CN114163376A - Synthetic method of indoline - Google Patents
Synthetic method of indoline Download PDFInfo
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- CN114163376A CN114163376A CN202111190197.6A CN202111190197A CN114163376A CN 114163376 A CN114163376 A CN 114163376A CN 202111190197 A CN202111190197 A CN 202111190197A CN 114163376 A CN114163376 A CN 114163376A
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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
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Abstract
The invention relates to a method for synthesizing indoline, which takes low-cost o-aminophenylethanol as a raw material, synthesizes a new compound 1- [ (4-methylphenyl) sulfonyl ] indoline through cyclic amino protection, and then carries out deprotection reaction on the new compound in a sulfuric acid solution so as to obtain a target product indoline.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a synthetic method of indoline.
Background
Indolines (also known as indolines) are also known as 2, 3-dihydroindoles (2, 3-dihydroindoles) and 2, 3-dihydro-1H-indoles (2, 3-dihydro-1H-indoles), abbreviated as IDN. Indoline is colorless to yellow transparent liquid at normal temperature and pressure. At present, indolines are mainly used for synthesizing derivative products of indoles, such as indoline dyes, sensitizers of solar cells, and intermediates of medicines and plant growth regulators.
Chinese patent publication No. CN112174871B entitled "method for preparing indoline" (application No. CN202011243305.7) discloses a method comprising the following steps: a. performing condensation and ring closure on phenylhydrazine hydrochloride or phenylhydrazine hydrochloride containing substituent groups and methyl ketone compounds in a solvent under the non-catalytic condition to generate C2-methylindole or derivatives thereof, and then cooling, salting out, filtering and desolventizing; b. c, dissolving the salt generated in the step b in water, then performing alkaline hydrolysis in a solvent and an alkali liquor, layering, desolventizing and distilling to obtain a product such as: 1,3, 3-trimethyl-2-methylindoline or a derivative thereof.
In the scheme, phenylhydrazine hydrochloride or phenylhydrazine hydrochloride containing substituent groups and methyl ketone compounds are condensed and cyclized to generate C2-methylindole or derivatives thereof, and the method has the disadvantages of complex process, expensive raw materials and high preparation cost.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a synthetic method of indoline, which has simple process and low raw material price so as to reduce the preparation cost.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a synthetic method of indoline comprises the following steps:
(1) cyclization reaction
Adding o-aminophenylethanol, an acid-binding agent and p-toluenesulfonyl chloride (PTSC) into a solvent, and stirring for reaction;
after the reaction is completed, removing excessive p-toluenesulfonyl chloride and an acid-binding agent by water washing liquid separation, evaporating part of the solvent of the obtained organic layer, dripping into methanol for crystallization, filtering, washing and drying to obtain a product for later use;
(2) deprotection reaction
Adding the product obtained in the step (1) into a sulfuric acid solution with a certain concentration, heating to reflux while stirring, and continuously keeping the temperature until the reaction is complete after the solution is clear;
slowly dropping the reaction solution into ice water, controlling the temperature below 10 ℃, adjusting the pH to 8-9, extracting with Ethyl Acetate (EA), and spin-drying the obtained organic layer to obtain a target product, namely the indoline.
In the present invention, the product obtained in step (1) is 1- [ (4-methylphenyl) sulfonyl ] indoline, which is a novel compound having the following structural formula:
the nuclear magnetic analysis result of the product obtained in the step (1) is as follows:1HNMR(500MHz，DMSO-d6)，δ：7.70(d,2H,14,18)，δ：7.48(d,1H,4)，δ：7.36(d,2H,15,17)，δ：7.19(t,1H,2)，δ：7.15(d,1H,1)，δ：6.97(t,1H,3)，δ：3.89(t,2H,9)，δ：2.89(t,2H,8)，δ：2.33(s,3H,19)。
the new compound 1- [ (4-methylphenyl) sulfonyl ] indoline synthesized in the step (1) can be used for preparing indoline, and indoline can be obtained through simple deprotection reaction, so that the preparation process of indoline is greatly simplified.
