Synthesis method of thiophene naphthenic amine derivative

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of a thiophene naphthenic amine derivative. The method comprises the following steps: reacting with benzylamine to generate a halogenated thiophene imine derivative, carrying out cyclization reaction in the presence of alkali to generate a thiophene naphthenic imine derivative, and reacting with organic acid to generate the product thiophene naphthenic amine derivative, so that the reaction conditions are mild, the yield is high, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, and specifically relates to a method for synthesizing thiophene cycloalkanamine derivatives. Background Technology

[0002] Thiophene cycloalkanamine derivatives are an important class of pharmaceutical intermediates. For example, patent CN108699048A discloses an intermediate for an oxadiazoleamine derivative compound that can serve as an inhibitor of histone deacetylase 6. Furthermore, this patent discloses the synthetic route for 1-(thien-2-yl)cyclopropyl-1-amine.

[0003]

[0004] Starting with thiophene-2-carboxynitrile, the reaction was carried out with 2-methoxy-2-methylpropane at -10°C for 1 h in the presence of titanium ethoxide and magnesium ethyl bromide. Then, boron trifluoride diethyl ether was added to the reaction solution and stirred at room temperature for 2 h. The reaction was then terminated by adding hydrochloric acid and stirring. Post-treatment yielded 1-(thiophene-2-yl)cyclopropyl-1-amine (9.4%), a light yellow solid.

[0005] However, this route requires the reaction to be carried out at -10°C, which is a harsh reaction condition, and the yield is only 9.4%, which is extremely low and not suitable for industrial production. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for synthesizing thiophene cycloalkanamine derivatives with high yield, which is more suitable for industrial production.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A method for synthesizing a thiophene cycloalkanamine derivative includes the following steps:

[0009] (1) React the halothiophenone derivative of Formula I with benzylamine in the presence of a catalyst and a first solvent to generate the halothiophenimine derivative of Formula II.

[0010] (2) React the halothiophene imine derivative shown in Formula II in the presence of a base and a second solvent to generate the thiophene cycloalkane imine derivative shown in Formula III.

[0011] (3) React the thiophene cycloalkane imine derivative shown in Formula III with an organic acid in the presence of a third solvent to generate the thiophene cycloalkane derivative shown in Formula IV.

[0012] In Formula I, R1 is selected from H, halogens or C2 to C6 alkyl groups, R2 is selected from halogens, and n is an integer from 2 to 4;

[0013] In Equation II, R1, R2, and n are the same as described above;

[0014] In Equations III and IV, R1 and n are the same as described above.

[0015] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, R1 is selected from H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl. More optionally, R1 is selected from H, Br, F, Cl, isopropyl, methyl, and ethyl. Still more optionally, R1 is selected from H, Br, F, and Cl.

[0016] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, R2 may optionally be selected from F, Cl, or Br, and more preferably, R2 may be Cl.

[0017] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, n is optionally selected from 2 or 3. More optionally, n is 2.

[0018] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, in Formulas I, II, III, and IV, when R1 is not H, R1 is the ortho or meta position of the S atom on the thiophene ring.

[0019] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, the thiophene cycloalkanamine derivative represented by Formula IV is selected from the following compounds:

[0020]

[0021] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, in step (1), the catalyst is a titanium-based catalyst, and the first solvent is one or a combination of ketone solvents and ether solvents.

[0022] Further optionally, the catalyst is one or a combination of titanate esters and titanium tetrachloride, and the first solvent is a ketone solvent. The titanate ester may be one or a combination of tetraisopropyl titanate and tetrabutyl titanate, the ketone solvent may be acetone, and the ether solvent may be one or a combination of petroleum ether and diethyl ether.

[0023] The inventors of this application discovered through experiments that, in step (1), using titanate ester as a catalyst and a ketone solvent as the first solvent helps to obtain a high yield of the halothiophene imine derivative shown in Formula II, ultimately yielding a high yield of the thiophene cycloalkanolamine derivative, and the reaction temperature does not need to be too harsh, such as -10°C. If tetraisopropyl titanate is further used as a catalyst and acetone as the first solvent, an even higher yield of the halothiophene imine derivative shown in Formula II can be obtained. Furthermore, in the reaction route of this invention, the product loss in steps (2) and (3) is minimal, or even negligible.

[0024] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, in step (1), the reaction is carried out at 40–70°C. More optionally, the reaction is carried out at 45–55°C.

