CN116606205A - Synthetic method of ester compound - Google Patents

Synthetic method of ester compound Download PDF

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CN116606205A
CN116606205A CN202310515537.0A CN202310515537A CN116606205A CN 116606205 A CN116606205 A CN 116606205A CN 202310515537 A CN202310515537 A CN 202310515537A CN 116606205 A CN116606205 A CN 116606205A
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solvent
reaction
compound
ester compound
ethyl acetate
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张逢质
张智晨
刘敏
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—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
    • 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
    • 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
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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    • 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

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Abstract

The invention discloses a method for synthesizing an ester compound, which comprises the steps of mixing a carboxylic acid compound (I), a 1,3, 4-oxadiazoline compound (II), a catalyst and a solvent, carrying out stirring reaction for 2-24 hours at the temperature of 0-50 ℃ under the irradiation of an LED lamp, and then carrying out post-treatment on a reaction solution to obtain an ester compound (III); the method has the advantages that the reaction operation is simple and efficient, the innovation point of the method is that the carbon-oxygen bond of the carboxylic ester is constructed by utilizing the photoinitiated carbene insertion reaction, and the yield of the obtained corresponding ester compound is up to 95%;

Description

Synthetic method of ester compound
Technical Field
The invention relates to a preparation method of a series of ester compounds, which are prepared from corresponding carboxylic acid substances and 1,3, 4-oxadiazoline compounds under certain conditions.
Background
Carboxylic esters are one of the most common functional groups in natural products, drug molecules, functional materials. The carboxylic ester structure is widely existed in nature, and glyceride of higher fatty acid is one of substances essential for life activities; in the field of pharmaceutical chemistry, carboxylic acid medicines are prepared into prodrugs of carboxylic acid esters, so that the solubility and bioavailability of the medicines can be greatly improved. Therefore, the research and construction of the ester substances are of great significance, and have also attracted wide attention at home and abroad.
The construction of ester materials has been focused on the construction of C-O bonds using carboxylic acids as raw materials. However, for the synthesis of ester related substances, the conventional preparation method is mainly embodied in an esterification method of related carboxylic acid and alcohol, and a large amount of byproducts are generated under the corresponding catalyst and severe conditions, such as: and the ethers, alcohols and the like are carbonized, and the products are not easy to separate and purify. At present, the main practice is to react carboxylic acid and alcohol under the system of condensing agent and alkali (Angew.chem.int.ed.1978, 17,522), the reaction system is mild, but equivalent condensing agent is needed, and the post-reaction treatment is troublesome and the atom economy is relatively poor. It is also possible to convert the corresponding carboxylic acids into the corresponding acid halides or anhydrides and then react with alcohol compounds to give ester compounds. Such processes are relatively cumbersome to operate, and the intermediate acid chloride is active in nature and not suitable for substrates that are not acid tolerant. The use of carboxylic acids with the corresponding halogenated hydrocarbons under electrochemical conditions has been reported by the team to give the corresponding carboxylic esters (Journal of Oleo Science,2014,63,539), but the electrochemical synthesis requires two steps of reaction and requires an excess of tetrabutylammonium fluoride as electrolyte. The preparation of carboxylic esters by hydrocarbon activation methods (org. Lett.2013,15,4098) has also been reported by the team, but such methods are complex in reaction system, cumbersome to operate, and require noble metal catalysts and ligands, which are not conducive to scale-up.
Therefore, the development of a synthesis method with high efficiency and mild conditions is particularly important. Since the first report of Hoffmann in 1966 on the production of 1,3, 4-oxadiazolines (Tetrahedron lett.1966,4,411), the use of this compound as a novel carbene precursor has been receiving extensive attention, and a great deal of excellent results have been reported successively through the continuous efforts of many workers (acc. Chem. Res.2009,42,1,205), and it has been reported that 1,3, 4-oxadiazolines can be excited under light to produce carbenes (Angew.Chem.Int.Ed.2017, 56,16602;Chem.Commun.2018,54,11685;J.Org.Chem.2018,83,15558), thereby inspiring whether or not the direct production of esters from related carboxylic acids and 1,3, 4-oxadiazolines can be attempted.