Preferably, the acid-binding agent in the step (1) is triethylamine or pyridine.
Preferably, the solvent described in step (1) is Tetrahydrofuran (THF) or Dichloromethane (DCM).
Preferably, the reaction temperature in step (1) is room temperature.
Preferably, the concentration of sulfuric acid in step (2) is not less than 80%.
Compared with the prior art, the invention has the advantages that: the invention takes low-price o-aminophenylethanol as a raw material, a new compound 1- [ (4-methylphenyl) sulfonyl ] indoline is synthesized through amino protection and cyclization, and then the new compound is subjected to deprotection reaction in a sulfuric acid solution, so that a target product indoline is obtained.
Drawings
FIG. 1 is a single crystal diffractogram of the product obtained in step (1) in example 1 of the present invention;
FIG. 2 is a diagram showing the results of the step (1) in example 1 of the present invention1A HNMR map;
FIG. 3 is a diagram showing the results of the step (2) in example 1 of the present invention1HNMR map.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1:
the synthesis method of indoline in this embodiment includes the following steps:
(1) cyclization reaction
Adding 25g of o-aminophenylethanol, 240g of Tetrahydrofuran (THF) and 22g of triethylamine into a 500mL three-necked flask, adding 108g of p-toluenesulfonyl chloride (PTSC) in 3 batches under the action of mechanical stirring at room temperature, heating to 50 ℃ after the addition is finished, refluxing, and keeping the temperature for 3 hours until the reaction is complete;
distilling at 40-60 ℃ under normal pressure and reduced pressure to remove Tetrahydrofuran (THF), adding the obtained dried substance into 160g of methanol, stirring and pulping under ice-water bath, filtering under reduced pressure, leaching with a small amount (30-50 g) of precooled methanol, and drying the obtained filter cake at 50 ℃ to obtain 1- [ (4-methylphenyl) sulfonyl ] indoline;
the reaction mechanism is as follows:
as shown in FIGS. 1 and 2, 1- [ (4-methylphenyl) sulfonyl group is a single crystal diffraction analysis and nuclear magnetic analysis of the product obtained in this step]The nuclear magnetic analysis results of indoline are:1HNMR(500MHz，DMSO-d6)，δ：7.70(d,2H,14,18)，δ：7.48(d,1H,4)，δ：7.36(d,2H,15,17)，δ：7.19(t,1H,2)，δ：7.15(d,1H,1)，δ：6.97(t,1H,3)，δ：3.89(t,2H,9)，δ：2.89(t,2H,8)，δ：2.33(s,3H,19)；
(2) deprotection reaction
Preparing 60g of sulfuric acid solution with volume concentration of 80%, adding 6g of the product obtained in the step (1), heating to reflux while stirring, and continuously keeping the temperature until the reaction is complete after the solution is clear;
slowly dripping the reaction solution into 100g of ice water, controlling the temperature to be below 10 ℃, adjusting the pH to 8-9 by using ammonia water after the addition is finished, extracting by using Ethyl Acetate (EA), and spin-drying an organic layer to obtain 2.39g of a target product with the yield of 92.3 percent
The reaction mechanism is as follows:
as shown in fig. 3, the target product was determined to be indoline. Indoline nuclear magnetic analysis results:1HNMR(500MHz，DMSO-d6)，δ：7.01(d,1H)，δ：6.88(t,1H)，δ：6.52-6.47(m,2H)，δ：5.43(s,1H)，δ：3.38(t,2H)，δ：2.88(t,2H)。
example 2:
the synthesis method of indoline in this embodiment includes the following steps:
(1) cyclization reaction
In 200g Dichloromethane (DCM) solvent, 25g o-aminophenylethanol, 17.2g pyridine and 108g p-toluenesulfonyl chloride (PTSC) are put into the solvent and stirred for reflux reaction;
after the reaction is completed, adding 150g of water, stirring, separating liquid, evaporating most of solvent by Dichloromethane (DCM), dropping into 150g of methanol, stirring and pulping in an ice-water bath, filtering under reduced pressure, leaching by using a small amount of precooled methanol (30-50 g), and drying the obtained filter cake at 50 ℃ to obtain 1- [ (4-methylphenyl) sulfonyl ] indoline;
(2) deprotection reaction
Preparing 60g of sulfuric acid solution with volume concentration of 80%, adding 6g of the product obtained in the step (1), heating to reflux while stirring, and continuously keeping the temperature until the reaction is complete after the solution is clear;
slowly dripping the reaction liquid into 100g of ice water, controlling the temperature to be below 10 ℃, adjusting the pH to 8-9 by using ammonia water after the addition is finished, extracting by using Ethyl Acetate (EA), and spin-drying an organic layer to obtain 2.19g of a target product with the yield of 84.6%.
