CN118239878A - Synthesis method of indole-3-propionic acid - Google Patents
Synthesis method of indole-3-propionic acid Download PDFInfo
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- CN118239878A CN118239878A CN202410328012.0A CN202410328012A CN118239878A CN 118239878 A CN118239878 A CN 118239878A CN 202410328012 A CN202410328012 A CN 202410328012A CN 118239878 A CN118239878 A CN 118239878A
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- GOLXRNDWAUTYKT-UHFFFAOYSA-N 3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(CCC(=O)O)=CNC2=C1 GOLXRNDWAUTYKT-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000003290 indole 3-propionic acid Substances 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 60
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 30
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 229910007926 ZrCl Inorganic materials 0.000 claims abstract description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 17
- 239000006227 byproduct Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000001988 toxicity Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 13
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 13
- 230000001105 regulatory effect Effects 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMGHKYYNDUANOZ-UHFFFAOYSA-N ethyl 3-(1h-indol-3-yl)propanoate Chemical compound C1=CC=C2C(CCC(=O)OCC)=CNC2=C1 ZMGHKYYNDUANOZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- KLRHPHDUDFIRKB-UHFFFAOYSA-M indium(i) bromide Chemical compound [Br-].[In+] KLRHPHDUDFIRKB-UHFFFAOYSA-M 0.000 description 2
- 210000005027 intestinal barrier Anatomy 0.000 description 2
- 230000007358 intestinal barrier function Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000000804 Pregnane X Receptor Human genes 0.000 description 1
- 108010001511 Pregnane X Receptor Proteins 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of indole-3-propionic acid, and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) Reacting indole with a compound shown in a formula A in the presence of a catalyst to obtain a compound shown in a formula B; (2) Under alkaline conditions, the compound shown in the formula B undergoes hydrolysis reaction to obtain indole-3-propionic acid. The catalyst is at least one of ZrCl 4、AlCl3 and SnCl 4. The method has the advantages of simple operation, less byproducts, high yield and high product purity. The method has low requirements on equipment, low reagent toxicity and low price, and is convenient for industrialized amplified production. The method has the advantages of wide reagent sources and short production period, and can realize mass production in a short time.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of indole-3-propionic acid.
Background
Indole-3-propionic acid is an indole derivative of intestinal microbiota which is metabolized by tryptophan, has the functions of anti-inflammatory, antioxidant, immunoregulation and the like, and is important for maintaining intestinal barrier steady state. Indole-3-propionic acid can activate pregnane X receptor to inhibit NF- κB signal path to inhibit enteritis under the action of indole. In addition, indole-3-propionic acid can maintain intestinal barrier steady state by inhibiting TNF-alpha and activating TLR4, and is expected to become a novel green feed additive.
The presently disclosed patents for synthesizing indole-3-propionic acid are few, and mainly comprise a biological method and a chemical method. For example, chinese patent invention CN117327721A and CN113677802A realize whole cell catalysis process of producing indole-3-propionic acid by using tryptophan as substrate by constructing engineering strain and original strain respectively. However, the problems of the biological synthesis of indole-3-propionic acid are: 1) The productivity and the production efficiency of the product are easily affected by the growth of microorganisms; 2) The preparation period of the product is long, and the cost is high through a plurality of complex steps such as microorganism culture, fermentation, bacterial liquid concentration, extraction and purification and the like. The international publication WO2008024914A2 synthesizes indole-3-propionic acid by a chemical method, the indole, acrylic acid, acetic acid and acetic anhydride are used as raw materials, the indole-3-propionic acid is obtained by reacting for 64 hours at 50 ℃ under the protection of nitrogen, the excessive acetic anhydride is required to be removed by distillation after the reaction is finished, more byproducts are required to be treated, and the yield is only 36%. The method has the advantages of harsh reaction conditions, more byproducts, low yield and complex process. Therefore, there is a need to develop a convenient, rapid, and economical synthetic route to produce inexpensive indole-3-propionic acid.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthetic method of indole-3-propionic acid, which has the advantages of simple process, low production cost and high yield, and is convenient for industrial production.
The synthesis method of indole-3-propionic acid provided by the invention comprises the following steps:
(1) Reacting indole with a compound shown in a formula A in the presence of a catalyst to obtain a compound shown in a formula B;
In the formula A and the formula B, R 1 is a linear or branched alkyl of C 1-C6, and can be specifically ethyl;
(2) Under alkaline conditions, the compound shown in the formula B undergoes hydrolysis reaction to obtain indole-3-propionic acid.
