A method for preparing a carboxylic acid

Abstract

This invention discloses a method for preparing carboxylic acids. Specifically, the method for preparing carboxylic acids provided by this invention includes the following steps: in a solvent, a compound of formula I is used as an oxidant to carry out an oxidation reaction in the presence of a strong base, thereby oxidizing a reactant containing a primary alcohol group or an aldehyde group to obtain the corresponding carboxylic acid; wherein the strong base is a hydroxide of a Group I element, a Group II element, a Group III element, or a transition metal element;

Description

Technical Field

[0001] This invention relates to a method for preparing carboxylic acids. Background Technology

[0002] Carboxylic acids are an important class of organic compounds, widely found in nature and synthetic chemicals, and are a crucial component of pesticides and pharmaceuticals. Carboxylic acids and their derivatives are widely used in industry, agriculture, and daily life. In organic synthesis, the oxidation reaction from alcohols or aldehydes to carboxylic acids is a fundamental and important functional group transformation reaction in organic chemistry, and carboxylic acids are often obtained through oxidation. Given the importance of carboxylic acids and their derivatives in the chemical industry, developing an efficient, inexpensive, mild, functionally compatible, environmentally friendly, chemoselective, and renewable oxidant oxidation system has significant academic value and promising prospects for industrial application. Traditionally, carboxylic acids have been synthesized using KMnO4 oxidation, Jones oxidation, and other CrO3-based oxidation methods, high-valent iodine oxidation, and catalytic oxidation using rare and precious metals and their complexes. The disadvantages of these oxidation methods include the presence of heavy metals in the oxidants, resulting in environmental pollution from wastewater; the oxidants being explosive; high cost; some reactions requiring strong acids; demanding conditions; and high equipment requirements. In addition, traditional oxidation methods are poor in selective oxidation, difficult to regenerate oxidants, and have poor environmental compatibility, which is not conducive to large-scale industrial production.(Oxidation of Primary Alcohols to Carboxylic Acids, Springer: Berlin, 2007; Mahmood, A.; Robinson, GE; Powell, L. Org. Process Res. Dev. 1999, 3, 363- 364; Thottathil, JK; Moniot, JL; Mueller, RH; Wong, MKY; Kissick, TPJOrg.Chem.1986,51,3140-3143; Tojo, G.; Practice; Springer: New York, 2007; Lappe, P.; Schulz, E. Aliphatic Carboxylic Acids via AldehydeOxidation. In Applied Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, WA, Eds.; Wiley-VCH: Weinheim, Germany, 1996, pp 424-464; Tojo, G.; Fernandez, M. Oxidation of Primary Alcohols to Carboxylic Acids. Basic Reactions in Organic Synthesis, Sprinter: New York, 2010).

[0003] Pinnick oxidation is commonly used in the preparation of carboxylic acids, but this reaction is limited to the oxidation of aldehydes to acids. Pinnick oxidation also requires the use of flammable and explosive additives such as 2-methyl-2-butene, and highly oxidizing sodium chlorite (NaClO2). (Kraus, GA, Roth, B. J. J. G. Chem. 1980, 45, 4825-4830)

[0004] TEMPO oxidation of 2,2,6,6-tetramethylpiperidine nitride is a commonly used oxidation method that can selectively oxidize primary and secondary alcohols. It is often used in combination with sodium hypochlorite and sodium chlorite, and there are also examples of its use in combination with transition metals. Substrates containing aniline and those with tert-butylsulfinyl functional groups are generally incompatible with TEMPO oxidation conditions (Giacomelli, G.; Masala, S.; Porcheddu, A. J. J. G. 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-catalyzed chemoselective alcohol oxidation for the synthesis of polyfunctional molecules, Tetrahedron Lett. 2020, 61, 151515–151525).

[0005] Oppenauer oxidation uses ketones and aldehydes as oxidants (proton transfer acceptors) to oxidize secondary alcohols to ketones and primary alcohols to aldehydes, while being reduced to the corresponding alcohols themselves. (Djerassi, C. Org. React. 1951, 6, 207-272) There is only one report in the existing literature of oxidizing 1,5-diols to lactones in 23% yield using fluorenone as the oxidant. (Eignerova, L.; Kasal, A. Collect. Czech. Chem. Commun. 1976, 41, 1065) Currently, there are no reports of Oppenauer oxidation methods achieving the oxidation of alcohols or aldehydes to acids. Summary of the Invention

[0006] This invention addresses the shortcomings of existing technologies, such as the use of heavy metals as oxidants, the participation of rare and precious transition metals in the reaction, harsh reaction conditions, narrow substrate applicability, difficulty in controlling the oxidizing power of the oxidant, and the non-renewable nature of the oxidant. It provides a method for preparing carboxylic acids. The method uses a ketone with a tertiary hydroxyl group at the ortho position as the oxidant, directly oxidizing primary alcohols or aldehydes to carboxylic acids in the presence of a strong base. The raw materials used in this invention are industrially inexpensive and readily available. Furthermore, the oxidant used can be recycled after the reaction using a safe and inexpensive inorganic oxidant, potassium persulfate complex salt (oxone), resulting in low cost, reduced waste pollution during the reaction, and advantages such as high efficiency, mild reaction, easy scale-up, and functional group compatibility.

[0007] The method for preparing carboxylic acids of the present invention can selectively oxidize primary alcohols to generate carboxylic acids in the presence of both secondary and primary alcohols. Furthermore, the method for preparing carboxylic acids has broad applicability and can be adapted to reaction substrates with a wide range of common functional groups, i.e., it is compatible with multiple functional groups.

[0008] This invention provides a method for preparing carboxylic acids, comprising the following steps: in a solvent, a compound of formula I is used as an oxidant to oxidize the primary alcohol group or aldehyde group in a reactant containing a primary alcohol group or aldehyde group to the corresponding carboxyl group in the presence of a strong base; wherein the strong base is a hydroxide of a Group I element, a Group II element, a Group III element, or a transition metal element.

[0009]

[0010] R1 and R2 are each independently C1-C3 alkyl, or R1 and R2 together with the atoms attached to them form a 5-6 membered carbon ring; n is 0, 1, 2, 3 or 4; R3 is H, C1-C3 alkyl, C1-C3 alkoxy or halogen.

[0011] In this invention, in the compound of formula I, R1 and R2 preferably form a 5-6 membered carbon ring together with the atoms they are attached to, and more preferably form cyclohexane.

[0012] In this invention, in the compound of formula I, n is preferably 0 or 1.

[0013] In this invention, in the compound of formula I, R3 is preferably H, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, chlorine or bromine; more preferably H.

[0014] In this invention, when n≥2, preferably, each R3 is the same or different.

[0015] In this invention, the most preferred compound of formula I is 1-hydroxycyclohexylphenyl ketone, i.e.

[0016] In this invention, when the reactants contain primary alcohol groups, the molar ratio of the oxidant to the reactants containing primary alcohol groups is preferably equal to or greater than 2:1; more preferably 2:1-3:1, and most preferably 2:1. When the reactants contain aldehyde groups, the molar ratio of the oxidant to the reactants containing aldehyde groups is preferably equal to or greater than 1:1; more preferably 1:1-2:1, and most preferably 1:1.

[0017] In this invention, the hydroxide of the first main group element is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and cesium hydroxide; the hydroxide of the second main group element is selected from one or more of calcium hydroxide, magnesium hydroxide, and barium hydroxide; the hydroxide of the third main group element is selected from aluminum hydroxide; and the hydroxide of the transition metal is selected from one or more of copper hydroxide, iron hydroxide, zinc hydroxide, and palladium hydroxide.

[0018] In this invention, when the reactants contain primary alcohol groups, the molar ratio of the strong base to the reactants containing primary alcohol groups is preferably 2:1-3:1; more preferably 2:1. When the reactants contain aldehyde groups, the molar ratio of the strong base to the reactants containing aldehyde groups is preferably 1.5:1-2:1, more preferably 2:1.

[0019] In this invention, the solvent can be an inert organic solvent commonly used in the art that does not affect the reaction, preferably a non-alcoholic solvent, and can be an ether solvent, preferably one or more of diethyl ether, dimethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, cyclopentyl methyl ether, dimethyl sulfoxide, pyridine, dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, benzene, and toluene, more preferably one or more of toluene, pyridine, and ethylene glycol dimethyl ether, and most preferably ethylene glycol dimethyl ether. The molar ratio of the volume of the solvent to the reactant containing a primary alcohol group or an aldehyde group is preferably (1.5 mL - 2 mL): 1 mmol, more preferably 1.5 mL: 1 mmol.

[0020] In this invention, the reaction temperature can be the temperature required to ensure the normal progress of the reaction, generally not lower than 20°C, preferably not lower than 60°C, and more preferably 60°C-80°C.

[0021] In this invention, the molar ratio of the reactant containing the primary alcohol group, the oxidant, and the strong base is preferably 1:(2-3):(2-3), more preferably 1:2:2 or 1:3:3.

[0022] In this invention, the molar ratio of the reactant containing the aldehyde group, the oxidant, and the strong base is preferably 1:(1-2):(1.5-2), and more preferably 1:1:2.

[0023] In this invention, the reactants containing primary alcohol groups or aldehyde groups can be any compound containing primary alcohol groups or aldehyde groups in the art, including aromatic compounds containing primary alcohol groups or aldehyde groups, alkane compounds containing primary alcohol groups or aldehyde groups, olefin compounds containing primary alcohol groups or aldehyde groups, alkyne compounds containing primary alcohol groups or aldehyde groups, cycloalkanes containing primary alcohol groups or aldehyde groups, heterocycloalkyl compounds containing primary alcohol groups or aldehyde groups, or heteroaryl compounds containing primary alcohol groups or aldehyde groups, such as steroidal compounds, terpenoid compounds, long-chain alkane compounds, long-chain olefin compounds, aromatic compounds, heteroaromatic compounds, adamantane compounds, heteroalkane compounds, etc.

[0024] In this invention, the preferred general formula for reactants containing primary alcohol groups is: R1'CH2OH; wherein R1' is a straight-chain or branched C1-C group. 17 Alkyl, straight-chain or branched C 2- C 17 Alkenyl, straight-chain or branched C 2- C 17 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocyclic, C6-C 14 Aryl or terpenoid. The straight-chain or branched C1-C... 17 Alkyl, straight-chain or branched C 2- C 17 Alkenyl, straight-chain or branched C 2- C 17 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocyclic, C6-C 14 The aryl and terpenoid groups may be optionally substituted with one or more of the following: amide, ester, ether, thioether, sulfinyl, sulfoxide, alkaloids, and steroids. The C6-C group... 14 The aryl group is preferably a substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracene, or other benzene ring derivative. The substituted phenyl group is preferably an alkoxy-substituted phenyl (e.g., methoxyphenyl), alkylthiophenyl, phenylthio, nitrophenyl, trifluoromethylphenyl, halophenyl, benzyloxyphenyl, or aminophenyl. The halophenyl group can be monosubstituted, polysubstituted fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl. The terpenoid is preferably a monoterpene, sesquiterpene, diterpene, or triterpene.

[0025] The C2-C8 heterocyclic group can be a C2-C8 heterocyclic alkyl group or a C2-C8 heterocyclic aryl group, preferably pyrrolithyl, pyrimidinyl, benzofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, hexahydropyridyl, tetrahydropyrrolithyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, dihydroindolyl, thiophenyl, benzothiophenyl, furanyl, pyridinyl or indolyl.

[0026] Preferably, R1' is a straight chain or a branched chain C2-C. 17Alkyl, C3-C8 cycloalkyl or C2-C8 heterocyclic, C6-C 14 Aryl or terpenoid; the straight-chain or branched C2-C 17 Alkyl, C3-C8 cycloalkyl or C2-C8 heterocyclic, C6-C 14 The aryl or terpene group may be optionally replaced by an amide group, ester group, ether group, thioether group, sulfinyl group or sulfoxide group.

[0027] More preferably, R1' is a straight chain or a branched chain C2-C. 16 Alkyl, C3-C8 cycloalkyl, oxygen- and / or sulfur-containing C2-C8 heterocyclic groups, C6-C 14 Aryl or terpenoid; the straight-chain or branched C2-C 16 Alkyl, C3-C8 cycloalkyl, oxygen- and / or sulfur-containing C2-C8 heterocyclic groups, C6-C 14 The aryl or terpene group may optionally be replaced by a phenyl, thiophene, furanyl, ester, ether, or thioether group.

[0028] In this invention, the reactants containing primary alcohol groups are preferably phenylpropanol, p-methoxybenzyl alcohol, 1-naphthaleneethanol, 4-(trifluoromethyl)benzyl alcohol, cinnamyl alcohol, 2-bromophenylethanol, 2-(4-benzylmethoxyphenyl)ethanol, 2-cyclopentylethanol, tetrahydropyran-4-methanol, 1-Boc-3-hydroxymethylpyrrolidine, N-Boc-4-piperidinemethanol, 1-adamantaneethanol, (1-phenylcyclohexyl)ethanol, 2-(4-ethoxyphenyl)-2-methylpropanol, 2,2-dimethyl-3-(m-tolyl)prop-1-ol, N-Boc-4-piperidinemethanol, furan-3-methanol, 2-(benzyloxy)ethanol, benzothiophene-2-methanol, 2-phenylthioethanol, 2-amino-3-hydroxymethylpyridine, 3-pyridinepropanol, etc. 3-(dimethylamino)benzyl alcohol, 1-(2-quinolinyl)ethanol-1-ol, 3-indoethanol, oleyl alcohol, citronellol, 10-undecen-1-ol, 5-phenyl-4-pentyn-1-ol, fructose diacetone, (2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3-ol, 3-(4-methoxyphenyl)propane-1,2-diol, lithochyl alcohol, chenodeoxycholic acid, primary alcohols of (R)-sulfinamides or (S)-sulfinamides, etc.

[0029] In this invention, the preferred general formula for reactants containing an aldehyde group is R2'CHO; wherein R2' is a straight-chain or branched C1-C 17 Alkyl, C3-C8 cycloalkyl, C2-C8 heterocyclic, C6-C 14 Aryl or terpenoid. The straight-chain or branched C1-C... 17 Alkyl, C3-C8 cycloalkyl, C2-C8 heterocyclic, C6-C 14The aryl or terpene group may be optionally substituted with one or more of the following: amide, ester, ether, thioether, sulfinyl, sulfoxide, alkaloid, and steroid. The C6-C group... 14 The aryl group is preferably a substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracene, or other benzene ring derivative. The substituted phenyl group is preferably an alkoxy-substituted phenyl (e.g., methoxyphenyl), alkylthiophenyl, phenylthio, nitrophenyl, trifluoromethylphenyl, halophenyl, benzyloxyphenyl, or aminophenyl. The halophenyl group can be monosubstituted, polysubstituted fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl. The terpenoid is preferably a monoterpene, sesquiterpene, diterpene, or triterpene.

[0030] The C2-C8 heterocyclic group can be a C2-C8 heterocyclic alkyl group or a C2-C8 heterocyclic aryl group, preferably furanyl, thiophene, pyridyl, pyrrole, pyrimidinyl, benzothiophene, benzofuranyl, indolyl, tetrahydrofuranyl, tetrahydrothiophene, hexahydropyridyl, tetrahydropyrrole, dihydrobenzothiophene, dihydrobenzofuranyl or dihydroindolyl.

[0031] Preferably, R2' is a straight chain or a branched chain C2-C. 17 Alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclic group. The straight-chain or branched C2-C8 group... 17 Alkyl, C3-C8 cycloalkyl or C2-C8 heterocyclic groups may be optionally substituted with one or more of amide, ester, ether, thioether, sulfinyl, sulfoxide, alkaloid and steroid.

[0032] In this invention, the reactants containing aldehyde groups are preferably polyaryl-substituted formaldehyde, heterocyclic-substituted formaldehyde, unsaturated aldehydes containing multiple substituents, or C2-C aldehydes. 17 Alkyl aliphatic aldehydes. The unsaturated aldehydes containing multiple substituents may refer to unsaturated aldehydes containing hydroxyl, methoxy, thienyl, benzothienyl, phenylthio, furanyl, pyridyl, indole, aminophenyl, or phenoloxy groups. The C2-C... 17 Alkyl aliphatic aldehydes may be substituted with hydroxyl, methoxy, thienyl, benzothienyl, phenylthio, furanyl, pyridyl, indole, aminophenyl, or phenoxy groups. In the polyaryl-substituted formaldehydes, the aryl groups may be the same or different. The aryl groups are preferably C6-C. 14 The aryl group is further preferably a substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracene, or other benzene ring derivative; wherein the substituted phenyl group is preferably an alkoxy-substituted phenyl (e.g., methoxyphenyl), alkylthiophenyl, phenylthio, nitrophenyl, trifluoromethylphenyl, halophenyl, benzyloxyphenyl, or aminophenyl. The halophenyl group may be a monosubstituted or polysubstituted fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl.

[0033] In this invention, the reactants containing primary alcohol groups or aldehyde groups can be chiral. After the corresponding carboxylic acids are prepared by the method of this invention, the chirality is retained, the yield of stereoproducts is very high, and the chiral specificity is strong. Preferably,

[0034] The preferred method of the present invention includes the following steps: at normal pressure and 60-80°C, in an organic solvent, 1-hydroxycyclohexylphenyl ketone is used as an oxidant, and hydroxides of Group I, Group II, Group III elements or transition metal elements (such as sodium hydroxide) are used as bases to oxidize the primary alcohol groups or aldehyde groups in the reactants containing primary alcohol groups or aldehyde groups to the corresponding carboxyl groups.

[0035] The method of the present invention can selectively oxidize the primary alcohol or aldehyde groups in primary alcohol or aldehyde compounds containing multiple functional groups such as carbon-carbon single bonds, carbon-carbon double bonds, carbon-carbon triple bonds, amides, amines, sulfinyl groups, sulfoxides, and thioethers to generate the corresponding carboxylic acids, while other groups other than primary alcohol or aldehyde groups are not oxidized.

[0036] In this invention, when both aldehyde and secondary alcohol groups are present in the reactants, only the aldehyde group is oxidized to the carboxylic acid group; when both primary and secondary alcohol groups are present in the reactants, only the primary alcohol is oxidized to the carboxylic acid group, without oxidizing the secondary alcohol.

[0037] In this invention, when both aldehyde and primary alcohol groups are present in the reactants, if the oxidant equivalent is 1, the aldehyde group is mainly oxidized; if the oxidant equivalent is greater than 2, both aldehyde and primary alcohol groups can be oxidized simultaneously.

[0038] This invention has many advantages, such as mild reaction conditions, high yield, simple operation, convenient separation and purification, good compatibility of substrate functional groups, environmentally friendly reaction process, and recyclable oxidant. It can be used for small-scale laboratory synthesis as well as industrial production.

[0039] This invention has the advantage of broad substrate applicability and can be used to oxidize primary alcohols with relatively complex structures, such as primary alcohols containing functional groups such as amide groups, ether groups, halogens, phenyl groups, heterocyclic groups, alkyne groups, double bonds, sulfinyl groups, and sulfoxide groups. Even terpenes, alkaloids, and steroid structures are compatible under the conditions of this invention.

[0040] This invention utilizes ketones with a tertiary hydroxyl group at the ortho position, particularly inexpensive 1-hydroxycyclohexylphenyl ketone, as the oxidant, replacing the oxidant used in traditional oxidant systems. All inorganic hydroxides used are industrially available raw materials. After the reaction, the oxidant 1-hydroxycyclohexylphenyl ketone is reduced to 1-hydroxycyclohexylbenzyl alcohol, which can be regenerated by oxidation with potassium persulfate (oxone) and potassium bromide in acetonitrile solvent to return the oxidant 1-hydroxycyclohexylphenyl ketone. The entire reaction process is simple to operate, requires minimal post-processing, yields high products, and is economical and environmentally friendly, representing a green chemical synthesis method.

[0041] Under the conditions of this invention, when secondary or tertiary alcohols coexist with primary alcohols, primary alcohols can be selectively oxidized to carboxylic acids. This advantage provides a green, environmentally friendly, low-cost, and efficient new synthetic method for the synthesis of drugs containing both primary and secondary alcohols, as well as for the modification of natural products. Detailed Implementation

[0042] The present invention will be further described in detail below with reference to the following embodiments. Except for the contents specifically mentioned below, the processes, conditions, and experimental methods for implementing the present invention are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0043] Example 1: Synthesis of phenylpropionic acid

[0044]

[0045] 1-Hydroxycyclohexylphenyl ketone (408.5 mg, 99% purity, 2 mmol), sodium hydroxide (80.0 mg, >95% purity, 2 mmol), phenylpropanol (139.0 mg, 98% purity, 1 mmol), and dimethyl ethylene glycol (DME, 1.5 mL) were added to an 8 mL reaction flask. The mixture was stirred at 80 °C until the reaction was complete, as monitored by thin-layer chromatography (TLC). After the reaction was complete, water (30 mL) was added, and the mixture was extracted three times (30 mL each time) with diethyl ether. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the diethyl ether was recovered by vacuum distillation. The crude reduced product 1-hydroxycyclohexylbenzyl alcohol obtained after distillation was collected and recovered for regeneration. The aqueous phase was acidified with HCl (12 M, 166.7 μl, 2 mmol), extracted three times (30 mL each time) with diethyl ether, and the organic phases were combined and evaporated to dryness to obtain the crude product. The crude product can be recrystallized or purified by column chromatography (petroleum ether: ethyl acetate: acetic acid = 5:1:0.1) to obtain pure phenylpropionic acid (145.7 mg, 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). 13 C-NMR (151MHz, CDCl3) δ179.2,140.3,130.3,128.7,128.6,128.4,126.5,35.7,30.7.

[0046] Example 2: Synthesis of p-methoxybenzoic acid

[0047]

[0048] Other procedures are as described in Example 1. The raw material used is p-methoxybenzyl alcohol, and the reaction time is 6 hours to obtain p-methoxybenzoic acid (144.5 mg, 95%). 1 H-NMR (400MHz, CDCl3) δ8.07 (d, J = 8.8Hz, 2H), 6.95 (d, J = 8.8Hz, 2H), 3.88 (s, 3H). 13 C-NMR (100MHz, CDCl3) δ171.9,164.2,132.5,121.8,113.9,55.6.

[0049] Example 3: Synthesis of 1-Naphthoic acid

[0050]

[0051] Other operations are as described in Example 1. The raw material used is 1-naphthyl alcohol, and the reaction time is 5 hours to obtain 1-naphthoic acid (142.4 mg, 90%). 1 H-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). 13 C-NMR (150MHz, DMSO-d6) δ168.7,133.5,132.9,130.7,129.8, 128.6,127.5,126.1,125.5,124.8.

[0052] Example 4: Synthesis of 4-(trifluoromethyl)benzoic acid

[0053]

[0054] Other operations are as described in Example 1. The raw material used is 4-(trifluoromethyl)benzyl alcohol, and the reaction time is 3 hours to obtain 4-(trifluoromethyl)benzoic acid (186.2 mg, 98%). 1 H-NMR (600MHz, DMSO- d6) δ13.42 (brs, 1H), 8.12 (d, J = 8.4Hz, 2H), 7.83 (d, J = 7.8Hz, 2H). 13 C-NMR (150MHz, DMSO) δ166.2,134.7,132.2-132.8(m),130.1,125.5,122.9,121.1.

[0055] Example 5: Synthesis of Cinnamic Acid

[0056]

[0057] Other operations are as described in Example 1. The raw material used is cinnamyl alcohol, and the reaction time is 30 minutes to obtain cinnamic acid (120.8 mg, 90%). 1 H-NMR (400MHz, CDCl3) δ7.81 (d, J = 16.0 Hz, 1H), 7.57 (m, 2H), 7.44-7.37 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H). 13 C-NMR (100MHz, CDCl3) δ172.7,147.3,134.2,130.9,129.1,128.5,117.5.

[0058] Example 6: Synthesis of 2-bromophenylacetic acid

[0059]

[0060] Other operations are as described in Example 1. The raw material used is 2-bromophenylethanol, and the reaction time is 30 hours to obtain 2-bromophenylacetic acid (150.5 mg, 70%). 1 H-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). 13 C-NMR (150MHz, CDCl3) δ176.9,133.7,133.0,131.7,129.3,127.7,125.2,41.5.

[0061] Example 7: Synthesis of 4-Benzyloxyphenylacetic acid

[0062]

[0063] Other operations are as described in Example 1. The raw material used is 2-(4-benzyloxyphenyl)ethanol, and the reaction time is 30 hours to obtain 4-benzyloxyphenylacetic acid (169.6 mg, 70%). 1 H-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). 13 C-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.

[0064] Example 8: Synthesis of 2-Cyclopentylic Acid

[0065]

[0066] Other operations are as described in Example 1. The raw material used is 2-cyclopentylethanol, and the reaction time is 30 hours to obtain 2-cyclopentylacetic acid (103.9 mg, 91%). 1 H-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). 13 C-NMR (100MHz, CDCl3) δ180.2, 40.3, 36.4, 32.5, 25.1.

[0067] Example 9: Synthesis of tetrahydropyran-4-carboxylic acid

[0068]

[0069] Other procedures are the same as in Example 1. The raw material used is tetrahydropyran-4-methanol, and the reaction time is 30 hours to obtain tetrahydropyran-4-carboxylic acid (123.6 mg, 95%). 1 H-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.

[0070] Example 10: Synthesis of 1-Boc-pyrrolidine-3-carboxylic acid

[0071]

[0072] Other procedures are the same as in Example 1. The raw material used is 1-Boc-3-hydroxymethylpyrrolidine, and the reaction time is 30 hours to obtain 1-Boc-pyrrolidine-3-carboxylic acid (140 mg, 65%). 1 H-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). 13 C-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.

[0073] Example 11: Synthesis of 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid

[0074]

[0075] Other operations were performed as described in Example 1, using N-Boc-4-piperidine methanol as the raw material and reacting for 30 hours to obtain 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (201.8 mg, 88%). 1 H-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). 13 C-NMR (100 MHz, CDCl3) δ180.1,154.9,80.0,43.0,40.9,28.5,27.8.

[0076] Example 12: Synthesis of 1-adamantane carboxylic acid

[0077]

[0078] Other operations are as described in Example 1. The raw material used is 1-adamantane methanol, and the reaction time is 4 days to obtain 1-adamantane carboxylic acid (165.8 mg, 92%).1 H-NMR (600MHz, CDCl3) δ2.02 (brs, 3H), 1.91 (d, J = 3Hz, 6H), 1.74–1.65 (m, 6H). 13 C-NMR (150MHz, CDCl3) δ 184.3, 40.6, 38.7, 36.6, 28.0.

[0079] Example 13: Synthesis of 1-Phenyl-1-cyclohexanecarboxylic acid

[0080]

[0081] Other operations are as described in Example 1. The raw material used is (1-phenylcyclohexyl)methanol. The reaction is carried out for 24 hours to obtain 1-phenyl-1-cyclohexylcarboxylic acid (183.8 mg, 90%). 1 H-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). 13 C-NMR (150MHz, CDCl3) δ182.0,143.1,128.7, 127.1,126.3,50.6,34.4,25.7,23.7.

[0082] Example 14: 2-(4-ethoxyphenyl)-2-methylpropionic acid

[0083]

[0084] Other operations are as described in Example 1. The raw material used is 2-(4-ethoxyphenyl)-2-methylpropanol, and the reaction time is 3 days to obtain 2-(4-ethoxyphenyl)-2-methylpropionic acid (187.4 mg, 90%). 1 H-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 C 12 H 16 O3 231.0991, found 231.0992.

[0085] Example 15: Synthesis of 2,2-dimethyl-3-(m-tolyl)propionic acid

[0086]

[0087] Other operations are as described in Example 1. The raw material used is 2,2-dimethyl-3-(m-tolyl)prop-1-ol, and the reaction time is 3 days to obtain 2,2-dimethyl-3-(m-tolyl)propionic acid (165.3 mg, 86%). 1 H- NMR (400MHz, CDCl3) δ7.15 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 6.96 (d, J = 7.2 Hz, 2H), 2.85 (s, 2H), 2.30 (s, 3H), 1.19 (s, 6H). 13 C-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 C 12 H 16 O2215.1044, found 215.1043.

[0088] Example 16: Synthesis of 1-Boc-4-methyl-4-piperidinecarboxylic acid

[0089]

[0090] Other procedures were performed as described in Example 1, using N-Boc-4-piperidinemethanol as the raw material and reacting for 42 hours to obtain 1-Boc-4-methyl-4-piperidinecarboxylic acid (231.1 mg, 95%). 1H-NMR (400MHz, CDCl3) δ10.01(brs.1H),3.75(brs,2H),3.04(t,J=11.6Hz,2H),2.05(d,J=13.6Hz,2H),1.43(s,9H),1.41–1.32(m,2H),1.25(s,3H). 13 C-NMR (100MHz, CDCl3) δ182.8,155.1,79.8,41.7,41.2,34.4,28.6,25.9.

[0091] Example 17: Synthesis of 3-Furfuric Acid

[0092]

[0093] Other operations are as described in Example 1. The raw material used is furan-3-methanol, and the reaction time is 5 hours to obtain 3-furoic acid (93.4 mg, 86%). 1 H-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). 13 C- NMR (150MHz, CDCl3) δ168.9,149.3,144.2,119.0,110.0.

[0094] Example 18: Synthesis of 2-(benzyloxy)acetic acid

[0095]

[0096] Other operations are as described in Example 1. The raw material used is 2-(benzyloxy)ethanol, and the reaction time is 30 hours to obtain 2-(benzyloxy)acetic acid (141.3 mg, 85%). 1 H-NMR (600MHz, CDCl3) δ9.92 (s,1H),7.38–7.32(m,5H),4.65(s,2H),4.16(s,2H). 13 C-NMR (150MHz, CDCl3) δ175.5,136.7,128.6,128.3,128.2,73.5,66.6.

[0097] Example 19: Synthesis of benzothiophene-2-carboxylic acid

[0098]

[0099] Other operations are as described in Example 1. The raw material used is benzothiophene-2-methanol, and the reaction time is 5 hours to obtain benzothiophene-2-carboxylic acid (171.1 mg, 96%). 1 H-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). 13 C-NMR (100MHz, DMSO-d6)δ163.5,141.3,138.7,134.7,130.2,127.0,125.7,125.0,123.0.

[0100] Example 20: Synthesis of phenylthioacetic acid

[0101]

[0102] Other operations are as described in Example 1. The raw material used is 2-phenylthioethanol, and the reaction time is 30 hours to obtain phenylthioacetic acid (153.2 mg, 91%). 1 H-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). 13 C- NMR (100MHz, CDCl3) δ175.9,134.6,130.0,129.2,127.2,36.6.

[0103] Example 21: Synthesis of 2-Aminonicotinic Acid

[0104]

[0105] Other procedures were performed as described in Example 1. The raw material used was 2-amino-3-hydroxymethylpyridine, and the reaction time was 3.5 hours to obtain 2-aminonicotinic acid (134.0 mg, 97%). 1 H-NMR (600MHz, DMSO-d6) δ 8.16 (dd, J = 4.2, 1.2 Hz, 1H), 8.03 (dd, J = 7.8, 1.2 Hz, 1H), 6.59 (dd, J = 7.2, 4.8 Hz, 1H). 13 C-NMR(150MHz,DMSO-d6)δ168.7,159.8,153.3,140.1,111.8, 105.8.

[0106] Example 22: Synthesis of 3-(3-pyridyl)propionic acid

[0107]

[0108] Other operations are as described in Example 1. The raw material used is 3-pyridinylpropanol, and the reaction time is 30 hours to obtain 3-(3-pyridyl)propionic acid (143.6 mg, 95%). 1 H-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). 13 C-NMR (100MHz, DMSO-d6) δ174.0,149.6,147.2,136.7,135.9,123.4,35.4,27.8.

[0109] Example 23: Synthesis of m-dimethylaminobenzoic acid

[0110]

[0111] Other operations are as described in Example 1. The raw material used is 3-(dimethylamino)benzyl alcohol, and the reaction time is 5 hours to obtain m-dimethylaminobenzoic acid (148.7 mg, 90%). 1 H-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). 13 C-NMR(100MHz,DMSO-d6)δ167.9,150.28,131.3,129.0,116.9,116.5, 112.4,40.0.

[0112] Example 24: Synthesis of Quinoline-2-carboxylic Acid

[0113]

[0114] Other procedures were performed as described in Example 1, using 1-(2-quinolinyl)ethanol-1-ol as the starting material and reacting for 5 hours to obtain quinoline-2-carboxylic acid (169.7 mg, 83%). 1 H-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).13 C-NMR (100MHz, DMSO-d6) δ167.2,151.5,146.8,137.2,130.1,129.8,128.5,128.0,127.9,121.0.

[0115] Example 25: Synthesis of 3-Indoleacetic Acid

[0116]

[0117] Other procedures are the same as in Example 1. The raw material used is 3-indoleethanol, and the reaction time is 24 hours to obtain 3-indoleacetic acid (105.1 mg, 60%). 1 H-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). 13 C-NMR (150MHz, CD3OD) δ176.5,137.8, 128.5,124.6,122.5,119.9,119.4,112.2,108.8,31.9

[0118] Example 26: Synthesis of Oleic Acid

[0119]

[0120] Other operations are as described in Example 1. The raw material used is oleyl alcohol, and the reaction time is 30 hours to obtain oleic acid (257 mg, 91%). 1 H-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). 13 C-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.

[0121] Example 27: Synthesis of Citronellolic Acid

[0122]

[0123] Other operations are as described in Example 1. The raw material used is citronellol, and the reaction time is 30 hours to obtain citronellolic acid (136.2 mg, 80%). 1 H-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). 13 C-NMR (100MHz, DMSO-d6) δ173.9,130.7,124.3, 41.3,36.2,29.3,25.5,25.0,19.4,17.5.

[0124] Example 28: Synthesis of 10-Undecenoic Acid

[0125]

[0126] Other procedures are the same as in Example 1. The raw material used is 10-undecen-1-ol, and the reaction time is 30 hours to obtain 10-undecenic acid (147.4 mg, 80%). 1 H-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). 13 C-NMR (100MHz, CDCl3) δ180.78, 139.20,114.26,34.25,33.89,29.37,29.29,29.15,29.00,24.76.

[0127] Example 29: Synthesis of 5-Phenylacetic-4-Oyneic Acid

[0128]

[0129] Other operations are as described in Example 1. The raw material used is 5-phenyl-4-pentyn-1-ol, and the reaction time is 30 hours to obtain 5-phenylpentyn-4-ynic acid (149.8 mg, 86%). 1 H-NMR(400MHz, CDCl3)δ 7.41–7.39(m,2H),7.29–7.28(m,3H),2.78–2.69(m,4H).13 C-NMR (100MHz, CDCl3) δ178.4,131.8,128.4,128.0,123.5,87.7,81.5,33.6,15.2.

[0130] Example 30: Synthesis of fructose dipyruvate

[0131]

[0132] Other operations are as described in Example 1. The raw material used is fructose diacetone, and the reaction time is 4 days to obtain fructose diacetone (219.6 mg, 80%, ee value greater than 98%). 1 H-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). 13 C-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.

[0133] Example 31: Synthesis of methyl 2,3-di-O-benzyl-α-D-glucopyranoside

[0134]

[0135] Other operations are as described in Example 1. The raw material used is (2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3-ol. The reaction time is 12 hours to obtain methyl 2,3-di-O-benzyl-α-D-glucopyranoside (310.7 mg, 80%, ee value greater than 98%). (c 0.66,MeOH). 1 H-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.

[0136] Example 32: Synthesis of 2-hydroxy-3-(4-methoxyphenyl)propionic acid

[0137]

[0138] Other operations are as described in Example 1. The raw material used is 3-(4-methoxyphenyl)propane-1,2-diol, and the reaction time is 12 hours to obtain 2-hydroxy-3-(4-methoxyphenyl)propionic acid (180.5 mg, 92%). 1 H- 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). 13 C-NMR (100MHz, DMSO-d6) δ175.2,157.7,130.34,129.9,113.4,71.2,55.0,39.1.

[0139] Example 33: Synthesis of Lithocholic Acid

[0140]

[0141] 1-Hydroxycyclohexylphenyl ketone (408.5 mg, 99.95% purity, 2 mmol), sodium hydroxide (80.0 mg, 99.99% purity, 2 mmol, ee value >98%), lithochyl alcohol (360.57 mg, 1 mmol), and pyridine (1.5 mL) were added to an 8 mL reaction flask. The mixture was stirred at 80 °C for 30 hours, and the reaction was monitored by TLC until completion. After the reaction was complete, the flask was cooled to room temperature, acidified to pH 2 with 2N HCl, and then extracted with diethyl ether (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (petroleum ether: ethyl acetate: acetic acid) to give pure lithochyl acid (338.00 mg, 90%, white solid). 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). 13 C-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.

[0142] Example 34: Synthesis of chenodeoxycholic acid

[0143]

[0144] Other operations are as described in Example 1. The raw material used is chenodeoxycholic acid, and the reaction time is 3 days to obtain chenodeoxycholic acid (353.3 mg, 90%, ee value greater than 98%). 1 H-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). 13 C-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.

[0145] Example 35: Synthesis of (R)-4-(((R)-tert-butylsulfinyl)(methyl)amino)-4-phenylbutyric acid

[0146]

[0147] 1-Hydroxycyclohexylphenyl ketone (408.5 mg, 99% purity, 2 mmol), sodium hydroxide (80.0 mg, >95% purity, 2 mmol, ee value >98%), (R)-N-((R)-4-hydroxy-1-phenylbutyl)-N,2-dimethylpropane-2-sulfinamide (283.4 mg, 1 mmol), and dimethyl glycol ether (DME, 1.5 mL) were added to an 8 mL reaction flask. The mixture was stirred at 80 °C for 18 hours, and the reaction was monitored by TLC until completion. After the reaction was complete, water (30 mL) was added, and the mixture was extracted three times (30 mL each time) with diethyl ether. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the diethyl ether was recovered by vacuum distillation. The crude reduced product 1-hydroxycyclohexylbenzyl alcohol was collected and recovered after distillation. The aqueous phase was acidified to a weakly acidic state using a weakly acidic ion exchange resin and then filtered through the resin. The solvent was removed by vacuum distillation, and the residue was purified by rapid chromatography (petroleum ether: ethyl acetate: methanol) to obtain (R)-4-(((R)-tert-butylsulfinyl)(methyl)amino)-4-phenylbutyric acid (270.6 mg, 91%). (c 0.87, CHCl3). 1 H-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). 13 C-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 for C 15 H 23 NO3S320.1286, found 320.1291.

[0148] Example 36: Synthesis of thiophene-2-carboxylic acid

[0149]

[0150] 1-Hydroxycyclohexylphenyl ketone (204.3 mg, 99% purity, 1 mmol), sodium hydroxide (80.0 mg, >95% purity, 2 mmol), 2-thiophenecarboxaldehyde (112.15 mg, 1 mmol), and dimethyl ethylene glycol ether (DME, 1.5 mL) were added to an 8 mL reaction flask. The mixture was stirred at 80 °C for 0.5 h, and the reaction was monitored by TLC until completion. After the reaction was complete, water (30 mL) was added, and the mixture was extracted three times (30 mL each time) with diethyl ether. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the diethyl ether was recovered by vacuum distillation. The crude reduced product 1-hydroxycyclohexylbenzyl alcohol was collected and recovered after distillation. The aqueous phase was acidified with HCl (12 M, 166.7 μL, 2 mmol), extracted three times (30 mL each time) with diethyl ether, and the organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: acetic acid = 5:1:0.1) to give the corresponding thiophene-2-carboxylic acid (106.4 mg, 83%). 1 H-NMR (400MHz, CDCl) 3) 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). 13 C-NMR (100MHz, CDCl3) δ167.9,135.2, 134.2,133.0,128.2.

[0151] Example 38: Synthesis of Isonicotinic Acid

[0152]

[0153] Other procedures are as described in Example 36, using 4-pyridinecarboxaldehyde as the raw material and reacting for 3 hours to obtain isonicotinic acid (110.8 mg, 90%). 1 H-NMR (400MHz, DMSO-d6) δ8.70 (d, J = 4.5 Hz, 2H), 7.79 (d, J = 4.5 Hz, 2H). 13 C-NMR (100MHz, DMSO-d6) δ167.02, 150.21, 140.88, 122.90.

[0154] Example 39: Synthesis of 4-(1H-imidazol-1-yl)benzoic acid

[0155]

[0156] Other operations are as described in Example 36, using 4-(imidazol-1-yl)benzaldehyde as the raw material and reacting for 2 hours to obtain 4-(1H-imidazol-1-yl)benzoic acid (171.3 mg, 91%). 1 H-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). 13 C-NMR (100MHz, DMSO-d6) δ167.8,139.5,135.7, 131.0,130.2,119.6,117.9.

[0157] Example 40: Synthesis of Cyclopentaic Acid

[0158]

[0159] Other operations are as described in Example 36, using cyclopentylformaldehyde as the raw material and reacting for 18 hours to obtain cyclopentanoic acid (113 mg, 99%). 1 H-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). 13 C- NMR (100MHz, CDCl3) δ183.6, 43.8, 30.1, 25.9.

[0160] Example 41: Synthesis of 4-Dimethylaminobenzoic acid

[0161]

[0162] Other procedures are as described in Example 36, using p-dimethylaminobenzaldehyde as the raw material and reacting for 5 hours to obtain 4-dimethylaminobenzoic acid (148.7 mg, 90%). 1 H-NMR (400MHz, CDCl3) δ 7.97 (d, J = 9.2 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 3.06 (s, 6H). 13 C-NMR (100 MHz, CDCl3) δ172.2,154.0,132.2,116.0,110.8,40.2.

