CN106966951B - 4-fluoro-2-methylindole and preparation method and application thereof - Google Patents
4-fluoro-2-methylindole and preparation method and application thereof Download PDFInfo
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- CN106966951B CN106966951B CN201710264550.8A CN201710264550A CN106966951B CN 106966951 B CN106966951 B CN 106966951B CN 201710264550 A CN201710264550 A CN 201710264550A CN 106966951 B CN106966951 B CN 106966951B
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- methylindole
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- 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
Abstract
The invention discloses new compounds 4-fluoro-2-methylindole, and discloses a preparation method and application thereof, wherein the structure of the 4-fluoro-2-methylindole is shown in formula 1, 2, 3-difluoronitrobenzene is used as a raw material, and the 4-fluoro-2-methylindole is obtained by substitution, protection, reduction and cyclization, the reaction conditions of the synthesis route of the provided new compound 4-fluoro-2-methylindole can be stable to obtain products, side reactions are avoided, the used raw materials are common and easy to obtain, the reaction conditions are mild, and the requirements on experimental equipment are low, and the new compound 4-fluoro-2-methylindole has a unique chemical structure, so that the derived medicine and pesticide have unique physiological activity and can be used as an intermediate of novel and efficient medicine and pesticide.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to novel compounds, namely 4-fluoro-2-methylindole, and a preparation method and application thereof.
Background
Indole has unique chemical structure, so that derived medicines and pesticides have unique physiological activity, and many natural substances with strong physiological activity are indole derivatives, which are attracted by attention of the world, such as downstream products of 2-methylindole, 3-methylindole, 1-butyl-2-methylindole, N-methyl-2-phenylindole, 3-dimethylaminomethylindole, indole-3-acetic acid, indole-3-butyric acid, indoline, 5-oxindole, 5-methoxyindole, indole-3-formaldehyde, 5-nitroindole, indole-3-carboxylic acid, indole-2-carboxylic acid, N-methylindole, 2-methylindole, indole-3-carbonitrile, indole-2-methylindole, indole-3-carbonitrile, indole-2-methyl indole, indole-3-carbonitrile, indole-2-methyl indole, The indolylacetonitrile is an important novel efficient intermediate of medicines and pesticides. In medicine, antipyretic analgesic, analeptic, hypotensor, vasodilator, and antiasthmatic may be synthesized. Many natural medicines have indole structures, for example, toad venom in Liushen pills, which is a Chinese patent medicine, contains 5-hydroxyindole derivatives, many alkaloids contain indole ring systems, and reserpine, which is a commonly used antihypertensive medicine, is an important derivative of indole.
Disclosure of Invention
The invention aims to provide novel compounds, namely 4-fluoro-2-methylindole, and provides a preparation method and application of the compounds in the aspects of medical intermediates or pesticides.
In order to achieve the purpose, the invention adopts the technical scheme that 4-fluoro-2-methylindole compounds have a molecular formula of C9H8NF having the structure of formula 1:
A process for preparing the 4-fluoro-2-methylindole, comprising the steps of:
(1) taking tetrahydrofuran as a solvent, dropwise adding ethyl acetoacetate at the temperature below 10 ℃ in the presence of sodium hydride, stirring for 30 minutes, then dropwise adding 2, 3-difluoronitrobenzene, and reacting at room temperature for more than 48 hours to obtain 2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate;
(2)2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate reacts for 24 hours at 90 ℃ under the condition of mixed acid consisting of concentrated hydrochloric acid and glacial acetic acid to obtain a substituent;
(3) taking toluene as a solvent, and carrying out reflux dehydration reaction on the substituent and ethylene glycol for 24 hours in the presence of a p-toluenesulfonic acid catalyst to obtain a protective substance;
(4) methanol is taken as a solvent, and the protective substance and ammonium formate carry out reflux reaction for 3 hours under the action of a palladium-carbon catalyst to obtain a reducing substance;
(5) methanol and water are used as solvents, and the reduced product is refluxed for 2 to 3 hours under the protection of hydrochloric acid and nitrogen to obtain 4-fluoro-2-methylindole
And , wherein the volume ratio of the concentrated hydrochloric acid to the glacial acetic acid in the mixed acid in the step 2 is 0.5-1.5: 1.
And , adding 2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate and mixed acid in the step 2 according to the proportion of 1 mol: 1-2L.
And , adding the substituent and the glycol in the step 3 in a molar ratio of 1: 2-4.
In step , the weight ratio of the protective substance to the ammonium formate added in step 4 is 1: 1.
kinds of 4-fluoro-2-methylindole are used as medicine intermediate or pesticide.
The new compound 4-fluoro-2-methylindole provided by the invention has the advantages that the reaction conditions of the synthetic route can stably obtain the product, and the side reaction is avoided. And the used raw materials are common and easy to obtain, the reaction condition is mild, and the requirement on experimental equipment is not high. The novel compound 4-fluoro-2-methylindole has unique chemical structure, so that the derived medicine and pesticide have unique physiological activity and can be used as a novel and efficient intermediate of the medicine and the pesticide.