Disclosure of Invention
The invention aims to provide a synthesis method of an ester compound. In the synthesis method, the corresponding ester product is directly prepared by taking the carboxylic acid compound and the 1,3, 4-oxadiazoline compound as reaction substrates under illumination by only adding the proper catalyst and the corresponding solvent at one time, and the reaction operation is simple and the yield is high.
The innovation point of the invention is that the carbon-oxygen bond of the carboxylic ester is constructed by utilizing the photoinitiated carbene insertion reaction, and the yield of the obtained corresponding ester compound is up to 95%.
The technical scheme of the invention is as follows:
a synthetic method of an ester compound comprises the following steps:
mixing a carboxylic acid compound (I), a 1,3, 4-oxadiazoline compound (II) and a catalyst with a solvent, stirring and reacting for 2-24 hours at the temperature of 0-50 ℃ under the irradiation of an LED lamp, and then performing post-treatment on the reaction solution to obtain an ester compound (III);
wherein the LED lamp is 6-18W, and the wavelength is 330-460 nm;
the molar ratio of the carboxylic acid compound (I), the 1,3, 4-oxadiazoline compound (II) and the catalyst is 1:1 to 2.5:0.001 to 0.01;
the catalyst is selected from bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2 '-bis (4-tert-butylpyridine) ] iridium bis (hexafluorophosphate), bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bipyridine ] iridium bis (hexafluorophosphate), tris (2-phenylpyridine) iridium, (4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2 ',4' -difluorophenyl) -5-methylpyridine ] iridium (III) hexafluorophosphate, 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile, benzophenone, anthraquinone, 9-thioxanthone or 9-thioxanthone substituted by one or more substituents (each independently selected from C1-C4 alkyl, methoxy or nitro);
the solvent is selected from deionized water, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, methanol or N, N-dimethylformamide; the volume mass ratio of the solvent to the carboxylic acid compound (I) is 60-200: 1, mL/g;
the specific post-treatment method is as follows:
when the solvent is water, after the reaction is finished, adding an organic solvent with the volume of 4-6 times into the reaction liquid, extracting and separating liquid, washing the extract liquid by water and saturated saline water in sequence, drying by anhydrous sodium sulfate, concentrating, purifying by column chromatography, collecting eluent containing a target compound by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as an eluent, evaporating the solvent and drying to obtain a product ester compound; wherein the organic solvent for extraction is ethyl acetate, diethyl ether or dichloromethane;
when the solvent is N, N-dimethylformamide, adding 5-15 times of water into the reaction liquid after the reaction is finished, adding 5-15 times of organic solvent into the reaction liquid, extracting and separating liquid, washing the extract liquid by water and saturated saline water in sequence, drying by anhydrous sodium sulfate, concentrating, purifying by column chromatography, collecting eluent containing target compounds by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as eluent, evaporating the solvent and drying to obtain the product ester compounds; wherein the organic solvent for extraction is ethyl acetate, diethyl ether or dichloromethane;
when the solvent is ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile or methanol, directly concentrating and retracting to perform column chromatography purification after the reaction is finished, collecting eluent containing a target compound by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as an eluent, evaporating the solvent and drying to obtain a product ester compound;
the reaction general formula is as follows:
in the formula (I), (II) or (III),
R 1 the method comprises the following steps: the parent ring group of oleanolic acid, the parent ring group of 5- (2, 4-difluorophenyl) salicylic acid, 2- (3-benzoylphenyl) -propyl, benzyl, nitrogen-containing heterocyclic group (preferably pyridyl or indolyl), thienyl, naphthyl, C2-C18 alkyl, C3-C8 cycloalkyl, phenyl or substituted phenyl; the benzene ring of the substituted phenyl is substituted by one or more substituents, wherein each substituent is independently selected from amino, C1-C6 alkyl (preferably methyl), C1-C3 alkoxy (preferably methoxy), halogen (such as F, cl, br or I), benzoyl, hydroxyl, ester, sulfonyl or cyano;
R 2 、R 3 each independently is: C1-C6 alkyl, C4-C12 cycloalkyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl, adamantyl, piperidinyl or substituted piperidinyl; the piperidine ring of the substituted piperidyl is substituted by one or more substituents which are each independently selected from phenyl, t-butoxycarbonyl or p-toluenesulfonyl;
or R is 2 、R 3 Together forming a cyclopentyl or 4-tetrahydrothiopyranyl group.