[0025] In the aforementioned method for synthesizing thiophene cycloalkanolamine derivatives, optionally, in step (1), the molar ratio of the halothiophene ketone derivative of Formula I to benzylamine is 1:1 to 2; the molar ratio of the halothiophene ketone derivative of Formula I to the catalyst is 1:0.4 to 0.8. Further optionally, in step (1), the molar ratio of the halothiophene ketone derivative of Formula I to benzylamine is 1:1.2 to 1.8; the molar ratio of the halothiophene ketone derivative of Formula I to the catalyst is 1:0.5 to 0.7.

[0026] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, in step (1), after the reaction is completed, the mixture is cooled and toluene and water are added to the reaction solution to quench it.

[0027] Optionally, the implementation of step (1) includes: dissolving the halothiophenone derivative of Formula I and benzylamine in a first solvent, adding a catalyst, heating to 40-70°C, refluxing, stirring for 4-8 hours, then cooling and adding toluene and water to quench the reaction, filtering, extracting, washing with water and combining the organic phases, drying, purifying by column chromatography, and evaporating to obtain the halothiophene imine derivative of Formula II.

[0028] Further optionally, in step (1), the cooling to a temperature of 15–45°C is performed, and the extraction is carried out using diethyl ether.

[0029] In the aforementioned method for synthesizing thiophene cycloalkanamine derivatives, optionally, in step (2), the base is one or a combination of potassium tert-butoxide, sodium tert-butoxide, and sodium methoxide.

[0030] In the aforementioned method for synthesizing thiophene cycloalkanolamine derivatives, optionally, in step (2), the second solvent is one or a combination of several of 1,4-dioxane, tetrahydrofuran, and N,N-dimethylformamide.

[0031] Optionally, in step (2), the molar ratio of the halothiophene imine derivative shown in Formula II to the base is 1:2 to 4, and further, the molar ratio of the halothiophene imine derivative shown in Formula II to the base is 1:2.5 to 3.5.

[0032] Optionally, in step (2), the reaction is carried out at 15–45°C.

[0033] Optionally, step (2) can be implemented by mixing the halothiophene imine derivative of formula II, the base and the second solvent, stirring and reacting at 15-45°C for 2-6 hours, then removing the second solvent by rotary evaporation, extracting, concentrating, recrystallizing, and filtering to obtain the thiophene cycloalkane imine derivative of formula III.

[0034] Optionally, in step (2), the extraction uses a mixture of water and ethyl acetate, and the recrystallization uses petroleum ether.

[0035] In the aforementioned method for synthesizing thiophene cycloalkanolamine derivatives, optionally, in step (3), the organic acid is one or a combination of formic acid, oxalic acid, acetic acid, and pyruvic acid.

[0036] Optionally, in step (3), the third solvent is one or a combination of several of tetrahydrofuran, N,N-dimethylformamide, methanol, and dichloromethane.

[0037] Optionally, in step (3), the reaction is carried out at 15–45°C.

[0038] Optionally, in step (3), the feed ratio of the thiophene cycloalkane imine derivative represented by Formula III to the organic acid is 1 mmol: 2-8 mL. More preferably, the feed ratio of the thiophene cycloalkane imine derivative represented by Formula III to the organic acid is 1 mmol: 4-6 mL.

[0039] Optionally, the implementation of step (3) includes: mixing the thiophene cycloalkane imine derivative shown in Formula III, an organic acid, and a third solvent, stirring and reacting at 15-45°C for 1-4 hours, removing the third solvent by rotary evaporation, extracting, concentrating, recrystallizing, and filtering to obtain the thiophene cycloalkane derivative shown in Formula IV.

[0040] Optionally, in step (3), the extraction uses a mixture of water and ethyl acetate, and the recrystallization uses n-hexane.

[0041] In this invention, unless otherwise specified, room temperature generally refers to 20–25°C.

[0042] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0043] The synthesis method of this invention uses halothiophenone derivatives as starting materials. First, it reacts with benzylamine to generate halothiophene imine derivatives. Then, it undergoes a cyclization reaction in the presence of a base to generate thiophene cycloalkane imine derivatives. Finally, it reacts with an organic acid to generate the product thiophene cycloalkaneamine derivative. The reaction conditions are mild, the yield is high, and it is more suitable for industrial production. Attached Figure Description

[0044] Figure 1 The NMR spectrum of 1-(thien-2-yl)cyclopropane-1-amine from Example 1 is shown. Detailed Implementation

[0045] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and comparative examples.

[0046] The raw materials and ingredients used in the following examples and comparative examples were all commercially available.

[0047] Example 1

[0048] This embodiment provides a method for synthesizing 1-(thiophene-2-yl)cyclopropane-1-amine, and the method route and procedure are as follows:

[0049]

[0050] 1) In a round-bottom flask, 3-chloro-1-(thiophen-2-yl)prop-1-one (1.74 g, 10 mmol) and benzylamine (1.64 mL, 15 mmol) were dissolved in acetone (40 mL), followed by the addition of tetraisopropyl titanate (6.4 mmol). The mixture was heated to 50 °C, refluxed, and stirred for 6 h. After the reaction was complete, the reaction mixture was cooled to room temperature. 20 mL of toluene was added to the reaction mixture, followed by 1 mL of water to quench the reaction. The mixture was stirred for another 30 min at room temperature until a precipitate (TiO2) formed. The reaction mixture was then filtered. The mixture was extracted with diethyl ether (3 × 10 mL), washed several times with water, and the organic phases were combined. The mixture was dried over anhydrous Na2SO4 and evaporated to dryness. The mixture was purified by column chromatography (using ethyl acetate / petroleum ether as the eluent, V / V = 1 / 10). Evaporation yielded (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)prop-1-imine (2.58 g, 97.9%).

[0051] 2) Add (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)propyl-1-imine (2.6 g, 10 mmol), potassium tert-butoxide (3.37 g, 30 mmol), and 100 mL of 1,4-dioxane solvent to a round-bottom flask. Stir the mixture at room temperature for 3 h. After the reaction is complete, remove the solvent by rotary evaporation, extract with water and ethyl acetate (EA) (V / V = 1 / 1), concentrate, recrystallize under cooling with petroleum ether, and filter to obtain (E)-1-phenyl-N-(1-(thiophen-2-yl)cyclopropyl)methylimine (2.25 g, 99%).

[0052] 3) Add (E)-1-phenyl-N-(1-(thiophen-2-yl)cyclopropyl)methylimine (2.25 g, 10 mmol), formic acid 50 mL, and tetrahydrofuran 20 mL to a round-bottom flask. Stir the mixture at room temperature for 2 h. After the reaction is complete, remove the solvent by rotary evaporation, extract with water and ethyl acetate (EA) (V / V = 1 / 1), concentrate, recrystallize under cooling with n-hexane, and filter to obtain 1-(thiophen-2-yl)cyclopropyl-1-amine (1.39 g, 100%).

[0053] The NMR spectrum in this example is as follows: Figure 1 As shown.

[0054] 1 H NMR (400MHz, CDCl3) δ7.30(dd,1H),7.03(t,1H),6.95(dd,1H),4.25(s,2H),2.43(s,4H).

[0055] Example 2

[0056] This embodiment provides a method for synthesizing 1-(3-bromothiophene-2-yl)cyclopropane-1-amine.

[0057]

[0058] 1) In a round-bottom flask, 10 mmol of 3-chloro-1-(3-bromothiophen-2-yl)prop-1-one and 15 mmol of benzylamine were dissolved in 40 mL of acetone. Tetraisopropyl titanate (6.4 mmol) was then added. The mixture was heated to 55 °C, refluxed, and stirred for 5 h. After this reaction, the reaction mixture was cooled to room temperature. 20 mL of toluene was added to the reaction mixture, followed by 1 mL of water to quench the reaction. The mixture was stirred for another 30 min at room temperature until a precipitate (TiO2) formed. The reaction mixture was then filtered. The mixture was extracted with diethyl ether (3 × 10 mL), washed several times with water, and the organic phases were combined. The mixture was dried over anhydrous Na2SO4 and evaporated to dryness. The solution was purified by column chromatography (using ethyl acetate / petroleum ether as the eluent (V / V = 1 / 10)). Evaporation yielded (E)-N-benzyl-3-chloro-1-(3-bromothiophen-2-yl)prop-1-imine (97.3%).

[0059] 2) Add (E)-N-benzyl-3-chloro-1-(3-bromothiophen-2-yl)propyl-1-imine (10 mmol), sodium tert-butoxide (30 mmol), and 100 mL of 1,4-dioxane solvent to a round-bottom flask. Stir the mixture at room temperature for 3 h. After the reaction is complete, remove the solvent by rotary evaporation, extract with water and ethyl acetate (EA), concentrate, recrystallize under cooling with petroleum ether, and filter to obtain (E)-1-phenyl-N-(1-(3-bromothiophen-2-yl)cyclopropyl)methylimine (99.9%).

[0060] 3) Add (E)-1-phenyl-N-(1-(3-bromothiophen-2-yl)cyclopropyl)methylimine (10 mmol), acetic acid (50 mL), and tetrahydrofuran (20 mL) to a round-bottom flask. Stir the mixture at room temperature for 2 h. After the reaction is complete, remove the solvent by rotary evaporation, extract with water and ethyl acetate (EA), concentrate, recrystallize under cooling with n-hexane, and filter to obtain 1-(3-bromothiophen-2-yl)cyclopropyl-1-amine (99.8%).

[0061] 1 H NMR (400MHz, CDCl3) δ7.46(d,1H),7.03(d,1H),4.08(s,2H),2.49(m,4H).

[0062] Example 3

[0063] This embodiment provides a method for synthesizing 1-(4-bromothiophene-2-yl)cyclopropane-1-amine.

[0064]

[0065] The difference between this example and Example 1 is that: in step 1), 10 mmol of 3-chloro-1-(4-bromothiophen-2-yl)prop-1-one was used instead of 3-chloro-1-(thiophen-2-yl)prop-1-one in the raw materials; in step 2), (E)-N-benzyl-3-chloro-1-(4-bromothiophen-2-yl)prop-1-imine was used instead of (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)prop-1-imine in the raw materials; and in step 3), (E)-1-phenyl-N-(1-(4-bromothiophen-2-yl)cyclopropyl)methylimine was used instead of (E)-1-phenyl-N-(1-(thiophen-2-yl)cyclopropyl)methylimine in the raw materials. The overall yield of the final product, 1-(4-bromothiophen-2-yl)cyclopropane-1-amine, was 97.1%.

[0066] 1 H NMR (400MHz, CDCl3) δ7.49(d,1H),7.11(d,1H),4.52(s,2H),2.44(s,4H).

[0067] Example 4

[0068] This embodiment provides a method for synthesizing 1-(5-bromothiophene-2-yl)cyclopropane-1-amine.

[0069]

[0070] The difference between this example and Example 1 is that: in step 1), 10 mmol of 3-chloro-1-(5-bromothiophen-2-yl)prop-1-one was used instead of 3-chloro-1-(thiophen-2-yl)prop-1-one in the raw materials; in step 2), (E)-N-benzyl-3-chloro-1-(5-bromothiophen-2-yl)prop-1-imine was used instead of (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)prop-1-imine in the raw materials; and in step 3), (E)-1-phenyl-N-(1-(5-bromothiophen-2-yl)cyclopropyl)methylimine was used instead of (E)-1-phenyl-N-(1-(thiophen-2-yl)cyclopropyl)methylimine in the raw materials. The overall yield of the final product, 1-(5-bromothiophen-2-yl)cyclopropane-1-amine, was 97.3%.

[0071] 1 H NMR (400MHz, CDCl3) δ7.02(d,1H),6.68(d,1H),4.12(s,2H),2.39(s,4H).

[0072] Example 5

[0073] This embodiment provides a method for synthesizing 1-(thiophen-2-yl)cyclopropane-1-amine, which is basically the same as in Example 1, except that in step 1), tetrabutyl titanate is used instead of tetraisopropyl titanate, resulting in a yield of 60% for (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)propane-1-imine.

[0074] Example 6

[0075] This embodiment provides a method for synthesizing 1-(thiophen-2-yl)cyclopropane-1-amine, which is basically the same as in Example 1, except that in step 1), titanium tetrachloride is used instead of tetraisopropyl titanate, resulting in a yield of 51% for (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)propane-1-imine.

[0076] Example 7

[0077] This embodiment provides a method for synthesizing 1-(thiophen-2-yl)cyclopropane-1-amine, which is basically the same as in Example 1, except that in step 1), diethyl ether is used instead of acetone, resulting in a yield of 44% for (E)-N-benzyl-3-chloro-1-(thiophen-2-yl)propane-1-imine.

[0078] Comparative Example 1

[0079] This embodiment provides a method for synthesizing 1-(thiophene-2-yl)cyclopropane-1-amine, which is basically the same as in Example 1, except that in step 1), toluene is used instead of acetone, and no reaction occurs.

[0080] The above embodiments are only used to illustrate the embodiments of the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the embodiments of the present invention. Therefore, all equivalent technical solutions also fall within the scope of the embodiments of the present invention, and the patent protection scope of the embodiments of the present invention should be defined by the claims.

