代。
14.如权利要求12所述的制备方法，其特征在于，含有伯醇基团的反应物为苯丙醇、对甲氧基苄醇、1-萘甲醇、4-(三氟甲基)苄醇、肉桂醇、2-溴苯乙醇、2-(4-苯甲氧基苯基)乙醇、2-环戊基乙醇、四氢吡喃-4-甲醇、1-Boc-3-羟甲基吡咯烷、N-Boc-4-哌啶甲醇、1-金刚烷甲醇、(1-苯基环己基)甲醇、2-(4-乙氧基苯基)-2-甲基丙醇、2,2-二甲基-3-(间甲苯基)丙-1-醇、N-Boc-4-哌啶甲醇、呋喃-3-甲醇、2-(苄氧基)乙醇、苯并噻吩-2-甲醇、2-苯硫基乙醇、2-氨基-3-羟甲基吡啶、3-吡啶丙醇、3-(二甲基氨基)苄醇、1-(2-喹啉基)乙-1-醇、3-吲哚乙醇、油醇、香茅醇、10-十一烯-1-醇、5-苯基-4-戊炔-1-醇、果糖二丙酮、(2R,3R,4S,5R,6S)-4,5-双(苄氧基)-2-(羟甲基)-6-甲氧基四氢-2H-吡喃-3-醇、3-(4-甲氧基苯基)丙烷-1,2-二醇、石胆醇、鹅去氧胆醇、(R)-亚磺酰胺的伯醇或(S)-亚磺酰胺的伯醇。
15.如权利要求1-3中任一项所述的制备方法，其特征在于，含有醛基的反应物通式为R2’CHO；
其中，R2’为直链或支链C1-C17烷基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类；所述直链或支链C1-C17烷基、C3-C8环烷基、C2-C8杂环基、C6-C14芳基或萜类任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代；优选地，所述C6-C14芳基为取代或未取代的苯基、萘基、联苯基或蒽基；所述取代的苯基优选烷氧基取代的苯基、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基；所述卤代苯基优选单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基；
优选地，所述萜类为单萜、倍半萜、二萜或三萜；
优选地，所述C2-C8杂环基可为C2-C8杂环烷基或者C2-C8杂环芳基；更优选为呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、苯并噻吩基、苯并呋喃基、吲哚基、四氢呋喃基、四氢噻吩基、六氢吡啶基、四氢吡咯基、二氢苯并噻吩基、二氢苯并呋喃基或二氢吲哚基。
16.如权利要求15所述的制备方法，其特征在于，所述R2’为直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基；所述直链或支链C2-C17烷基、C3-C8环烷基或C2-C8杂环基任选被酰胺基、酯基、醚基、硫醚基、亚磺酰基、亚砜基、生物碱和甾体中的一种或多种取代。
17.如权利要求15所述的制备方法，其特征在于，含有醛基的反应物为多芳基取代的甲醛、含杂环取代的甲醛、含多种取代基的不饱和醛或C2-C17烷基脂肪醛，所述C2-C17烷基脂肪醛任选被羟基、甲氧基、噻吩基、苯并噻吩基、苯硫基、呋喃基、吡啶基、吲哚基、胺基苯基或酚氧基所取代；优选地，所述多芳基取代的甲醛中，芳基可以相同或不同；所述芳基优选C6-C14芳基，进一步优选取代或未取代的苯基、萘基、联苯基或蒽基；其中，取代的苯基优选为烷氧基取代的苯基、烷硫基苯基、苯硫基、硝基苯基、三氟甲基苯基、卤代苯基、苄氧基苯基或胺基苯基；所述卤代苯基优选为单取代、多取代氟代苯基、氯代苯基、溴代苯基或碘代苯基。
18.如权利要求1的制备方法，其特征在于，所述含有伯醇基团或醛基的反应物选自以下任一化合物：
Figure FDA0003144288200000051
Figure FDA0003144288200000061
19.如权利要求1所述的制备方法，其特征在于，包括如下步骤：
在常压60～80℃下，有机溶剂中，1-羟基环己基苯基甲酮作为氧化剂，第一主族元素、第二主族元素、第三主族元素或过渡金属元素的氢氧化物作碱，将含有伯醇基团或醛基的反应物中的伯醇基团或醛基氧化成相应的羧基。
CN202110745730.4A 2021-07-01 2021-07-01 一种羧酸的制备方法 Pending CN115557836A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110745730.4A CN115557836A (zh) 2021-07-01 2021-07-01 一种羧酸的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110745730.4A CN115557836A (zh) 2021-07-01 2021-07-01 一种羧酸的制备方法