[0163] Example 42: Synthesis of (R)-(+)-citronellolic acid

[0164]

[0165] Other operations are described in Example 36. The raw material used is (R)-(+)-citronellal, and the reaction time is 2 days to obtain (R)-(+)-citronellalic acid (119.2 mg, 70%, ee value 98%). 1 H-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). 13 C-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

1. A method for preparing a carboxylic acid, characterized in that, The process includes the following steps: In a solvent, 1-hydroxycyclohexylphenyl ketone is used as an oxidant to oxidize the primary alcohol groups or aldehyde groups in the reactants containing primary alcohol groups or aldehyde groups to the corresponding carboxyl groups in the presence of a strong base. The strong alkali mentioned is sodium hydroxide; Reactants containing primary alcohol groups are compounds with the general formula R1'CH2OH. R1' is a straight chain or a branched chain C2-C 16 Alkyl, substituted or unsubstituted phenyl, unsubstituted naphthyl, C2-C8 heterocyclic, terpenoid, C3-C8 cycloalkyl or straight-chain or branched C 2- C 17 Alkenyl; the straight-chain or branched C2-C 16 Alkyl groups and C3-C8 cycloalkyl groups are optionally substituted with phenyl groups; the C2-C8 heterocyclic groups are optionally substituted with ester groups; the substituted phenyl groups are alkoxy-substituted phenyl, alkylthiophenyl, phenylthio, nitrophenyl, trifluoromethylphenyl, halophenyl, benzyloxyphenyl, or aminophenyl. Compounds containing an aldehyde group and having the general formula R2'CHO R2' is a C3-C8 cycloalkyl, C2-C8 heterocyclic, or substituted or unsubstituted phenyl group; the substituted phenyl group is an aminophenyl group; When the reactants contain primary alcohol groups, the molar ratio of the oxidant to the reactants containing primary alcohol groups is 2:1-3:1; When the reactants contain aldehyde groups, the molar ratio of the oxidant to the reactants containing aldehyde groups is 1:1 to 2:1; When the reactants contain primary alcohol groups, the molar ratio of the strong base to the reactants containing primary alcohol groups is 2:1-3:1; When the reactants contain aldehyde groups, the molar ratio of the strong base to the reactants containing aldehyde groups is 1.5:1-2:1; The oxidation reaction temperature is 60℃~80℃.

2. The preparation method according to claim 1, characterized in that, When the reactants contain primary alcohol groups, the molar ratio of the oxidant to the reactants containing primary alcohol groups is 2:1; When the reactants contain aldehyde groups, the molar ratio of the oxidant to the reactants containing aldehyde groups is 1:

1.

3. The preparation method according to claim 1, characterized in that, When the reactants contain primary alcohol groups, the molar ratio of the strong base to the reactants containing primary alcohol groups is 2:1; When the reactants contain aldehyde groups, the molar ratio of the strong base to the reactants containing aldehyde groups is 2:

1.

4. The preparation method according to claim 1, characterized in that, The solvent is a non-alcoholic solvent.

5. The preparation method according to claim 4, characterized in that, The solvent is an ether solvent.

6. The preparation method according to claim 4, characterized in that, The solvent is one or more selected from diethyl ether, dimethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, cyclopentyl methyl ether, dimethyl sulfoxide, pyridine, dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, benzene, and toluene.

7. The preparation method according to claim 4, characterized in that, The solvent is one or more of toluene, pyridine, and ethylene glycol dimethyl ether.

8. The preparation method according to claim 4, characterized in that, The solvent is ethylene glycol dimethyl ether.

9. The preparation method according to claim 1, characterized in that, The volume ratio of the solvent to the molar ratio of the reactant containing a primary alcohol group or an aldehyde group is (1.5 mL - 2 mL): 1 mmol.

10. The preparation method according to claim 9, characterized in that, The volume ratio of the solvent to the reactant containing a primary alcohol group or an aldehyde group is 1.5 mL: 1 mmol.

11. The preparation method according to claim 1, characterized in that, The molar ratio of reactants containing primary alcohol groups, oxidants, and strong bases is 1:(2-3):(2-3).

12. The preparation method according to claim 11, characterized in that, The molar ratio of reactants containing primary alcohol groups, oxidants, and strong bases is 1:2:2 or 1:3:

3.

13. The preparation method according to claim 1, characterized in that, Reactants containing primary alcohol groups include phenylpropanol, p-methoxybenzyl alcohol, 1-naphthaleneethanol, 4-(trifluoromethyl)benzyl alcohol, cinnamyl alcohol, 2-bromophenylethanol, 2-(4-benzylmethoxyphenyl)ethanol, 2-cyclopentylethanol, tetrahydropyran-4-methanol, 1-Boc-3-hydroxymethylpyrrolidine, N-Boc-4-piperidinemethanol, 1-adamantaneethanol, (1-phenylcyclohexyl)methanol, 2-(4-ethoxyphenyl)-2-methylpropanol, 2,2-dimethyl-3-(m-tolyl)prop-1-ol, N-Boc-4-piperidinemethanol, furan-3-methanol, 2-(benzyloxy)ethanol, and benzothiophene-2-methyl. Alcohols, 2-phenylthioethanol, 2-amino-3-hydroxymethylpyridine, 3-pyridinepropanol, 3-(dimethylamino)benzyl alcohol, 1-(2-quinolinyl)ethyl-1-ol, 3-indoleethanol, oleyl alcohol, citronellol, 10-undecen-1-ol, 5-phenyl-4-pentyn-1-ol, fructose diacetone, (2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3-ol, 3-(4-methoxyphenyl)propane-1,2-diol, lithochyl alcohol, chenodeoxycholic acid, primary alcohols of (R)-sulfinamides or primary alcohols of (S)-sulfinamides.

14. The preparation method according to claim 1, characterized in that, The reactants containing primary alcohol groups or aldehyde groups are selected from any of the following compounds:

15. The preparation method according to claim 1, characterized in that, Includes the following steps: At ambient pressure and 60–80 °C, in an organic solvent, 1-hydroxycyclohexylphenyl ketone is used as an oxidant and sodium hydroxide is used as a base to oxidize the primary alcohol groups or aldehyde groups in reactants containing primary alcohol groups or aldehyde groups to the corresponding carboxyl groups.

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