The ester compound synthesized by the method can be used as a prodrug of carboxylic acid drugs or natural products, and the method is a method for protecting the ester group of carboxylic acid with high selectivity and high substrate universality.
The invention has the following advantages:
the preparation method provided by the invention can obtain the corresponding ester compound by one step, the reaction can be carried out at room temperature, the reaction system is simple, the condition is mild, the reaction speed is high, the byproducts are fewer, the whole reaction is carried out in a neutral environment, and the post-treatment is simple. The catalyst used in the reaction is low in dosage, and the used starting raw materials and related solvents are cheap and easy to obtain and can be used without further treatment. The yield of the product is high (up to 95%), the application range of the substrate is wide, and the method is suitable for pilot scale production.
Detailed Description
The present invention is further described below by way of specific examples, but the scope of the present invention is not limited thereto.
In the following examples, the catalysts were all purchased from Shanghai Bi, medical science and technology Co., ltd, with a purity of 98%; the relevant carboxylic acid raw materials are purchased from Anhui Zerewrites Co., ltd, and the purity is 98%; solvents were all purchased from Hangzhou square flattening chemical Co., ltd and had a purity of AR; the light source was purchased from Shenzhen kiwi photoelectric limited.
Example 1.
The starting material 3, 3-dimethoxy-4-oxa-1, 2-diaza- [4.4] spiro-1-nonene may be synthesized according to the procedure described in acc.chem.res.2009,42,1,205-212.
4-Methoxybenzoic acid (30.4 mg,0.2 mmol), 3-dimethoxy-4-oxa-1, 2-diaza- [4.4]Spiro-1-nonene (74.5 mg,0.4 mmol), bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine][2-2' -bis (4-t-butylpyridine)]Iridium bis (hexafluorophosphate) (0.6 mg,0.0005 mmol) and 4mL of methylene dichloride are reacted in a 10mL reaction tube under the irradiation of a 420nm 12W blue light source for 3 hours, and after the reaction is completed, the reaction is directly concentrated and purified by column chromatography silica gel to obtain 39.6mg of 4-methoxy-benzoic acid cyclopentyl ester (3 a), the yield is 90%, and the product is colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ8.05–7.92(m,2H),6.96–6.88(m,2H),5.40(m,1H),3.87(s,3H),2.02–1.92(m,2H),1.89–1.76(m,4H),1.67(m,2H)； 13 C NMR(101MHz,Chloroform-d)δ166.38,165.57,134.69,133.70,129.48,52.43,32.78,23.83.
Example 2.
The procedure described in example 1 was followed except that the product was 35.5mg of cyclopentylacetate (3 b) as the substrate (27.2 mg,0.2 mmol) and 87% yield, and was a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ7.41–7.23(m,5H),5.20(m,1H),3.60(s,2H),1.86(m,2H),1.70(m,4H),1.64–1.54(m,2H). 13 C NMR(101MHz,Chloroform-d)δ171.39,134.37,129.20,128.50,126.94,77.53,41.76,32.62,23.70.
Example 3.
The procedure as described in example 1 was repeated except that the catalyst was 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (3.9 mg,0.005 mmol) to give 31.2mg of the product, cyclopentylmethoxybenzoate (3 a), in 71% yield, as a colorless liquid. The structural information is the same as in embodiment 1.
Example 4.
The procedure described in example 1 was followed except that 3, 3-dimethoxy-4-oxa-1, 2-diaza- [4.4] spiro-1-nonene (37.3 mg,0.2 mmol) was added to give the product, cyclopentylmethoxybenzoate (3 a) 25.3mg, in 58% yield, as a colorless liquid. The structural information is the same as in embodiment 1.
Example 5.
