CN115417804A - Synthesis method of 7-methyl-1H-indole-5-carboxylic acid - Google Patents
Synthesis method of 7-methyl-1H-indole-5-carboxylic acid Download PDFInfo
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- CN115417804A CN115417804A CN202211128598.3A CN202211128598A CN115417804A CN 115417804 A CN115417804 A CN 115417804A CN 202211128598 A CN202211128598 A CN 202211128598A CN 115417804 A CN115417804 A CN 115417804A
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- synthesis according
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- methyl
- indole
- carboxylic acid
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- OAWWSPFYTYUIHU-UHFFFAOYSA-N 7-methyl-1h-indole-5-carboxylic acid Chemical compound CC1=CC(C(O)=O)=CC2=C1NC=C2 OAWWSPFYTYUIHU-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000000758 substrate Substances 0.000 claims abstract description 14
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims abstract description 11
- XDTTUTIFWDAMIX-UHFFFAOYSA-N 3-methyl-4-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1[N+]([O-])=O XDTTUTIFWDAMIX-UHFFFAOYSA-N 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910004298 SiO 2 Inorganic materials 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 10
- 229910052763 palladium Inorganic materials 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 abstract description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000005415 magnetization Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- UYVXZUTYZGILQG-UHFFFAOYSA-N methoxyboronic acid Chemical compound COB(O)O UYVXZUTYZGILQG-UHFFFAOYSA-N 0.000 description 1
- IVZPRTUZPQFXKG-UHFFFAOYSA-N methyl 7-bromo-1h-indole-5-carboxylate Chemical compound COC(=O)C1=CC(Br)=C2NC=CC2=C1 IVZPRTUZPQFXKG-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052905 tridymite Inorganic materials 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method of 7-methyl-1H-indole-5-carboxylic acid, which takes 3-methyl-4-nitrobenzoic acid as a substrate to react with vinyl magnesium bromide to obtain a target product. Compared with the conventional Sonogashira coupling or Suzuki coupling reaction, the method avoids the use of expensive palladium catalyst, reduces the cost more economically, simplifies the route, changes the multi-step method into the one-step method, and improves the total reaction yield.
Description
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to a synthesis method of 7-methyl-1H-indole-5-carboxylic acid.
Background
7-methyl-1H-indole-5-carboxylic acid is an important chemical intermediate and has wide application. The structure of 7-methyl-1H-indole-5-carboxylic acid is:
two methods have been reported for the synthesis of 7-methyl-1H-indole-5-carboxylic acid: one method is to take 3-methyl-4-methyl aminobenzoate as a substrate to obtain the product through iodination, sonogashira coupling, cyclization and hydrolysis, the total yield is 38% in 4 steps, and the related documents are as follows: [ Journal of Organic Chemistry,1996, vol.61, #17, p.5804-5812]. The method has long process route, uses expensive palladium catalyst and has low total yield. The second method is to take 7-bromo-1H-indole-5-carboxylic acid methyl ester as a substrate, and perform Suzuki coupling reaction with methyl boric acid under palladium catalysis, and then hydrolyze the product, wherein the yield of the route is not mentioned in two steps, and the related patents: US2012077797A1. This method is expensive in substrate and also uses expensive palladium catalyst, and the small amount reported in literature is low in yield.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of 7-methyl-1H-indole-5-carboxylic acid, which comprises the following technical route:
in order to solve the technical problem, the invention provides a synthesis method of 7-methyl-1H-indole-5-carboxylic acid, which is characterized in that a substrate 3-methyl-4-nitrobenzoic acid is added into a reaction solvent, the reaction is reduced to a low temperature below zero under the protection of nitrogen, vinyl magnesium bromide is added into the reaction at the low temperature below zero, the mixture is stirred for 0.5 to 2 hours, then the temperature is naturally raised to 15 to 20 ℃, and the product 7-methyl-1H-indole-5-carboxylic acid is obtained after the quenching reaction and purification treatment.
Specifically, the mass-to-volume ratio (m: V) of the substrate to the reaction solvent is 1.
Specifically, the vinyl magnesium bromide is 1mol/L tetrahydrofuran solution.
Specifically, the feeding molar ratio of the substrate to the vinyl magnesium bromide is 1: (3-10).
Specifically, the reaction solvent is selected from one or more of tetrahydrofuran and 2-methyltetrahydrofuran.
Specifically, the subzero temperature is-70 ℃ to-65 ℃.
Specifically, the quenching reaction is carried out by adding the reaction system into an ammonium chloride aqueous solution for quenching.
Specifically, the concentration of the ammonium chloride aqueous solution is 20% m/v.
Specifically, the purification treatment is to extract twice with 50mL ethyl acetate, then combine the organic phases, wash the organic phase once with 50mL sodium chloride aqueous solution (20% m/v), finally dry the organic phase with sodium sulfate, concentrate under reduced pressure, purify with column chromatography, and concentrate the fractions to obtain the product.