Drawings
FIG. 1 is a high performance liquid phase diagram of 4-fluoro-2-methylindole prepared in example 1.
FIG. 2 is a mass spectrum of 4-fluoro-2-methylindole prepared in example 1.
Detailed Description
The invention is further illustrated in step with reference to specific examples.
Example 1
A1L reaction bottle is matched with a mechanical stirring device, a thermometer and a constant pressure dropping funnel, 450mL tetrahydrofuran and 45g sodium hydride are added under the cooling of ice water bath, the temperature is controlled below 10 ℃, 140g ethyl acetoacetate is added dropwise, and stirring is carried out for 30 minutes after the dropping is finished. 85g of 2, 3-difluoronitrobenzene were added dropwise. After the dripping is finished, the temperature is raised to the room temperature and the mixture is stirred for 48 hours. Concentrated to dryness under reduced pressure, cooled and extracted with 800mL of 2N hydrochloric acid and ethyl acetate, and the ethyl acetate layer was concentrated to dryness to give 223.2g of an oil. 630g of glacial acetic acid and 540g of hydrochloric acid are added, the temperature is raised to reflux, and the temperature is kept for 24 h. Concentrating under reduced pressure until the indole substitute is dry, cooling, adjusting the pH value to 7-8 with a saturated sodium carbonate solution, extracting with ethyl acetate, washing an ethyl acetate layer with water, drying, and concentrating until the indole substitute is dry, wherein 100g of the indole substitute is obtained.
A1L reaction flask was equipped with a mechanical stirrer, condenser, and thermometer, and 300mL of toluene, 100g of indole substituent, 89g of ethylene glycol, and 6g of p-toluenesulfonic acid were added. Heating to reflux and carrying water, supplementing 8.9g of ethylene glycol and 0.6g of p-toluenesulfonic acid every 3 hours, and carrying out reflux reaction for 24 hours. After the reaction, the temperature is reduced, 300mL of saturated sodium bicarbonate is added, the aqueous layer is extracted with 100mL of toluene for a plurality of times, the toluene layers are combined, washed with water, dried and concentrated to dryness to obtain an oil, and 40mL of ethyl acetate is added: petroleum ether is 1: and 1, putting the mixture into a refrigerator for freezing overnight. Filtration afforded 50g of a solid.
A1L reaction bottle is provided with a mechanical stirrer, a condenser tube and a thermometer, 50g of indole protective compound, 12.5g of palladium carbon and 500mL of methanol are added under the protection of nitrogen, the temperature is raised to reflux, 50g of ammonium formate is added in 5 batches under the reflux state, and the reaction is carried out for 3 hours. Hot filtration under nitrogen protection. The filtrate was concentrated to dryness under reduced pressure to obtain 49g of an oily liquid.
A1L reaction bottle is provided with a mechanical stirrer, a condenser tube and a thermometer, 49g of indole reducing substance, 26g of hydrochloric acid, 500mL of methanol and 40mL of water are added under the protection of nitrogen, the temperature is raised to reflux, and the temperature is kept for 3 hours. Concentrating under reduced pressure to dryness, adding 200mL of water, extracting with 150mL of ethyl acetate for 2 times, combining ethyl acetate layers, washing with water, drying, and concentrating to dryness to obtain 31g of oily liquid with purity: 99.7%, molar yield: 38.9 percent.
FIG. 1 is a high performance liquid phase diagram of the product 4-fluoro-2-methylindole, and FIG. 2 is a mass spectrum showing a target ion [ ES- ] mass-to-nuclear ratio of 148.5 at 12.14 minutes, resulting from a molecular weight of 149.16 .
Example 2
A1L reaction bottle is matched with a mechanical stirring device, a thermometer and a constant pressure dropping funnel, 450mL tetrahydrofuran and 45g sodium hydride are added under the cooling of ice water bath, the temperature is controlled below 10 ℃, 140g ethyl acetoacetate is added dropwise, and stirring is carried out for 30 minutes after the dropping is finished. 85g of 2, 3-difluoronitrobenzene were added dropwise. After the dripping is finished, the temperature is raised to the room temperature and the mixture is stirred for 48 hours. Concentrated to dryness under reduced pressure, cooled and extracted with 800mL of 2N hydrochloric acid and ethyl acetate, and the ethyl acetate layer was concentrated to dryness to give 227.5g of an oil. 630g of glacial acetic acid and 540g of hydrochloric acid are added, the temperature is raised to reflux, and the temperature is kept for 24 h. Concentrating under reduced pressure until the indole substitute is dry, cooling, adjusting the pH value to 7-8 with a saturated sodium carbonate solution, extracting with ethyl acetate, washing an ethyl acetate layer with water, drying, and concentrating until the indole substitute is dry, wherein 105g of the indole substitute is obtained.