4-methoxybenzoic acid (30.4 mg,0.2 mmol), 3-dimethoxy-4-oxa-1, 2-diaza- [4.4] spiro-1-nonene (74.5 mg,0.4 mmol), bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bis (4-tert-butylpyridine) ] iridium bis (hexafluorophosphoric acid) salt (0.6 mg,0.0005 mmol), deionized water 4mL were taken in a 10mL reaction tube, reacted for 24 hours at room temperature under the irradiation of a 420nm 12W blue light source, 20mL dichloromethane was added to the reaction solution after the reaction, the extract was separated, washed with water and saturated saline, dried with anhydrous sodium sulfate, concentrated, purified by column chromatography, eluent containing the target compound was collected with petroleum ether/ethyl acetate=30:1 as eluent, the solvent was distilled off and dried to obtain the product 4-methoxybenzoic acid cyclopentester (3 a) 33.9mg, 77% colorless product as liquid yield. The structural information is the same as in embodiment 1.
Example 6.
4-Methoxybenzoic acid (30.4 mg,0.2 mmol), 3-dimethoxy-4-oxa-1, 2-diaza- [4.4] spiro-1-nonene (74.5 mg,0.4 mmol), bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bis (4-t-butylpyridine) ] iridium bis (hexafluorophosphate) (0.6 mg,0.0005 mmol), and 2mL of N, N-dimethylformamide were taken in a 10mL reaction tube, and reacted at room temperature for 3 hours under the irradiation of a 420nm 12W blue light source. After the reaction, 20mL of water is added into the reaction liquid, then 20mL of ethyl acetate is added, extraction is repeated for three times, the extract liquid is sequentially washed by water and saturated saline water after the organic phase is combined, anhydrous sodium sulfate is dried, column chromatography purification is carried out after concentration, petroleum ether/ethyl acetate=30:1 is used as eluent, eluent containing target compounds is collected, solvent is distilled off and dried, and the product of 29.5mg of 4-methoxy-benzoic acid cyclopentyl ester (3 a) is obtained, the yield is 67%, and the product is colorless liquid. The structural information is the same as in embodiment 1.
Example 7.
The procedure described in example 1 was followed except that the light source was a 12W,460nm LED, to give 34.8mg of the product, 4-methoxybenzoic acid cyclopentyl ester (3 a), in 79% yield, as a colorless liquid. The structural information is the same as in embodiment 1.
Example 8.
The procedure described in example 1 was followed except that the product was pyridine-4-carboxylic acid (24.6 mg,0.2 mmol) and was cyclopentylpyridine-4-carboxylic acid (3 c) 31.0mg in 81% yield as colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ8.89–8.69(m,2H),7.93–7.71(m,2H),5.44(m,1H),2.03–1.93(m,2H),1.84(m,4H),1.72–1.62(m,2H). 13 C NMR(101MHz,Chloroform-d)δ164.83,150.47,138.05,122.83,78.79,32.72,23.77.HRMS m/z(ESI):calcd for C 11 H 13 O 2 Na[M+Na] + 214.0838,found:214.0843.
Example 9.
The procedure described in example 1 was followed except that the product was indole-3-carboxylic acid (32.2 mg,0.2 mmol) as the substrate and was cyclopenta-3-carboxylate (3 d) 25.7mg in 56% yield as a pale yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.24–8.13(m,1H),7.93(d,J＝2.9Hz,1H),7.48–7.40(m,1H),7.31–7.25(m,2H),5.50(tt,J＝6.2,2.9Hz,1H),2.06–1.98(m,2H),1.96–1.85(m,4H),1.70m,2H). 13 C NMR(101MHz,Chloroform-d)δ165.32,136.17,131.11,125.76,123.10,121.97,121.52,111.57,109.53,76.58,32.98,23.93.HRMS m/z(ESI):calcd for C 14 H 15 O 2 Na[M+Na] + 252.0995,found:252.0996.
Example 10.