Claims (7)
1. The method for synthesizing indoline is characterized by comprising the following steps:
(1) cyclization reaction
Adding o-aminophenylethanol, an acid-binding agent and p-toluenesulfonyl chloride into a solvent, and stirring for reaction;
after the reaction is completed, removing excessive p-toluenesulfonyl chloride and an acid-binding agent by water washing liquid separation, evaporating part of the solvent of the obtained organic layer, dripping into methanol for crystallization, filtering, washing and drying to obtain a product for later use;
(2) deprotection reaction
Adding the product obtained in the step (1) into a sulfuric acid solution, heating to reflux under stirring, and continuously keeping the temperature until the reaction is complete after the solution is clear;
slowly dropping the reaction solution into ice water, controlling the temperature below 10 ℃, adjusting the pH value to 8-9, extracting with ethyl acetate, and spin-drying the obtained organic layer to obtain a target product, namely the indoline.
2. The method for synthesizing indoline according to claim 1, wherein: the product obtained in the step (1) is 1- [ (4-methylphenyl) sulfonyl ] indoline, and the structural formula of the product is as follows:
3. the method for synthesizing indoline according to claim 2, wherein: the nuclear magnetic analysis result of the product obtained in the step (1) is as follows:1HNMR(500MHz，DMSO-d6)，δ：7.70(d,2H,14,18)，δ：7.48(d,1H,4)，δ：7.36(d,2H,15,17)，δ：7.19(t,1H,2)，δ：7.15(d,1H,1)，δ：6.97(t,1H,3)，δ：3.89(t,2H,9)，δ：2.89(t,2H,8)，δ：2.33(s,3H,19)。
4. the method for synthesizing indoline according to claim 1, 2 or 3, wherein: the acid-binding agent in the step (1) is triethylamine or pyridine.
5. The method for synthesizing indoline according to claim 1, 2 or 3, wherein: the solvent in the step (1) is tetrahydrofuran or dichloromethane.
6. The method for synthesizing indoline according to claim 1, 2 or 3, wherein: the reaction temperature in step (1) is room temperature.
7. The method for synthesizing indoline according to claim 1, 2 or 3, wherein: the concentration of the sulfuric acid in the step (2) is not less than 80%.
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| CN202111190197.6A CN114163376A (en) | 2021-10-12 | 2021-10-12 | Synthetic method of indoline |
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- 2021-10-12 CN CN202111190197.6A patent/CN114163376A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| CHEN LI ET AL.: ""A robust and facile method for desulfonation to amines"", 《ORG. CHEM. FRONT.》, vol. 8, pages 6182 - 6187 * |
| S. N. MISHRA ET AL.: ""Studies Related to the Chemistry of Melanins. Part 111 Synthesis of 5, 6- Di hydroxyindoline"", 《J. CHEM. SOC. C》, vol. 1967, pages 1424 - 1427 * |
| TOMAS JAVORSKIS ET AL.: ""Chemoselective Deprotection of Sulfonamides Under Acidic Conditions: Scope, Sulfonyl Group Migration, and Synthetic Applications"", 《J. ORG. CHEM.》, vol. 82, pages 13423 - 13439 * |
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