In the above method step (1), the catalyst may be at least one of ZrCl 4、AlCl3 and SnCl 4;
the reaction is carried out in an organic solvent;
The organic solvent is at least one of dichloromethane, tetrahydrofuran and N, N-dimethylformamide;
The molar ratio of indole, the compound of formula A, and the catalyst (e.g., zrCl 4) may be 1: (1.0-1.5): (0.1 to 0.3) (preferably, the end point value of 0.1 is not preferable), specifically, 1:1.2:0.2 to 0.3;
The mass ratio of the indole to the organic solvent is 1: (20-50);
The reaction temperature can be 20-50 ℃ and the reaction time is 4-8 h;
the reaction is carried out under magnetic stirring;
After the reaction is finished, adding saturated sodium bicarbonate aqueous solution, regulating the pH value of the system, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography to obtain a compound shown in a formula B;
Wherein the pH value of the system is 8.0-8.5, and the leaching solution in the silica gel chromatographic column is ethyl acetate: petroleum ether=1:3 (v/v).
The operation of the method step (2) is as follows: adding sodium hydroxide aqueous solution into the compound shown in the formula B, stirring for a certain time at normal temperature, adding acid to adjust pH, and carrying out suction filtration to obtain white powdery indole-3-propionic acid.
Wherein, the mass concentration of the sodium hydroxide aqueous solution is 1-10%, and the mass ratio of the compound shown in the formula B to the sodium hydroxide aqueous solution is 1: (4-10), stirring time is 3-12 h, and final pH value of the system is 1-6.
Compared with the prior art, the indole-3-propionic acid synthesis process has the following characteristics:
1) The method has the advantages of simple operation, less byproducts, high yield and high product purity.
2) The method has low requirements on equipment, low reagent toxicity and low price, and is convenient for industrialized amplified production.
3) The method has the advantages of wide reagent sources and short production period, and can realize mass production in a short time.
Drawings
FIG. 1 is a reaction equation for synthesizing indole-3-propionic acid according to the present invention.
FIG. 2 shows the nuclear magnetic resonance hydrogen spectrum of indole-3-propionic acid prepared in example 1 of the present invention.
FIG. 3 is a nuclear magnetic resonance carbon spectrum of indole-3-propionic acid prepared in example 1 of the present invention.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The specifications and sources of reagents used in the following examples are as follows:
Indole, ethyl acrylate and ZrCl 4 are all purchased from Shanghai Meilin Biochemical technologies, and dichloromethane, ethyl acetate, petroleum ether, hydrochloric acid, sodium hydroxide and sodium bicarbonate are all purchased from Shanghai national pharmaceutical Congress chemical reagent, and are all analytically pure reagents.
EXAMPLE 1 Synthesis of indole-3-propionic acid
(1) Indole, ethyl acrylate and ZrCl 4 are mixed according to a mol ratio of 1:1.2:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and the reaction was stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate, wherein the yield is 87% and the purity is 97%.
(2) 100G of indole-3-propionic acid ethyl ester is added into 500g of sodium hydroxide aqueous solution (the mass concentration of sodium hydroxide is 10%), after stirring for 6 hours at normal temperature, dilute hydrochloric acid is added to adjust the pH to 1-3, and suction filtration is carried out to obtain white powdery indole-3-propionic acid, the yield is 100%, and the purity is 96%.
EXAMPLE 2 Synthesis of indole-3-propionic acid
(1) Indole, ethyl acrylate and AlCl 3 are mixed according to a mole ratio of 1:1.2:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate, wherein the yield is 72%, and the purity is 98%.
(2) 100G of indole-3-propionic acid ethyl ester is added into 500g of sodium hydroxide aqueous solution (the mass concentration of sodium hydroxide is 10%), after stirring for 6 hours at normal temperature, dilute hydrochloric acid is added to adjust the pH to 1-3, and suction filtration is carried out to obtain white powdery indole-3-propionic acid, the yield is 100%, and the purity is 95%.
EXAMPLE 3 Synthesis of indole-3-propionic acid
(1) Indole, ethyl acrylate and SnCl 4 are mixed according to a mole ratio of 1:1.2:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, a proper amount of saturated sodium bicarbonate aqueous solution is added, the pH value of the system is regulated to 8.0-8.5, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) is carried out, so that indole-3-ethyl propionate is obtained, the yield is 76%, and the purity is 96%.
(2) 100G of indole-3-propionic acid ethyl ester is added into 500g of sodium hydroxide aqueous solution (the mass concentration of sodium hydroxide is 10%), after stirring for 6 hours at normal temperature, dilute hydrochloric acid is added to adjust the pH to 1-3, and suction filtration is carried out to obtain white powdery indole-3-propionic acid, the yield is 100%, and the purity is 96%.
Comparative example 1
Indole, ethyl acrylate and ZrCl 4 are mixed according to a mol ratio of 1:1.2:0.05 was added to a round bottom flask, dichloromethane (30 times the mass of indole) was added and the reaction was stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate with the yield of 43%.
The results show that: the yield of the obtained target product is low, which indicates that the addition amount of the catalyst ZrCl 4 is too low to effectively promote the reaction.
Comparative example 2
Indole, ethyl acrylate and ZrCl 4 are mixed according to a mol ratio of 1:2:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate with the yield of 18%.
The results show that: the yield of the obtained target product is low, and a large amount of byproducts are generated, which indicates that the addition amount of the ethyl acrylate is excessive, side reaction with indole occurs in the reaction process, and competitive inhibition occurs with the synthesis of the target product.