The procedure described in example 1 was followed except that the product was thiophene-2-carboxylic acid (25.6 mg,0.2 mmol) as the substrate was thiophene-2-carboxylic acid cyclopentyl ester (3 e) 23.5mg, the yield was 60%, and the product was a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.79(dd,J＝3.7,1.3Hz,1H),7.55(dd,J＝5.0,1.2Hz,1H),7.10(dd,J＝4.9,3.7Hz,1H),5.39(tt,J＝6.1,2.8Hz,1H),1.96m,2H),1.89–1.78(m,4H),1.67(m,2H). 13 C NMR(101MHz,Chloroform-d)δ162.10,134.67,133.03,132.00,127.63,78.04,32.76,23.78.HRMS m/z(ESI):calcd for C 10 H 13 O 2 S[M+H] + 197.0631,found:197.0628.
Example 11.
The procedure described in example 1 was followed except that the product having the substrate 2- (3-benzoylphenyl) -propionic acid (25.6 mg,0.2 mmol) was 61.2mg of cyclopentyl 2- (3-benzoylphenyl) -propionate (3 f), the yield was 95%, and the product was whiteColor solids. 1 H NMR(400MHz,Chloroform-d)δ7.84–7.79(m,2H),7.76(d,J＝1.8Hz,1H),7.69(dt,J＝7.6,1.5Hz,1H),7.64–7.59(m,1H),7.56(dt,J＝7.7,1.5Hz,1H),7.50(t,J＝7.6Hz,2H),7.46(t,J＝7.7Hz,1H),5.18(tt,J＝5.6,2.3Hz,1H),3.76(q,J＝7.2Hz,1H),1.81(m,2H),1.72–1.58(m,4H),1.57(m,2H),1.53(d,J＝7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ196.65,173.83,141.06,137.82,132.53,131.53,130.08,129.23,128.91,128.51,128.33,77.64,45.58,23.68,23.63,18.38.
Example 12.
The procedure described in example 1 was followed except that the product having the substrate 5- (2, 4-difluorophenyl) salicylic acid (25.6 mg,0.2 mmol) was cyclopentyl5- (2, 4-difluorophenyl) salicylate (3 g) 47.7mg, yield 75% and was a white solid. 1 H NMR(400MHz,Chloroform-d)δ11.05(s,1H),7.94(dd,J＝2.3,1.3Hz,1H),7.60(dt,J＝8.6,2.0Hz,1H),7.38(td,J＝8.7,6.4Hz,1H),7.07(d,J＝8.6Hz,1H),7.02–6.87(m,2H),5.48(tt,J＝6.2,2.8Hz,1H),2.08–1.97(m,2H),1.96–1.81(m,4H),1.76–1.64(m,2H). 13 C NMR(101MHz,Chloroform-d)δ169.86,163.39,161.31,160.88,158.40,135.96,131.10,130.07,125.90,117.84,113.03,111.63,104.41,78.79,32.74,23.82.HRMS m/z(ESI):calcd for C 18 H 17 F 2 O 3 [M+H] + 319.1140,found:319.1138.
Example 13.
The procedure described in example 1 was followed, except that the product having the substrate oleanolic acid (91.2 mg,0.2 mmol) was 62.9mg of cyclopentanol (3 h), yield 60%, and the product was a white solid. 1 H NMR(400MHz,Chloroform-d)δ5.28(t,J＝3.7Hz,1H),5.10(tq,J＝5.2,3.3,2.1Hz,1H),3.22(dd,J＝11.2,4.9Hz,1H),2.85(dd,J＝14.0,4.5Hz,1H),1.95–1.26(m,31H),1.14(s,3H),0.99(s,3H),0.92(d,J＝1.9Hz,6H),0.90(s,3H),0.78(s,3H),0.77(s,3H). 13 C NMR(101MHz,Chloroform-d)δ122.26,78.98,76.57,55.24,47.63,46.38,45.95,41.76,41.34,39.40,38.75,38.50,37.03,33.95,33.13,32.86,32.62,32.44,32.42,30.72,28.14,27.58,27.20,25.77,23.68,23.61,23.57,23.45,22.98,18.35,17.15,15.62,15.36.HRMS m/z(ESI):calcd for C 35 H 56 O 3 K[M+K] + 563.3861,found:563.3849.