Claims

1. A method for synthesizing a thiophene cycloalkanamine derivative, characterized in that, The synthesis method includes the following steps: (1) React the halothiophenone derivative of Formula I with benzylamine in the presence of a catalyst and a first solvent to generate the halothiophenimine derivative of Formula II. (2) React the halothiophene imine derivative shown in Formula II in the presence of a base and a second solvent to generate the thiophene cycloalkane imine derivative shown in Formula III. (3) React the thiophene cycloalkane imine derivative shown in Formula III with an organic acid in the presence of a third solvent to generate the thiophene cycloalkane derivative shown in Formula IV. In Formula I, R1 is selected from H, halogens or C2 to C6 alkyl groups, R2 is selected from halogens, and n is an integer from 2 to 4; In Equation II, R1, R2, and n are the same as described above; In Equations III and IV, R1 and n are the same as described above.

2. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 1, characterized in that, R1 is selected from H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; and / or R2 is selected from F, Cl, Br; and / or n is selected from 2 or 3.

3. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 2, characterized in that, R1 is selected from H, Br, F, Cl; and / or R2 is Cl, and n is 2.

4. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 1, characterized in that, In step (1), the catalyst is a titanium-based catalyst, and the first solvent is one or a combination of ketone solvents and ether solvents.

5. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 4, characterized in that, In step (1), the catalyst is one or a combination of tetraisopropyl titanate, tetrabutyl titanate, and titanium tetrachloride, and the first solvent is one or a combination of acetone, petroleum ether, and diethyl ether.

6. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 4, characterized in that, In step (1), the catalyst is tetraisopropyl titanate, and the first solvent is acetone; and / or, In step (1), the reaction is carried out at 40–70°C; and / or, In step (1), the molar ratio of the halothiophenone derivative of Formula I to benzylamine is 1:1 to 2; the molar ratio of the halothiophenone derivative of Formula I to the catalyst is 1:0.4 to 0.8; and / or, In step (1), after the reaction is completed, the mixture is cooled and toluene and water are added to the reaction solution to quench it.

7. The method for synthesizing the thiophenecycloalkanamine derivative according to any one of claims 1 to 6, characterized in that, The implementation of step (1) includes: dissolving the halothiophenone derivative of formula I and benzylamine in a first solvent, adding a catalyst, heating to 40-70°C, refluxing, stirring for 4-8 hours, then cooling and adding toluene and water to quench the reaction, filtering, extracting, washing with water and combining the organic phases, drying, purifying by column chromatography, and evaporating to obtain the halothiophene imine derivative of formula II.

8. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 1, characterized in that, In step (2), the alkali is one or a combination of sodium tert-butoxide, potassium tert-butoxide, and sodium methoxide; and / or, In step (2), the second solvent is one or a combination of several of 1,4-dioxane, tetrahydrofuran, and N,N-dimethylformamide; and / or, In step (2), the reaction temperature is 15–45°C; and / or, In step (2), the molar ratio of the halothiophene imine derivative shown in Formula II to the base is 1:2 to 4.

9. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 1, characterized in that, In step (3), the organic acid is one or a combination of several of formic acid, oxalic acid, acetic acid, and pyruvic acid; and / or, In step (3), the third solvent is one or a combination of several of tetrahydrofuran, methanol, N,N-dimethylformamide, and dichloromethane; and / or, In step (3), the reaction is carried out at 15–45°C; and / or, In step (3), the ratio of the thiophene cycloalkane imine derivative represented by formula III to the organic acid is 1 mmol: 2-8 mL.

10. The method for synthesizing thiophene cycloalkanamine derivatives according to claim 1, characterized in that, Step (2) includes the following implementation: mixing the halothiophene imine derivative of Formula II, a base, and a second solvent, stirring the mixture at 15–45°C for 2–6 h, then rotary evaporating to remove the second solvent, extracting, concentrating, recrystallizing, and filtering to obtain the thiophene cycloalkane imine derivative of Formula III; and / or, The implementation of step (3) includes: mixing the thiophene cycloalkane imine derivative shown in Formula III, an organic acid, and a third solvent, stirring and reacting at 15-45°C for 1-4 hours, removing the third solvent by rotary evaporation, extracting, concentrating, recrystallizing, and filtering to obtain the thiophene cycloalkane derivative shown in Formula IV.

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