阅读说明：本技术 一种4-羟基吲哚的合成方法 (Synthesis method of 4-hydroxyindole ) 是由 庄明晨 陶康 谢坤山 亢兴龙 徐兴兵 郭鹏 于 2020-12-30 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一种4-羟基吲哚的合成方法。针对现有技术中,4-羟基吲哚工业化生产中存在的问题,本发明的技术方案是其包括如下步骤：(1)将化合物3中的羟基用保护基团保护,得到化合物4；(2)将化合物4与N,N-二甲基甲酰胺二甲基缩醛反应得到化合物5；(3)将化合物5与NH-2NH-2·H-2O和MeOH混合后反应,得到化合物6；(4)脱去化合物6的保护基团,即得4-羟基吲哚。本发明合成4-羟基吲哚的方法成起始原料的成本低,合成过程反应条件温和,操作方便,后处理简单,收率高。(The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 4-hydroxyindole. Aiming at the problems in the industrial production of 4-hydroxyindole in the prior art, the technical scheme of the invention is that the method comprises the following steps: (1) protecting hydroxyl in the compound 3 with a protecting group to obtain a compound 4; (2) reacting the compound 4 with N, N-dimethylformamide dimethyl acetal to obtain a compound 5; (3) reacting compound 5 with NH 2 NH 2 ·H 2 Mixing O and MeOH, and reacting to obtain a compound 6; (4) removing the protecting group of the compound 6 to obtain the 4-hydroxyindole. The method for synthesizing the 4-hydroxyindole has the advantages of low cost of initial raw materials, mild reaction conditions in the synthesis process, convenient operation, simple post-treatment and high yield.)

1. The synthesis method of the 4-hydroxyindole is characterized by comprising the following synthetic routes:

wherein R is a protecting group;

which comprises the following steps:

(1) protecting hydroxyl in the compound 3 with a protecting group to obtain a compound 4;

(2) reacting the compound 4 with N, N-dimethylformamide dimethyl acetal to obtain a compound 5;

(3) mixing the compound 5 with a reducing agent and a catalyst and then reacting to obtain a compound 6;

(4) removing the protecting group of the compound 6 to obtain the 4-hydroxyindole.

2. A method of synthesis according to claim 1, characterized in that: and R is selected from alkyl or benzyl.

3. A method of synthesis according to claim 1, characterized in that: the specific process of the step (1) is as follows: mixing the compound 3 with alkali, dissolving in a solvent, slowly adding RBr under the protection of inert gas, heating for reaction after the dropwise addition is finished, and separating and purifying after the reaction is finished to obtain a compound 4;

preferably, the base is selected from K₂CO₃、Na₂CO₃、Cs₂CO₃Or NaH; and/or, the solvent is selected from at least one of DMF, THF, DCM or EtOAc; and/or controlling the temperature to be 25-30 ℃ in the process of slowly adding the RBr; and/or the temperature of the heating reaction is 30-80 ℃, preferably 60 ℃; and/or the heating reaction time is 10 to 14 hours, preferably 12 hours; and/or the dosage ratio of the compound 3 to the RBr is 1 eq: 1-1.4eq, preferably 1 eq: 1.2 eq.

4. A method of synthesis according to claim 1, characterized in that: the specific processes of the step (2) and the step (3) are as follows:

(2) dissolving a compound 4 and N, N-dimethylformamide dimethyl acetal in a solvent, and heating for reaction to obtain a reaction solution containing a compound 5;

(3) after the temperature of the reaction solution is reduced to room temperature, adding a reducing agent and a catalyst for heating reaction, and separating and purifying after the reaction is finished to obtain a reactant 6;

preferably, the solvent is selected from at least one of DMF, THF, DCM or EtOA; and/or the temperature of the heating reaction in the step (2) is 100-120 ℃, preferably 100 ℃; and/or the heating reaction time in the step (2) is 12 to 24 hours, preferably 24 hours; and/or the temperature of the heating reaction in the step (3) is 70-100 ℃, preferably 100 ℃; and/or the heating reaction time of the step (3) is 10 to 14 hours, preferably 12 hours; and/or the compound 4 and the N, N-dimethylformamide dimethyl acetal are used in a ratio of 1 eq: 3 to 5eq, preferably 1 eq: 4 eq; and/or the compound 4, the reducing agent and the catalyst are used in a proportion of 1 eq: 4-6 eq: 0.05 to 0.15eq, preferably 1 eq: 5 eq: 0.1 eq.

5. A method of synthesis according to claim 1, characterized in that: in the step (3), the reducing agent is NH₂NH₂·H₂O, the catalyst is FeCl₃At least one of Ni, NiB or Carbon; and/or the reducing agent is H₂The catalyst is at least one of Pd/C or Pt/C.

6. A method of synthesis according to claim 1, characterized in that: the specific process of the step (4) is as follows: dissolving the compound 6 in a solvent, adding a catalyst, reacting in a hydrogen atmosphere, and separating and purifying after the reaction is finished to obtain 4-hydroxyindole;

preferably, the solvent is selected from at least one of MeOH, EtOH or THF; and/or the catalyst is at least one of Pd/C, Pt/C, PtO2 or Raney nickel.

7. A method of synthesis according to claim 1, characterized in that: the compound 3 was synthesized by the following synthetic route:

reacting the compound 1 with methanol to obtain a compound 2;

(II) reacting Compound 2 with BBr₃Reaction to give compound 3.

8. The synthesis method according to claim 7, wherein the specific process of step (I) is as follows: dissolving the compound 1, a catalyst, alkali and methanol in a solvent, heating and reacting under the protection of inert gas, and separating and purifying after the reaction is finished to obtain a compound 2;

preferably, the solvent is selected from at least one of toluene, benzene or dioxane; and/or, the catalyst is selected from BrettPhos Pd G3; and/or, the alkali is selected from Cs₂CO₃(ii) a And/or the temperature of the heating reaction is 60-80 ℃, preferably 70 ℃; and/or the heating reaction time is 14 to 18 hours, preferably 16 hours; and/or the dosage ratio of the compound 1 to the methanol is 1 eq: 5 to 20eq, preferably 1 eq: 10 eq.

9. The synthesis method according to claim 7, wherein the specific process of step (II) is as follows: dissolving Compound 2 in solvent, and slowly adding BBr at low temperature₃Reacting at room temperature, and separating and purifying after the reaction is finished to obtain a compound 3;

preferably, the solvent is selected from at least one of DCM or THF; and/or, adding BBr₃The temperature of (a) is-5 to 0 ℃; and/or the reaction time is 1 to 12 hours, preferably 12 hours; and/or, said compound 2 with BBr₃The dosage proportion is 1 eq: 1-1.4eq, preferably 1 eq: 1.2 eq.

10. 4-hydroxyindole prepared by the synthesis method of any one of claims 1 to 9.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 4-hydroxyindole.

Background

Oxindoles are starting materials for the synthesis of many natural compounds, and in many of the natural products and pharmaceutically active compounds found, the indole core often serves as a significant structural unit. Therefore, the development of new methods for the synthesis of indole core backbones with different substitution patterns is an important goal of current organic synthesis. It is well known that many of these indole derivatives are intermediates for the synthesis of physiologically active drugs.

4-hydroxyindole is an important organic chemical raw material and intermediate, can be used for synthesizing dye, spice and some medicines, and can also be used as auxin, feed additive and the like. 4-hydroxyindole is also an important intermediate for the synthesis of a large number of physiologically active compounds, such as Pindolo1 and 4-hydroxytryptamine Psilocin.

In recent years, many methods for synthesizing 4-hydroxyindole have been described in the literature, for example:

the synthesis method of the nitrogen heterocyclic ring styrene under the catalysis of palladium has the advantages of rigorous synthesis reaction conditions, use of expensive reagents, difficult post-treatment, long reaction time and total reaction yield of 29 percent. The one-step synthesis method for reducing 1, 5, 6, 7-tetrahydro-4H-indole 4-ketone by palladium-carbon has long reaction time and complex post-treatment. Torrii et al reported a convenient method for synthesizing 4-hydroxyindole, which uses 2, 4-dinitrotoluene and paraformaldehyde as starting materials to synthesize 2, 4-dinitrophenethyl alcohol by an electrochemical method, under the condition of 5-9MPa hydrogen, Raney Ni reduces 2, 4-dinitrophenethyl alcohol to obtain 2, 4-aminophenylethanol, 70% phosphoric acid is cyclized at 220 ℃ to generate 4-hydroxyindoline, 4-hydroxyindole is obtained by Pd/C reduction, and the total yield of the route is 54.72%. However, this method uses high temperature and high pressure, and is not suitable for industrial production. The 4-hydroxyindole is also synthesized by using m-nitrophenol as a raw material, but the m-nitrophenol is expensive and belongs to a dangerous article.

The synthesis method adopted in the industry at present has a long route, and the method comprises the steps of using resorcinol as a raw material, obtaining 1, 3-cyclohexanedione through catalytic hydrogenation and isomerization, using ethyl lactate as a raw material, obtaining brominated ethyl bromopyruvate, cyclizing the brominated ethyl bromopyruvate and the brominated ethyl bromopyruvate to obtain 4-oxo-tetrahydro-L-maleopimaric acid, adding the 4-oxo-tetrahydro-L-maleopimaric acid into a methanol solution saturated by ammonia, heating in a high-pressure kettle for reaction to generate 4-oxo-tetrahydro indole, and finally obtaining the 4-hydroxy-indole through dehydrogenation and isomerization. The method has the disadvantages of high requirement on equipment, complex operation and high cost.

In conclusion, the method for synthesizing 4-hydroxyindole in the prior art has the problems of high raw material cost, harsh reaction conditions, high equipment requirements, long reaction time, inconvenient post-treatment and the like, so that the method is not beneficial to industrial production.

Disclosure of Invention

Aiming at the problems in the industrial production of 4-hydroxyindole in the prior art, the invention provides a synthesis method of 4-hydroxyindole, which aims to: the cost of the synthetic starting material is reduced, the reaction condition in the synthetic process is mild, the operation is convenient, the post-treatment is simple, and the yield is high.

A synthetic method of 4-hydroxyindole is carried out by the following synthetic route:

wherein R is a protecting group;

which comprises the following steps:

(1) protecting hydroxyl in the compound 3 with a protecting group to obtain a compound 4;

(2) reacting the compound 4 with N, N-dimethylformamide dimethyl acetal to obtain a compound 5;

(3) mixing the compound 5 with a reducing agent and a catalyst and then reacting to obtain a compound 6;

(4) removing the protecting group of the compound 6 to obtain the 4-hydroxyindole.

Preferably, R is selected from alkyl or benzyl.

Preferably, the specific process of step (1) is as follows: mixing the compound 3 with alkali, dissolving in a solvent, slowly adding RBr under the protection of inert gas, heating for reaction after the dropwise addition is finished, and separating and purifying after the reaction is finished to obtain a compound 4;

preferably, the base is selected from K₂CO₃、Na₂CO₃、Cs₂CO₃Or NaH; and/or, the solvent is selected from at least one of DMF, THF, DCM or EtOAc; and/or controlling the temperature to be 25-30 ℃ in the process of slowly adding the RBr; and/or the temperature of the heating reaction is 30-80 ℃, preferably 60 ℃; and/or the heating reaction time is 10 to 14 hours, preferably 12 hours; and/or the dosage ratio of the compound 3 to the RBr is 1 eq: 1-1.4eq, preferably 1 eq: 1.2 eq.

Preferably, the specific processes of step (2) and step (3) are as follows:

(2) dissolving a compound 4 and N, N-dimethylformamide dimethyl acetal in a solvent, and heating for reaction to obtain a reaction solution containing a compound 5;

(3) after the temperature of the reaction solution is reduced to room temperature, adding a reducing agent and a catalyst for heating reaction, and separating and purifying after the reaction is finished to obtain a reactant 6;

preferably, the solvent is selected from at least one of DMF, THF, DCM or EtOA; and/or the temperature of the heating reaction in the step (2) is 100-120 ℃, preferably 100 ℃; and/or the heating reaction time in the step (2) is 12 to 24 hours, preferably 24 hours; and/or the temperature of the heating reaction in the step (3) is 70-100 ℃, preferably 100 ℃; and/or the heating reaction time of the step (3) is 10 to 14 hours, preferably 12 hours; and/or the compound 4 and the N, N-dimethylformamide dimethyl acetal are used in a ratio of 1 eq: 3 to 5eq, preferably 1 eq: 4 eq; and/or the compound 4, the reducing agent and the catalyst are used in a proportion of 1 eq: 4-6 eq: 0.05 to 0.15eq, preferably 1 eq: 5 eq: 0.1 eq.

Preferably, in the step (3), the reducing agent is NH₂NH₂·H₂O, the catalyst is FeCl₃At least one of Ni, NiB or Carbon; and/or the reducing agent is H₂The catalyst is at least one of Pd/C or Pt/C.

Preferably, the specific process of step (4) is as follows: dissolving the compound 6 in a solvent, adding a catalyst, reacting in a hydrogen atmosphere, and separating and purifying after the reaction is finished to obtain 4-hydroxyindole;

preferably, the solvent is selected from at least one of MeOH, EtOH or THF; and/or the catalyst is at least one of Pd/C, Pt/C, PtO2 or Raney nickel.

Preferably, said compound 3 is synthesized by the following synthetic route:

reacting the compound 1 with methanol to obtain a compound 2;

(II) reacting Compound 2 with BBr₃Reaction to give compound 3.

Preferably, the specific process of step (I) is as follows: dissolving the compound 1, a catalyst, alkali and methanol in a solvent, heating and reacting under the protection of inert gas, and separating and purifying after the reaction is finished to obtain a compound 2;

preferably, the solvent is selected from at least one of toluene, benzene or dioxane; and/or, the catalyst is selected from BrettPhos Pd G3; and/or, the alkali is selected from Cs₂CO₃(ii) a And/or the temperature of the heating reaction is 60-80 ℃, preferably 70 ℃; and/or the heating reaction time is 14 to 18 hours, preferably 16 hours; and/or the dosage ratio of the compound 1 to the methanol is 1 eq: 5 to 20eq, preferably 1 eq: 10 eq.

Preferably, the specific process of step (ii) is: dissolving Compound 2 in solvent, and slowly adding BBr at low temperature₃Reacting at room temperature, and separating and purifying after the reaction is finished to obtain a compound 3;

preferably, the solvent is selected from at least one of DCM or THF; and/or, adding BBr₃The temperature of (a) is-5 to 0 ℃; and/or the reaction time is 1 to 12 hours, preferably 12 hours; and/or, said compound 2 with BBr₃The dosage proportion is 1 eq: 1-1.4eq, preferably 1 eq: 1.2 eq.

The invention also provides the 4-hydroxyindole prepared by the synthesis method.

The technical scheme provided by the invention for synthesizing the 4-hydroxyindole has the advantages of mild reaction conditions, convenience in operation, simplicity in post-treatment and high yield. Compared with the prior art, the 4-hydroxyindole product is directly obtained after the cyclization reaction is finished, and further dehydrogenation reaction is not needed, so that the method does not need high-temperature and high-pressure conditions, and special equipment such as a high-pressure reaction kettle and the like is not needed, and the production cost of the method is greatly reduced. In the preferred scheme, the synthesized starting material compound 1 is low in price and convenient to obtain, and the production cost is favorably reduced.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

Example 1

The synthetic route of the embodiment is as follows:

this example of a process for preparing 4-hydroxyindole includes the following steps:

1. preparation of compound 2:

the method comprises the following specific operations:

(1) 1-chloro-2-methyl-3-nitrobenzene (100g,1eq), BrettPhos, was added at room temperature Pd G3(0.53g,0.001eq),Cs₂CO₃(379.78g,2eq) and methanol (186.74g,10eq) were added to 500mL of toluene, and the reaction mixture was stirred under N₂The temperature is raised to 70 ℃ under protection and the reaction is carried out for 16 hours.

(2) Less than 5% of the control starting material remained in the TLC plate, and one main spot was generated.

(3) The reaction solution was cooled to room temperature and added to 1L of water. The aqueous phase was extracted with ethyl acetate (500 mL. times.3) and the organic phases were combined. Washing the organic phase with saturated saline (800ML × 1), drying with anhydrous sodium sulfate, decolorizing with 5g of activated carbon, filtering with 0.1kg of silica gel;

(4) the organic phase is condensed to be dry, petroleum ether (0.5L) is added for pulping, and 72g of product is obtained after drying, and the yield is 73.9%.

Results of nuclear magnetic resonance testing of compound 2:¹HNMR(400MHz,CDCl₃)：2.35(3H,s),3.85(3H,s),7.05(1H,m),7.21(1H,m),7.37(1H,m).

2. preparation of Compound 3

The method comprises the following specific operations:

(1) dissolving the compound 2(72g,1eq) in 400ML DCM, cooling the reaction system to-5 ℃ and N₂Slow BBr under protection₃(130g,1.2eq) and the temperature was controlled at-5-0 ℃. After the dropwise addition, naturally heating to room temperature, and reacting for 12 hours;

(2) TLC monitoring completion of the reaction;

(3) cooling the reaction system to 0 ℃, slowly dropping 200ML of water to quench the reaction, and using saturated Na₂CO₃The pH of the system was adjusted to 8 and the aqueous phase was extracted with DCM (400ML × 2). Mixing the organic phases, adding anhydrous sodium sulfate, drying, decolorizing with 5g of activated carbon, and filtering with 0.1kg of silica gel;

(4) the organic phase is condensed to be dry, added with petroleum ether (0.1L) for pulping and dried to obtain 46g of product with the yield of 69.7 percent.

Results of nuclear magnetic resonance testing of compound 3:¹HNMR(400MHz,CDCl₃)：2.38(3H,s),5.32(1H,s),7.02(1H,m),7.19(1H,m),7.47(1H,m).

3. preparation of Compound 4

The method comprises the following specific operations:

(1) mixing compound 3(46g,1eq) with K₂CO₃(106.5g,2eq) in 250ML DMF, N₂The BnBr (61.7g,1.2eq) was slowed under protection and the temperature was controlled at 25-30 ℃. After the dropwise addition, heating to 60 ℃ for reaction for 12 hours;

(2) TLC monitoring completion of the reaction;

(3) the reaction was cooled to 25 ℃, 400ML of water was added, and the aqueous phase was extracted with ethyl acetate (400ML × 3). The organic phases were combined, washed with saturated brine (400ML × 3), dried over anhydrous sodium sulfate, decolorized with 3g of activated carbon, filtered over 0.1kg of silica gel;

(4) the organic phase is condensed to be dry, added with petroleum ether (0.1L) for pulping and dried to obtain 35.5g of product with the yield of 48.6 percent.

Results of nuclear magnetic resonance testing of compound 4:¹HNMR(400MHz,CDCl₃):2.46(3H,s),5.10(2H,s),7.08(1H,m),7.24(1H,m),7.30-7.50(6H,m).

4. preparation of Compound 6

The method comprises the following specific operations:

(1) dissolving compound 4(35.5g,1eq) and DMF-DMA (69.6g,4eq) in 100ML DMF, and heating to 120 ℃ for reaction for 24 hours;

(2) TLC monitoring completion of the reaction;

(3) reducing the temperature of the reaction system to 25 ℃, adding FeCl₃(2.4g,0.1eq) and NH₂NH₂·H₂O (36.5g,5eq), and the reaction system was heated to 100 ℃ for 12 hours.

(4) TLC monitoring completion of the reaction;

(5) 150ML of water was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (200 ML. times.3). Mixing organic phases, washing with saturated saline (200ML × 3), drying with anhydrous sodium sulfate, decolorizing with 3g of activated carbon, and filtering with 0.1kg of silica gel;

(6) the organic phase is combined and concentrated to obtain a crude product, and the crude product is purified by column chromatography to obtain 15g of a product, wherein the yield is 46.0%.

Results of nuclear magnetic resonance testing of compound 6:¹HNMR(400MHz,CDCl₃):5.32(2H,s),6.68-6.70(1H,d),680(1H,s),7.02-7.10(2H,m),7.13-7.20(1H,t),7.37-7.55(3H,m),7.55-7.66(2H,m),8.20-8.45(1H,m)。

5. preparation of 4-hydroxyindoles

The method comprises the following specific operations:

(1)N₂compound 6(15g,1eq) was dissolved in 100ML MeOH under protection, and Pd/C (0.15g,0.1eq), H, was added to the reaction system₂Replacement 3 times, H₂Reacting at room temperature for 12 hours under the protection of (15 psi);

(2) TLC monitoring completion of the reaction;

(3) Pd/C is filtered, mother liquor is concentrated to obtain a crude product, the crude product is pulped by petroleum ether ethyl acetate (PE: EA-10:1) to obtain 8g of product, and the yield is 89.4%.

Results of nuclear magnetic resonance testing of 4-hydroxyindole:¹HNMR(DMSO-d6):6.35(1H，d)，6.46(1H，d),6.81-6.87(2H,t),7.14(1H,s),9.25(1H,s),10.90(1H,m).

the examples show that 4-hydroxyindole can be prepared by the method provided by the invention, the starting material is compound 1, and the method is low in price, convenient to obtain and beneficial to reduction of production cost. In addition, the method has the advantages of mild reaction conditions (the highest temperature is 120 ℃), convenient operation, simple post-treatment and high yield.