Comparative example 3
Indole, ethyl acrylate and ZrCl 4 are mixed according to a mol ratio of 1:1.2:0.5 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 6h. After the reaction is completed, a proper amount of saturated sodium bicarbonate aqueous solution is added, the pH value of the system is regulated to 8.0-8.5, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) is carried out, so that indole-3-ethyl propionate is obtained, the yield is 52%, and the purity is 73%.
The results show that: the purity of the obtained target product is lower, which indicates that too large an addition amount of the catalyst ZrCl 4 can introduce more byproducts which are difficult to separate, increase the separation difficulty of the product and reduce the purity of the product.
Comparative example 4
Indole, ethyl acrylate and ZrCl 4 are mixed according to a mol ratio of 1:0.8:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 8h. After the reaction is completed, a proper amount of saturated sodium bicarbonate aqueous solution is added, the pH value of the system is regulated to 8.0-8.5, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) is carried out, so that indole-3-ethyl propionate is obtained, the yield is 46%, and the purity is 79%.
The results show that: the yield of the obtained target product is lower, which indicates that the addition amount of the ethyl acrylate is too small, more byproducts are generated, and the purity of the product is reduced.
Comparative example 5
Indole, ethyl acrylate and AlCl 3 are mixed according to a mole ratio of 1:1.2:0.05 was added to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 8h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate with the yield of 23%.
The results show that: the yield of the obtained target product is low, which indicates that the addition amount of the catalyst AlCl 3 is too small to effectively promote the reaction.
Comparative example 6
Indole, ethyl acrylate and SnCl 4 are mixed according to a mole ratio of 1:1.2:0.1 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 8h. After the reaction is completed, adding a proper amount of saturated sodium bicarbonate aqueous solution, regulating the pH value of the system to 8.0-8.5, adding ethyl acetate for extraction to obtain an organic phase, and performing silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) to obtain indole-3-ethyl propionate with a yield of 31%.
The results show that: the yield of the obtained target product is low, which indicates that the addition amount of the catalyst SnCl 4 is too small to effectively promote the reaction.
Comparative example 7
Indole, ethyl acrylate and indium bromide (InBr 3) are mixed according to a molar ratio of 1:1.2:0.2 to a round bottom flask, dichloromethane (30 times the mass of indole) was added and stirred at room temperature (25 ℃ C.) for 8h. After the reaction is completed, a proper amount of saturated sodium bicarbonate aqueous solution is added, the pH value of the system is regulated to 8.0-8.5, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) is carried out, so that indole-3-ethyl propionate is obtained, the yield is 15%, and the purity is 59%.
The results show that: the yield of the obtained target product is lower, and the purity of the product is lower, which indicates that the catalytic efficiency of the catalyst InBr 3 is lower and a large amount of byproducts are generated.
The present application is described in detail above. It will be apparent to those skilled in the art that the present application can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the application and without undue experimentation. While the application has been described with respect to specific embodiments, it will be appreciated that the application may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains.
Claims (9)
1. A synthetic method of indole-3-propionic acid comprises the following steps:
(1) Reacting indole with a compound shown in a formula A in the presence of a catalyst to obtain a compound shown in a formula B;
In the formula A and the formula B, R 1 is a linear or branched alkyl of C 1-C6;
(2) Under alkaline conditions, the compound shown in the formula B undergoes hydrolysis reaction to obtain indole-3-propionic acid.
2. The method of claim 1, wherein in step (1), the catalyst is at least one of ZrCl 4、AlCl3 and SnCl 4.
3. The process according to claim 1, wherein in step (1), the reaction is carried out in an organic solvent;
The organic solvent is at least one of dichloromethane, tetrahydrofuran and N, N-dimethylformamide.
4. The method according to claim 1, wherein in step (1), the molar ratio of indole, the compound of formula a, and the catalyst is 1: (1.0-1.5): (0.1-0.3).
5. The method according to claim 1, wherein in the step (1), the reaction is carried out at a temperature of 20 to 50 ℃ for a time of 4 to 8 hours.
6. The method according to claim 1, wherein in the step (1), after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added, the pH value of the system is adjusted, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography is performed to obtain the compound shown in the formula B.
7. The method according to claim 6, wherein the pH value of the system is 8.0-8.5, and the leaching solution in the silica gel chromatographic column is ethyl acetate: petroleum ether=1:3, v/v.
8. The method of claim 1, wherein the operation of step (2) is: adding sodium hydroxide aqueous solution into the compound shown in the formula B, stirring for a certain time at normal temperature, adding acid to adjust pH, and carrying out suction filtration to obtain white powdery indole-3-propionic acid.
9. The method according to claim 8, wherein the mass concentration of the aqueous sodium hydroxide solution is 1-10%, and the mass ratio of the compound represented by formula B to the aqueous sodium hydroxide solution is 1: (4-10), stirring time is 3-12 h, and final pH value of the system is 1-6.
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