Specifically, the column chromatography adopts an SiO2 column, and the volume ratio of the adopted petroleum ether/ethyl acetate is 5:1-1:1.
Specifically, the inert atmosphere refers to that the reaction is carried out under the protection of nitrogen or inert gas (such as helium, argon and the like).
In the invention, 3-methyl-4-nitrobenzoic acid is used as a substrate and reacts with vinyl magnesium bromide to obtain a target product. Compared with the conventional Sonogashira coupling or Suzuki coupling reaction, the method avoids the use of expensive palladium catalyst, reduces the cost more economically, simplifies the route, changes the multi-step method into the one-step method, and improves the total reaction yield.
Detailed Description
In the following, the technical solutions in the present invention are clearly and completely described, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example one
Adding a substrate of 3-methyl-4-nitrobenzoic acid (10.0g, 1eq) into THF (200 mL), cooling the reaction system to-70 ℃ to-65 ℃ under the protection of nitrogen, adding vinyl magnesium bromide (220mL, 4eq, 1mol/L THF solution) into the reaction system within the temperature range, stirring at the temperature for half an hour, and naturally heating to 15-20 ℃. Adding the reaction system to an aqueous ammonium chloride solution (20% m/v) at 15-20 deg.C, extracting twice with 50mL of ethyl acetate, combining the organic phases, washing the organic phase once with 50mL of aqueous sodium chloride solution (20% m/v), drying the organic phase with sodium sulfate, concentrating under reduced pressure, and performing column chromatography (SiO) 2 Petroleum ether/ethyl acetate 5:1-1:1) and concentrated fractions to give a light gray solid (6.8 g, 58.4% yield, 90% purity).
The nuclear magnetization of the product is as follows: 1H NMR (400MHz, meOD) delta 8.17 (s, 1H), 7.60 (s, 1H), 7.31 (d, J =3.2Hz, 1H), 6.56 (d, J =3.2Hz, 1H), 2.53 (s, 3H)
Example two
Adding a substrate of 3-methyl-4-nitrobenzoic acid (10.0g, 1eq) into THF (200 mL), cooling a reaction system to-70 ℃ to-65 ℃ under the protection of nitrogen, adding vinyl magnesium bromide (276mL, 5eq, 1mol/L THF solution) into the reaction system within the temperature range, stirring at the temperature for half an hour, and naturally heating to 15-20 ℃. Adding the reaction system to an aqueous ammonium chloride solution (20% m/v) at 15-20 deg.C, extracting twice with 50mL of ethyl acetate, combining the organic phases, washing the organic phase once with 50mL of aqueous sodium chloride solution (20% m/v), drying the organic phase with sodium sulfate, concentrating under reduced pressure, and performing column chromatography (SiO) 2 Petroleum ether/ethyl acetate 5:1-1:1) and concentrated fractions to give a light gray solid (7.1 g, 61% yield, 90% purity).
The nuclear magnetization of the product is as follows: 1H NMR (400MHz, meOD) delta 8.17 (s, 1H), 7.60 (s, 1H), 7.31 (d, J =3.2Hz, 1H), 6.56 (d, J =3.2Hz, 1H), 2.53 (s, 3H)
EXAMPLE III
Adding a substrate of 3-methyl-4-nitrobenzoic acid (10.0g, 1eq) into THF (200 mL), cooling a reaction system to-70 ℃ to-65 ℃ under the protection of nitrogen, adding vinyl magnesium bromide (331mL, 6eq, 1mol/L THF solution) into the reaction system within the temperature range, stirring at the temperature for half an hour, and naturally heating to 15-20 ℃. Adding the reaction system to an aqueous ammonium chloride solution (20% m/v) at 15-20 deg.C, extracting twice with 50mL of ethyl acetate, combining the organic phases, washing the organic phase with 50mL of aqueous sodium chloride solution (20% m/v)Drying the organic phase with sodium sulfate, concentrating under reduced pressure, and performing column chromatography (SiO) 2 Petroleum ether/ethyl acetate 5:1-1:1) and concentrated fractions to give a light gray solid (7.0 g, 60% yield, 90% purity).
The nuclear magnetization of the product is as follows: 1H NMR (400MHz, meOD) delta 8.17 (s, 1H), 7.60 (s, 1H), 7.31 (d, J =3.2Hz, 1H), 6.56 (d, J =3.2Hz, 1H), 2.53 (s, 3H)
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (11)
1. A synthesis method of 7-methyl-1H-indole-5-carboxylic acid is characterized in that a substrate 3-methyl-4-nitrobenzoic acid is added into a reaction solvent, the reaction is reduced to a subzero temperature under an inert atmosphere, vinyl magnesium bromide is added into the reaction at the subzero temperature, the mixture is stirred for 0.5 to 2 hours, then the temperature is naturally raised to 15 to 20 ℃, and the product 7-methyl-1H-indole-5-carboxylic acid is obtained after quenching reaction and purification treatment.
2. The method of synthesis according to claim 1, characterized in that: the mass-to-volume ratio (m: V) of the substrate to the reaction solvent is 1.
3. The method of synthesis according to claim 1, characterized in that: the vinyl magnesium bromide is 1mol/L tetrahydrofuran solution.
4. The method of synthesis according to claim 1, characterized in that: the feeding molar ratio of the substrate to the vinyl magnesium bromide is 1: (3-10).
5. The method of synthesis according to claim 1, characterized in that: the reaction solvent is selected from one or more of tetrahydrofuran and 2-methyltetrahydrofuran.
6. The method of synthesis according to claim 1, characterized in that: the subzero temperature is-70 ℃ to-65 ℃.
7. The method of synthesis according to claim 1, characterized in that: the quenching reaction is to add the reaction system to an aqueous ammonium chloride solution for quenching.
8. The method of synthesis according to claim 7, characterized in that: the concentration of the ammonium chloride aqueous solution was 20% by volume m/v.
9. The method of synthesis according to claim 1, characterized in that: the purification treatment is carried out by extracting twice with 50mL ethyl acetate, combining the organic phases, washing the organic phase once with 50mL sodium chloride aqueous solution (20% m/v), drying the organic phase with sodium sulfate, concentrating under reduced pressure, purifying by column chromatography, and concentrating the fractions to obtain the product.
10. The method of synthesis according to claim 9, characterized in that: the column chromatography adopts SiO 2 The column adopts the volume ratio of the petroleum ether to the ethyl acetate of 5:1 to 1:1.
11. The method of synthesis according to claim 1, characterized in that: the inert atmosphere means that the reaction is carried out under the protection of nitrogen or inert gas (such as helium, argon and the like).
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|---|---|---|---|
| CN202211128598.3A CN115417804A (en) | 2022-09-16 | 2022-09-16 | Synthesis method of 7-methyl-1H-indole-5-carboxylic acid |
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| CN202211128598.3A CN115417804A (en) | 2022-09-16 | 2022-09-16 | Synthesis method of 7-methyl-1H-indole-5-carboxylic acid |
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| CN202211128598.3A Pending CN115417804A (en) | 2022-09-16 | 2022-09-16 | Synthesis method of 7-methyl-1H-indole-5-carboxylic acid |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB997638A (en) * | 1961-03-22 | 1965-07-07 | Merck & Co Inc | Indole derivatives |
| CN103080103A (en) * | 2010-09-27 | 2013-05-01 | 詹森药业有限公司 | Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors |
| US20140128391A1 (en) * | 2012-11-02 | 2014-05-08 | Acetylon Pharmaceuticals, Inc. | Selective hdac1 and hdac2 inhibitors |
| CN106478500A (en) * | 2015-09-02 | 2017-03-08 | 广东东阳光药业有限公司 | Carboxylic acid-substituted（Miscellaneous）Aromatic ring analog derivative and its production and use |
| CN113024440A (en) * | 2021-03-17 | 2021-06-25 | 凯莱英医药集团（天津）股份有限公司 | Method for continuously synthesizing substituted indole-2-carboxylic acid |
-
2022
- 2022-09-16 CN CN202211128598.3A patent/CN115417804A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB997638A (en) * | 1961-03-22 | 1965-07-07 | Merck & Co Inc | Indole derivatives |
| CN103080103A (en) * | 2010-09-27 | 2013-05-01 | 詹森药业有限公司 | Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors |
| US20140128391A1 (en) * | 2012-11-02 | 2014-05-08 | Acetylon Pharmaceuticals, Inc. | Selective hdac1 and hdac2 inhibitors |
| CN106478500A (en) * | 2015-09-02 | 2017-03-08 | 广东东阳光药业有限公司 | Carboxylic acid-substituted（Miscellaneous）Aromatic ring analog derivative and its production and use |
| CN113024440A (en) * | 2021-03-17 | 2021-06-25 | 凯莱英医药集团（天津）股份有限公司 | Method for continuously synthesizing substituted indole-2-carboxylic acid |
Non-Patent Citations (2)
| Title |
|---|
| EZQUERRA JESUS，等: "Efficient Reagents for the Synthesis of 5-, 7-and 5, 7-substituted Indoles Starting from Aromatic Amines： Scope and Limitations", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, no. 17, pages 5805 * |
| KERSTIN KNEPPER，等: "Bartoli Indole Synthesis on Solid Supports", ORGANIC LETTERS, vol. 5, no. 6, pages 2829 - 2832 * |
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