A1L reaction flask was equipped with a mechanical stirrer, condenser, and thermometer, and 300mL of toluene, 105g of indole substituent, 93g of ethylene glycol, and 6.3g of p-toluenesulfonic acid were added. Heating to reflux and carrying water, supplementing 9.3g of ethylene glycol and 0.63g of p-toluenesulfonic acid every 3 hours, and carrying out reflux reaction for 24 hours. After the reaction, the temperature is reduced, 300mL of saturated sodium bicarbonate is added, the aqueous layer is extracted with 100mL of toluene for a plurality of times, the toluene layers are combined, washed with water, dried and concentrated to dryness to obtain an oil, and 40mL of ethyl acetate is added: petroleum ether is 1: and 1, putting the mixture into a refrigerator for freezing overnight. Filtration afforded 55g of a solid.
A1L reaction bottle is provided with a mechanical stirrer, a condenser tube and a thermometer, 55g of indole protective compound, 13.8g of palladium-carbon and 500mL of methanol are added under the protection of nitrogen, the temperature is raised to reflux, 55g of ammonium formate is added in 5 batches under the reflux state, and the reaction is carried out for 3 hours. Hot filtration under nitrogen protection. The filtrate was concentrated to dryness under reduced pressure to obtain 53g of an oily liquid.
A1L reaction bottle is provided with a mechanical stirrer, a condenser tube and a thermometer, 53g of indole reducing substance, 28g of hydrochloric acid, 500mL of methanol and 40mL of water are added under the protection of nitrogen, the temperature is raised to reflux, and the temperature is kept for 3 hours. Concentrating under reduced pressure to dryness, adding 200mL of water, extracting with 150mL of ethyl acetate for 2 times, combining ethyl acetate layers, washing with water, drying, and concentrating to dryness to obtain 34g of oily liquid with purity: 99.8%, molar yield: 42.6 percent.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. Any simple modifications, equivalent variations and modifications of the above examples, which are in accordance with the principles of the present technology and methods, remain within the scope of the technical and method solutions of the present invention.
Claims (5)
- The preparation method of kinds of 4-fluoro-2-methylindole is characterized by comprising the following steps:(1) taking tetrahydrofuran as a solvent, dropwise adding ethyl acetoacetate at the temperature below 10 ℃ in the presence of sodium hydride, stirring for 30 minutes, then dropwise adding 2, 3-difluoronitrobenzene, and reacting at room temperature for more than 48 hours to obtain 2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate;(2)2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate reacts for 24 hours at 90 ℃ under the condition of mixed acid consisting of concentrated hydrochloric acid and glacial acetic acid to obtain a substituent;
(3) taking toluene as a solvent, and carrying out reflux dehydration reaction on the substituent and ethylene glycol for 24 hours in the presence of a p-toluenesulfonic acid catalyst to obtain a protective substance;
(4) methanol is taken as a solvent, and the protective substance and ammonium formate carry out reflux reaction for 3 hours under the action of a palladium-carbon catalyst to obtain a reducing substance;
(5) methanol and water are used as solvents, and the reduced product is refluxed for 2 to 3 hours under the protection of hydrochloric acid and nitrogen to obtain 4-fluoro-2-methylindole
- 2. The method of claim 1, wherein: in the step 2, the volume ratio of concentrated hydrochloric acid to glacial acetic acid in the mixed acid is 0.5-1.5: 1.
- 3. the method of claim 1, wherein: adding 2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate into the step 2, wherein the ratio of the added 2- (2-fluoro-6-nitrophenyl) -3-ethyl acetoacetate to the mixed acid is 1 mol: 1-2L.
- 4. The method of claim 1, wherein: the molar ratio of the substituent to the ethylene glycol added in the step 3 is 1: 2 to 4.
- 5. The method of claim 1, wherein: the weight ratio of the added protective substance to the ammonium formate in the step 4 is 1: 1.
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| 4-氟-5-羟基-2-甲基吲哚的合成;孙敏等;《中国医药工业杂志》;20121231;第43卷(第10期);第811页图1和左栏第1和2段 * |
| Condensed Heteroaromatic Ring Systems. VI. Synthesis of Indoles and Pyrrolopyridines from o-Nitroarylacetylenes;TAKAO SAKAMOTO et al.,;《Chem. Pharm. Bull》;19861231;第34卷(第6期);第2363页图2和第2366页第2-3段 * |
| Synthesis and serotonin transporter activity of sulphur-substituted α-alkyl phenethylamines as a new class of anticancer agents;Suzanne M. Cloonan et al.,;《European Journal of Medicinal Chemistry》;20090806;第44卷;第4868页Scheme 3和第4897页右栏第1-2段 * |
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