Example 14.
The starting material 2, 2-dimethyl-5, 5-dimethoxy-2, 5-dihydro-1, 3, 4-oxadiazole can be synthesized according to the method in acc.chem.res.2009,42,1,205-212.
The procedure described in example 1 was followed except that the substrate was 4-methoxybenzoic acid (30.4 mg,0.2 mmol) and 2, 2-dimethyl-5, 5-dimethoxy-2, 5-dihydro-1, 3, 4-oxadiazole (64.0 mg,0.4 mmol), the product was isopropyl 4-methoxybenzoate (3 i) 16.3mg, yield 42% and the product was a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ8.06–7.97(m,2H),6.95–6.91(m,2H),5.24(m,1H),3.88(s,3H),1.37(d,J＝6.3Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ165.91,163.18,131.50,123.39,113.49,67.95,55.42,22.01.
Example 15.
The starting material 2, 2-diethyl-5, 5-dimethoxy-2, 5-dihydro-1, 3, 4-oxadiazole can be synthesized according to the procedure described in ACS catalyst.2023, 13,3,1964-1973.
The procedure described in example 1 was followed except that the substrate was 4-methoxybenzoic acid (30.4 mg,0.2 mmol) and 2, 2-diethyl-5, 5-dimethoxy-2, 5-dihydro-1, 3, 4-oxadiazole (75.2 mg,0.4 mmol), the product was (4-methoxybenzoic acid) -3-pentyl ester (3 j) 38.7mg, the yield was 60%, and the product was a colorless liquid. 1 H NMR(400MHz,Chloroform-d)δ8.12–7.95(m,2H),7.00–6.89(m,2H),5.01(m,1H),3.87(s,3H),1.76–1.66(m,4H),0.96(t,J＝7.5Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ166.23,163.20,131.51,123.29,113.53,76.89,55.39,26.61,9.67.
Example 16.
The starting material 3, 3-dimethoxy-4-oxa-8-thia 1, 2-diaza- [4.4] spiro-1-decene may be synthesized according to the procedure described in ACS Catal.2023,13,3,1964-1973.
The procedure described in example 1 was followed, except that the substrates were 4-methoxybenzoic acid (30.4 mg,0.2 mmol) and 3, 3-dimethoxy-4-oxa-8-thia 1, 2-diaza- [4.4]Spiro-1-decene (87.2 mg,0.4 mmol), product (4-methoxybenzoic acid) -4-tetrahydrothiopyran ester (3 j) 30.8mg, yield 61%, product as white solid. 1 H NMR(400MHz,Chloroform-d)δ8.12–7.90(m,2H),7.04–6.85(m,2H),5.10(tt,J＝8.1,3.3Hz,1H),3.88(s,3H),2.99–2.83(m,2H),2.75–2.57(m,2H),2.21(m,2H),2.04(m,2H). 13 C NMR(101MHz,Chloroform-d)δ165.35,163.43,131.61,122.87,113.63,70.41,55.46 32.53,25.75.HRMS m/z(ESI):calcd for C 13 H 16 O 3 SNa[M+Na] + 275.0712,found:275.0721.
Application examples
The product obtained in example 11, cyclopentyl 2- (3-benzoylphenyl) -propionate (64.4 mg,0.2 mmol) was taken in a 25mL flask, 10mL of 2N hydrochloric acid was added, and the mixture was refluxed for 2h. After the reaction is completed, 20mL of ethyl acetate is added into the reaction liquid, the liquid is separated by extraction, the organic phase of the extract liquid is washed by water and saturated saline water, dried by anhydrous sodium sulfate and concentrated to obtain 48.3mg of ketoprofen, the yield is 95%, and the product is white solid. Ketoprofen is a class of non-steroidal anti-inflammatory drugs.

Claims (6)

1. The synthesis method of the ester compound is characterized by comprising the following steps:
mixing a carboxylic acid compound (I), a 1,3, 4-oxadiazoline compound (II) and a catalyst with a solvent, stirring and reacting for 2-24 hours at the temperature of 0-50 ℃ under the irradiation of an LED lamp, and then performing post-treatment on the reaction solution to obtain an ester compound (III);
wherein the catalyst is selected from bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2 '-bis (4-t-butylpyridine) ] iridium bis (hexafluorophosphate), bis [2- (2, 4-difluorophenyl) -5-trifluoromethylpyridine ] [2-2' -bipyridine ] iridium bis (hexafluorophosphate), tris (2-phenylpyridine) iridium, (4, 4 '-di-t-butyl-2, 2' -bipyridine) bis [2- (2 ',4' -difluorophenyl) -5-methylpyridine ] iridium (III) hexafluorophosphate, 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile, benzophenone, anthraquinone, 9-thioxanthone or 9-thioxanthone substituted with one or more substituents;
the reaction general formula is as follows:
in the formula (I), (II) or (III),
R 1 the method comprises the following steps: the mother ring group of oleanolic acid, the mother ring group of 5- (2, 4-difluorophenyl) salicylic acid, 2- (3-benzoylphenyl) -propyl, benzyl, nitrogen-containing heterocyclic group, thienyl, naphthyl, C2-C18 alkyl, C3-C8 cycloalkyl, phenyl or substituted phenyl; the benzene ring of the substituted phenyl is substituted by one or more substituents, and each substituent is independently selected from amino, C1-C6 alkyl, C1-C3 alkoxy, halogen, benzoyl, hydroxyl, ester, sulfonyl or cyano;
R 2 、R 3 each independently is: C1-C6 alkyl, C4-C12 cycloalkyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl, adamantyl, piperidinyl or substituted piperidinyl; the piperidine ring of the substituted piperidyl is substituted by one or more substituents which are each independently selected from phenyl, t-butoxycarbonyl or p-toluenesulfonyl;
or R is 2 、R 3 Together forming a cyclopentyl or 4-tetrahydrothiopyranyl group.
2. The method for synthesizing an ester compound according to claim 1, wherein the LED lamp is 6-18W and has a wavelength of 330-460 nm.
3. The method for synthesizing the ester compound according to claim 1, wherein the molar ratio of the carboxylic acid compound (I), the 1,3, 4-oxadiazoline compound (II) and the catalyst is 1:1 to 2.5:0.001 to 0.01.
4. The method for synthesizing an ester compound according to claim 1, wherein the solvent is selected from deionized water, ethyl acetate, methylene chloride, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, methanol, and N, N-dimethylformamide.
5. The method for synthesizing ester compounds according to claim 1, wherein the volume mass ratio of the solvent to the carboxylic acid compound (I) is 60 to 200:1, mL/g.
6. The method for synthesizing an ester compound according to claim 4 or 5, wherein the post-treatment method is as follows:
when the solvent is water, after the reaction is finished, adding an organic solvent with the volume of 4-6 times into the reaction liquid, extracting and separating liquid, washing the extract liquid by water and saturated saline water in sequence, drying by anhydrous sodium sulfate, concentrating, purifying by column chromatography, collecting eluent containing a target compound by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as an eluent, evaporating the solvent and drying to obtain a product ester compound; wherein the organic solvent for extraction is ethyl acetate, diethyl ether or dichloromethane;
when the solvent is N, N-dimethylformamide, adding 5-15 times of water into the reaction liquid after the reaction is finished, adding 5-15 times of organic solvent into the reaction liquid, extracting and separating liquid, washing the extract liquid by water and saturated saline water in sequence, drying by anhydrous sodium sulfate, concentrating, purifying by column chromatography, collecting eluent containing target compounds by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as eluent, evaporating the solvent and drying to obtain the product ester compounds; wherein the organic solvent for extraction is ethyl acetate, diethyl ether or dichloromethane;
when the solvent is ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile or methanol, directly concentrating and retracting to perform column chromatography purification after the reaction is finished, collecting eluent containing a target compound by taking the volume ratio of petroleum ether/ethyl acetate=100:1-10:1 as an eluent, evaporating the solvent and drying to obtain the product ester compound.
CN202310515537.0A 2023-05-09 2023-05-09 Synthetic method of ester compound Pending CN116606205A (en)

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