Publications (1)

Publication Number Publication Date
CN115557836A true CN115557836A (zh) 2023-01-03

Family

ID=84737095

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110745730.4A Pending CN115557836A (zh) 2021-07-01 2021-07-01 一种羧酸的制备方法

Country Status (1)

Country Link
CN (1) CN115557836A (zh)

Similar Documents

Publication Publication Date Title
Piers et al. Dilithium (trimethylstannyl)(2-thienyl)(cyano) cuprate, a synthetically useful higher-order cuprate reagent
CN108299296B (zh) 一种菲啶类杂环化合物的制备方法
Nie et al. Chiral bifunctional thiourea-catalyzed enantioselective aldol reaction of trifluoroacetaldehyde hemiacetal with aromatic ketones
Kesharwani et al. Benzylic C–H activation and C–O bond formation via aryl to benzylic 1, 4-palladium migrations
CN104892387A (zh) 一种合成氟代芴酮类化合物的方法
Samanta et al. Thiol-mediated tandem Michael–aldol reaction: a convenient method for the synthesis of fused cyclopentenones
CN101774953A (zh) 一种取代二苯硫醚的制备方法
CN112142694A (zh) 一种多取代四氢呋喃与四氢吡喃双烯体类化合物及其制备方法
Faigl et al. A one-pot synthesis of ibuprofene involving three consecutive steps of superbase metalation
Kumar Amino acid catalyzed thio-Michael addition reactions
Mudiganti et al. Ytterbium triflate-catalyzed conjugate addition of β-ketoesters to activated 1, 4-naphthoquinones
CN109293593A (zh) 一种合成碘代异噁唑啉类化合物的方法
Zhu et al. Electronic tuning cyclization of aryl-1, 4-enediones: AlCl3-mediated Nazarov-type cyclization to synthesize polysubstituted-1-indanones
CN115557836A (zh) 一种羧酸的制备方法
Kamimura et al. Expanding the scope of Et3B/O2-mediated coupling reactions of O, Te-acetal
Alaime et al. Scalable, easy synthesis, and efficient isolation of arylnitromethanes: a revival of the Victor Meyer reaction
Wei et al. Asymmetric synthesis of chiral β-iodo Baylis–Hillman esters using MgI2 as promoter via a one-pot three-component reaction
Tzalis et al. Ru-centered coordination complexes as a new phase transfer catalyst for alkylation of enolates and Michael additions
Ranu et al. Selective reductive cleavage of 2, 3-epoxybromides by the InCl3–NaBH4 reagent system
WO2001057046A1 (fr) Procede de conversion d'un groupe fonctionnel par reaction d'echange halogene-metal
Cheng et al. Difluorocarbene chemistry: synthesis of gem-difluorocyclopropenylalkynes and 3, 3, 3′, 3′-tetrafluorobicyclopropyl-1, 1′-dienes
CN111362795B (zh) 一类取代丁酸酯类衍生物的制备方法
Kamlar et al. Highly enantioselective organocatalytic α-selenylation of aldehydes using hypervalent iodine compounds
CN111675650A (zh) 一种芳香乙烯基溴衍生物的制备方法
CN107021883B (zh) 一种多取代基联苯卤代物液晶中间体的合成方法及应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination