A tertiary alkyl amine compound, a synthesis method and application thereof

Abstract

This invention relates to a tertiary alkylamine compound, its synthesis method, and its applications. The invention uses tertiary alkyl bromides and 3-substituted indole derivatives as substrates, reacting them at 40°C for 8-12 hours under the action of a catalyst, ligand, reducing agent, and additives to obtain tertiary alkylamines. This invention has advantages such as using inexpensive metal catalysts, readily available and simple raw materials, mild reaction conditions, simple steps, safe operation, and high yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a tertiary alkylamine compound, its synthesis method, and its application. Background Technology

[0002] Amine compounds are an important component of the biological and pharmaceutical fields, playing an irreplaceable role in human life. Tertiary alkylamine compounds possess potential biological activity and medicinal value.

[0003] Existing synthetic methods utilize palladium to catalyze the reaction of aryl halides or halides with tert-butylamine. However, palladium is too expensive and not suitable for mass production. Another method involves the reaction of aniline with tert-butyl 2,2,2-trichloroiminocarbamate, but this method has a complex raw material preparation process and is limited by the reaction.

[0004] In summary, current methods have significant drawbacks. The raw materials for synthesizing tertiary alkylamines are difficult to prepare, expensive, and have limited applicability. Therefore, it is necessary to find a more convenient and cost-effective method to solve these problems. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art by providing a tertiary alkylamine compound, its synthesis method, and its applications. The tertiary alkylamine is obtained by reacting a tertiary alkyl bromide and a 3-substituted indole derivative as substrates at 40°C for 8-12 hours under the action of a catalyst, ligand, reducing agent, and additives. This invention has advantages such as using inexpensive metal catalysts, readily available and simple raw materials, mild reaction conditions, simple steps, safe operation, and high yield.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] A tertiary alkylamine compound, the general structural formula of which is:

[0008]

[0009] Wherein, R is selected from any one of the alkyl groups containing an ester group or an amide group;

[0010] R1, R2, and R3 are each selected from either alkyl or aryl groups.

[0011] Furthermore, R is selected from 2-methoxy-2-oxoethyl;

[0012] R1, R2, and R3 are each independently selected from any one of methyl, ethyl, or phenyl.

[0013] Furthermore, the tertiary alkylamine compounds include:

[0014]

[0015] This invention also provides a method for synthesizing tertiary alkylamine compounds, the specific steps of which are as follows:

[0016] Using 3-substituted indole or its derivatives of Formula II and tertiary alkyl bromides of Formula III as starting materials, a catalyst, ligand, reducing agent, and additives were added sequentially, and after stirring, a tertiary alkylamine compound of Formula I was obtained.

[0017] The structural formulas I to III are shown below:

[0018]

[0019] Wherein, R is selected from any one of the alkyl groups containing an ester group or an amide group;

[0020] R1, R2, and R3 are each selected from either alkyl or aryl groups.

[0021] Furthermore, R is selected from 2-methoxy-2-oxoethyl;

[0022] R1, R2, and R3 are selected from methyl, ethyl, or phenyl, respectively.

[0023] Further, in a molar mass ratio, the ratio of 3-substituted indole or its derivatives of Formula II to tertiary alkyl bromide of Formula III is 1:(1.9-2.1):(0.08-0.12):(0.10-0.15):(0.5-1.0):(1.0-2.0).

[0024] Furthermore, the catalyst is cuprous bromide (CuBr), the ligand is 4-di-tert-butyldipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate.

[0025] Furthermore, in an air atmosphere, using 3-substituted indole or its derivatives of Formula II and tertiary alkyl bromide of Formula III as raw materials, a catalyst, ligand, reducing agent and additive are added sequentially, and a solvent is added to obtain a reaction solution. The reaction solution is stirred uniformly and the reaction is carried out to obtain a tertiary alkylamine compound of Formula I.

[0026] Furthermore, the stirring temperature is 38–42°C, and the stirring time is 8–12 hours.

[0027] Furthermore, the solvent is dichloromethane and trifluorotoluene.

[0028] Furthermore, according to the volume ratio, dichloromethane:trifluorotoluene = 1:1.

[0029] Furthermore, the ratio of 3-substituted indole or its derivatives with the structure shown in Formula II to dichloromethane is 1:1 to 2.

[0030] Furthermore, the present invention also provides an application of tertiary alkylamine compounds, which have potential applications in the preparation of antidepressant or antipsychotic drugs.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] 1. This invention uses tertiary alkyl bromides and indole derivatives as substrates, and reacts them at 40°C for 8-12 hours under the action of a catalyst, ligand, reducing agent, and additives to obtain tertiary alkylamines.

[0033] 2. This invention has the advantages of using inexpensive metal catalysts, simple and readily available raw materials, mild reaction, simple steps, safe operation, and high yield.

[0034] 3. The method of the present invention is simple, easy to implement, and low in cost, making it suitable for widespread use. Attached Figure Description

[0035] Figure 1 This is the reaction formula of the present invention. Detailed Implementation

[0036] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0037] The principle of this invention is as follows Figure 1 As shown, a tertiary alkylamine compound has the following general structural formula I:

[0038]

[0039] Wherein, R is selected from any one of the alkyl groups containing an ester group or an amide group;

[0040] R1, R2, and R3 are each selected from either alkyl or aryl groups.

[0041] Furthermore, R is selected from 2-methoxy-2-oxoethyl;

[0042] R1, R2, and R3 are selected from methyl, ethyl, or phenyl, respectively.

[0043] Furthermore, the tertiary alkylamine compounds include:

[0044]

[0045] This invention also provides a method for synthesizing tertiary alkylamine compounds, the specific steps of which are as follows:

[0046] Using 3-substituted indole or its derivatives of Formula II and tertiary alkyl bromides of Formula III as starting materials, a catalyst, ligand, reducing agent, and additives were added sequentially, and after stirring, a tertiary alkylamine compound of Formula I was obtained.

[0047] The structural formulas I to III are shown below:

[0048]

[0049] Wherein, R is selected from any one of the alkyl groups containing an ester group or an amide group;

[0050] R1, R2, and R3 are each selected from either alkyl or aryl groups.

[0051] Furthermore, R is selected from 2-methoxy-2-oxoethyl;

[0052] R1, R2, and R3 are selected from methyl, ethyl, or phenyl, respectively.

[0053] Further, in a molar mass ratio, the ratio of 3-substituted indole or its derivatives of Formula II to tertiary alkyl bromide of Formula III is 1:(1.9-2.1):(0.08-0.12):(0.10-0.15):(0.5-1.0):(1.0-2.0).

[0054] Furthermore, the catalyst is cuprous bromide (CuBr), the ligand is 4-di-tert-butyldipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate.

[0055] Furthermore, in an air atmosphere, using 3-substituted indole or its derivatives of Formula II and tertiary alkyl bromide of Formula III as raw materials, a catalyst, ligand, reducing agent and additive are added sequentially, and a solvent is added to obtain a reaction solution. The reaction solution is stirred uniformly and the reaction is carried out to obtain a tertiary alkylamine compound of Formula I.

[0056] Furthermore, the stirring temperature is 38–42°C, and the stirring time is 8–12 hours.

[0057] Furthermore, the solvent is dichloromethane and trifluorotoluene.

[0058] Furthermore, according to the volume ratio, dichloromethane:trifluorotoluene = 1:1.

[0059] Furthermore, the ratio of 3-substituted indole or its derivatives with the structure shown in Formula II to dichloromethane is 1:1 to 2.

[0060] Furthermore, the present invention also provides an application of tertiary alkylamine compounds, which have potential applications in the preparation of antidepressant or antipsychotic drugs.

[0061] The above-described embodiments will be described in more detail below with reference to specific examples.

[0062] Example 1

[0063] A method for synthesizing a tertiary alkylamine compound, using indole-3-acetic acid methyl ester and tert-butyl bromide as raw materials to synthesize product 1, the specific steps of which are as follows:

[0064] Add the following to a dry Schlenk tube in sequence: indole-3-acetic acid methyl ester (0.30 mmol, 56.8 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%). Seal the Schlenk tube with sealing film. Add tert-butyl bromide (0.60 mmol, 82.2 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane using a syringe. Stir in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 1 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 1 and a yield of 89-91%.

[0065]

[0066] The product synthesized by the method in this embodiment was characterized as follows:

[0067] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.5Hz,2H),7.26(s,1H),7.20–7.17(m,1H),7.12(m,1H),3.77(s,2H),3.71(s,3H),1.73(s,9H).

[0068] 13 C NMR (101MHz, CDCl3) δ172.8,135.2,129.4,124.4,120.9,119.2,118.8,113.4,105.7,55.8,52.0,31.2,29.9.

[0069] Example 2

[0070] A method for synthesizing a tertiary alkylamine compound, using methyl indole-3-propionate and tert-butyl bromide as raw materials to synthesize product 2, the specific steps of which are as follows:

[0071] Add the following to a dry Schlenk tube in sequence: indole-3-acetic acid methyl ester (0.30 mmol, 61.0 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%). Seal the Schlenk tube with sealing film. Add tert-butyl bromide (0.60 mmol, 82.2 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane via a syringe. Stir in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 2 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 2 and a yield of 87-91%.

[0072]

[0073] The product synthesized by the method in this embodiment was characterized as follows:

[0074] 1 H NMR (400MHz, CDCl3) δ7.64–7.58(m,2H),7.20–7.15(m,1H),7.12–7.07(m,2H),3.69(s,3H),3.09(m,2H),2.75–2.69(m,2H),1.71(s,9H).

[0075] 13 C NMR (101MHz, CDCl3) δ174.1,135.3,129.3,122.9,120.9,119.0,118.5,113.4,112.2,55.7,51.7,35.1,29.9,20.8.

[0076] Example 3

[0077] A method for synthesizing a tertiary alkylamine compound, using phthalimide-protected tryptophan and tert-butyl bromide as raw materials to synthesize product 3, the specific steps of which are as follows:

[0078] Phthalimide-protected tryptamine (0.30 mmol, 87.1 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%) were added sequentially to a dry Schlenk tube. The Schlenk tube was then sealed with sealing film. Tert-butyl bromide (0.60 mmol, 82.2 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane were added via syringe. The mixture was stirred in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 3 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 3 and a yield of 71-73%.

[0079]

[0080] The product synthesized by the method in this embodiment was characterized as follows:

[0081] 1 H NMR (400MHz, CDCl3) δ7.85 (m, 2H), 7.78 (m, 1H), 7.71 (m, 2H), 7.61 (m, J = 8.3Hz, 1H), 7.21–7.16(m,2H),7.13(m,1H),4.03–3.97(m,2H),3.16–3.09(m,2H),1.71(s,9H).

[0082] 13 C NMR (101MHz, CDCl3) δ168.5,135.3,134.0,132.4,129.6,123.6,123.3,120.9,119.3,118.7,113.4,109.6,55.7,53.6,38.7,29.9,24.6.

[0083] Example 4

[0084] A method for synthesizing a tertiary alkylamine compound, using Obz-protected chromoyl alcohol and tert-butyl bromide as starting materials to synthesize product 4, the specific steps of which are as follows:

[0085] Add the following to a dry Schlenk tube in sequence: Obz-protected chromolate (0.30 mmol, 80.0 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%). Seal the Schlenk tube with sealing film. Add tert-butyl bromide (0.60 mmol, 82.2 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane via syringe. Stir in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 4 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 4 and a yield of 51-54%.

[0086]

[0087] The product synthesized by the method in this embodiment was characterized as follows:

[0088] 1 H NMR(400MHz, CDCl3)δ8.07(d,J=8.3Hz,2H),7.69(m,1H),7.63(m,1H),7.57(m,1H),7.45(m,2H), 7.21–7.17(m,2H),7.15–7.10(m,1H),4.59(t,J=7.4Hz,2H),3.23(t,J=7.4Hz,2H),1.72(s,9H).

[0089] 13 C NMR (101MHz, CDCl3) δ166.8,135.3,133.0,130.6,129.7,128.5,123.7,121.0,119.2,118.7,113.5,109.2,65.3,55.8,53.6,30.0,25.0.

[0090] Example 5

[0091] A method for synthesizing a tertiary alkylamine compound, using indole-3-acetic acid methyl ester and 1-bromo-1-methylcyclohexane as raw materials to synthesize product 5, the specific steps of which are as follows:

[0092] Add the following to a dry Schlenk tube in sequence: indole-3-acetic acid methyl ester (0.30 mmol, 56.8 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%). Seal the Schlenk tube with sealing film. Add 1-bromo-1-methylcyclohexane (0.60 mmol, 106.3 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane using a syringe. Stir in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 5 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 5 and a yield of 67-69%.

[0093]

[0094] The product synthesized by the method in this embodiment was characterized as follows:

[0095] 1H NMR (400MHz, CDCl3) δ7.68–7.60(m,2H),7.35(s,1H),7.14(m,2H),3.78(s,2H),3.72(s ,3H),2.35(m,2H),2.08–2.01(m,2H),1.68-1.58(m,5H)1.64(s,3H),1.43-1.19(m,1H).

[0096] 13C NMR (101MHz, CDCl3) δ172.9,135.1,129.5,124.7,120.8,119.2,118.8,113.8,105.9,58.8,52.0,37.7,31.3,25.8,22.8.

[0097] HRMS(ESI)m / z:[M+H]+Calced for C18H24NO2 286.1802; Found:282.1790.

[0098] Example 6

[0099] A method for synthesizing a tertiary alkylamine compound, using indole-3-acetic acid methyl ester and 2-bromo-2-benzylpropane as raw materials to synthesize product 6, the specific steps of which are as follows:

[0100] Add the following to a dry Schlenk tube in sequence: indole-3-acetic acid methyl ester (0.30 mmol, 56.8 mg, 100 mol%), Zn (0.15 mmol, 9.8 mg, 50 mol%), 4-di-tert-butylbipyridine (0.03 mmol, 8.0 mg, 10 mol%), CuBr (0.03 mmol, 4.3 mg, 10 mol%), and MgCO3 (0.60 mmol, 50.6 mg, 200 mol%). Seal the Schlenk tube with sealing film. Add 2-bromo-2-benzylpropane (0.60 mmol, 127.9 mg, 200 mmol%), 0.5 mL of trifluorotoluene solvent, and 0.5 mL of dichloromethane via a syringe. Stir in an oil bath at 40 °C for 8–12 hours. After the reaction is complete, no post-processing is required. The pale yellow oily liquid 6 can be obtained by direct separation by column chromatography (ethyl acetate: petroleum ether = 3:97), with the structure shown in Formula 6 and a yield of 61-63%.

[0101]

[0102] The product synthesized by the method in this embodiment was characterized as follows:

[0103] 1 H NMR (400MHz, CDCl3) δ7.70–7.63(m,2H),7.29(s,1H),7.24–7.13(m,5H),7.00(d,J=7. 1Hz,2H),3.80(s,2H),3.72(s,3H),2.42–2.37(m,2H),2.29–2.23(m,2H),1.78(s,6H).

[0104] 13 C NMR (101MHz, CDCl3) δ172.8,141.9,135.3,129.6,128.5,128.4,125.9,125 .3,121.3,119.3,119.1,113.3,106.0,58.6,52.1,43.2,31.3,30.5,28.5.

[0105] As can be seen from the above examples, the method for synthesizing tertiary alkylamines of the present invention uses tertiary alkyl bromides and indole derivatives as substrates, and reacts them at 40°C for 8-12 hours under the action of a catalyst, ligand, reducing agent, and additives to obtain tertiary alkylamines. The present invention has the advantages of inexpensive metal catalysts, readily available and simple raw materials, mild reaction conditions, simple steps, safe operation, and high yield.

[0106] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for synthesizing a tertiary alkyl amine compound, characterized by, The specific steps are as follows: The 3-substituted indole of the structure shown in formula II and the tertiary alkyl bromide of the structure shown in formula III are used as raw materials, a catalyst, a ligand, a reducing agent and an additive are sequentially added, and after stirring, the tertiary alkyl amine compound of the structure shown in formula I is obtained, The general structures of formula I to formula III are as follows: R is selected from 2-methoxy-2-oxoethyl; R1, R2, R3 are respectively selected from methyl, ethyl or phenyl; The catalyst is cuprous bromide, the ligand is 4-di-tert-butylbipyridine, the reducing agent is zinc powder, and the additive is magnesium carbonate; The stirring temperature is 38-42℃.

2. The method for synthesizing a tertiary alkylamine compound according to claim 1, characterized in that, According to the molar mass ratio, the 3-substituted indole of the structure shown in formula II: the tertiary alkyl bromide of the structure shown in formula III: the catalyst: the ligand: the reducing agent: the additive = 1: (1.9-2.1): (0.08-0.12): (0.10-0.15): (0.5-1.0): (1.0-2.0).

3. The method for synthesizing a tertiary alkylamine compound according to claim 1, characterized in that, The 3-substituted indole of the structure shown in formula II and the tertiary alkyl bromide of the structure shown in formula III are used as raw materials, a catalyst, a ligand, a reducing agent and an additive are sequentially added, a solvent is added to obtain a reaction solution, the reaction solution is uniformly stirred, and reaction is carried out to obtain the tertiary alkyl amine compound of the structure shown in formula I.

4. The method for synthesizing a tertiary alkylamine compound according to claim 3, characterized in that, The stirring time is 8-12 hours, The solvent is dichloromethane and trifluorotoluene, According to the volume ratio, dichloromethane: trifluorotoluene = 1: 1, The 3-substituted indole of the structure shown in formula II: dichloromethane = 1: 1-2.

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