A method for synthesizing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane

Abstract

The invention provides a method for synthesizing 4,4'-(1,3-propanediyl)bipyridine and 1,3-bis(4-piperidyl)propane, and belongs to the field of organic synthesis. The invention adopts 4-pyridine carboxaldehyde and acetyl pyridine as starting materials to prepare 4,4'-(1,3-propanediyl)bipyridine and 1,3-bis(4-piperidyl)propane, and can first obtain 4,4'-(1,3-propanediyl)bipyridine by a step-by-step method, and then obtain 1,3-bis(4-piperidyl)propane, or directly use an intermediate to prepare 1,3-bis(4-piperidyl)propane. Compared with the method for preparing 4,4'-(1,3-propanediyl)bipyridine and 1,3-bis(4-piperidyl)propane in the prior art, the invention avoids the use of highly toxic and hazardous substances, has less harm to people and the environment, has a relatively simple synthesis process, has a higher yield, and is suitable for industrialized amplification production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane. Background Art

[0002] 4,4'-(1,3-propanediyl)bipyridine is an important raw material for the synthesis of 1,3-bis(4-piperidinyl)propane. 1,3-bis(4-piperidinyl)propane can react with dialdehydes in the presence of sulfur to form polysulfamides, which are widely used in industrial fields such as plastics and rubber. 1,3-bis(4-piperidinyl)propane can also be used as an organic nitrogen ligand to synthesize metal organic frameworks, which are widely used in the fields of catalysis and materials. The structural formula of 4,4'-(1,3-propanediyl)bipyridine is as follows:

[0003]

[0004] At present, there are few reports on the synthesis method of 4,4'-(1,3-propylenediyl)bipyridine. Document US2624738A uses 4-vinylpyridine and 4-methylpyridine to synthesize 4,4'-(1,3-propylenediyl)bipyridine under the action of solvent benzene and metallic potassium, but the yield of this method is only 44%, and the use of Class 1 carcinogen benzene as a solvent is very unfriendly to human health. The process also uses very active metallic potassium, which has a greater safety risk. These problems increase the risk and cost of the scale-up process, which is not conducive to future industrial scale-up. The synthesis route is as follows:

[0005]

[0006] Therefore, there is an urgent need to develop a new method for preparing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane that is environmentally friendly, has a relatively simple synthesis process, and has a higher product yield. Summary of the invention

[0007] In order to overcome the defects of the prior art, the purpose of the present invention is to provide a method for preparing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane which is environmentally friendly, has a relatively simple synthesis process, and has a higher product yield and is suitable for industrial scale-up production.

[0008] The present invention provides a method for preparing 4,4'-(1,3-propanediyl)bipyridine, the method comprising the following steps:

[0009]

[0010] The intermediate reacts with a reducing agent to obtain 4,4'-(1,3-propanediyl)bipyridine.

[0011] Furthermore, the molar ratio of the intermediate to the reducing agent is 1:4-6; the reducing agent is zinc powder; the solvent of the reaction is an organic solvent; the temperature of the reaction is 70-100° C., and the time is 0.5-2 hours.

[0012] Furthermore, the molar ratio of the intermediate to the reducing agent is 1:5.5; the solvent of the reaction is anhydrous methanol; the temperature of the reaction is 75-90° C., and the reaction time is 1 hour.

[0013] Furthermore, after the reaction for preparing 4,4'-(1,3-propylenediyl)bipyridine is completed, the following purification step is also included: filtering the reaction solution, rinsing with ethanol, concentrating under reduced pressure, adding water and potassium hydroxide, extracting with ethyl acetate, drying the filtrate, and concentrating under reduced pressure to obtain 4,4'-(1,3-propylenediyl)bipyridine.

[0014] Furthermore, the preparation method of the intermediate comprises the following steps:

[0015]

[0016] 4-acetylpyridine and 4-pyridinecarboxaldehyde react to obtain an intermediate; the reaction is carried out under the action of a base, and the base is an organic base or an inorganic base; the mass ratio of the 4-acetylpyridine, 4-pyridinecarboxaldehyde and the base is 1:0.6-1:0.01-0.2; the solvent of the reaction is an organic solvent; the temperature of the reaction is 70-90°C, and the time is 3-5 hours.

[0017] Furthermore, the base is piperidine; the mass ratio of 4-acetylpyridine, 4-pyridinecarboxaldehyde and base is 1:0.8-0.9:0.05-0.1; the solvent of the reaction is methanol, ethanol or isopropanol; the reaction temperature is 80°C and the reaction time is 4 hours.

[0018] Furthermore, after the reaction for preparing the intermediate is completed, the following purification step is also included: cooling the reaction solution to 25±5°C, beating for 0.5h, filtering, eluting with n-heptane, and drying to obtain the intermediate.

[0019] The present invention also provides a method for preparing 1,3-di(4-piperidinyl)propane, the method comprising the following steps:

[0020]

[0021] (1) preparing 4,4'-(1,3-propanediyl)bipyridine according to the above method;

[0022] (2) reacting 4,4'-(1,3-propanediyl)bipyridine with a catalyst to obtain a mixture;

[0023] (3) The mixture is reacted with a base to obtain 1,3-di(4-piperidinyl)propane.

[0024] Furthermore, in step (2), the mass ratio of the 4,4'-(1,3-propanediyl)bipyridine to the catalyst is 1:0.1-0.5; the catalyst is 10% palladium carbon; the solvent of the reaction is an organic solvent; the reaction temperature is 50-90°C, the pressure is 2-6MPa, and the reaction time is 12-18 hours;

[0025] In step (3), the mass ratio of the base to the 4,4'-(1,3-propylenediyl)bipyridine in step (2) is 1:2-3; the base is an organic base or an inorganic base; the solvent of the reaction is an organic solvent; the reaction temperature is 55-65°C and the reaction time is 2-4 hours.

[0026] Furthermore, in step (2), the mass ratio of the 4,4'-(1,3-propanediyl)bipyridine to the catalyst is 1:0.2; the solvent of the reaction is acetic acid; the reaction temperature is 60-80°C, the pressure is 3-5MPa, and the reaction time is 16 hours;

[0027] In step (3), the mass ratio of the base to the 4,4'-(1,3-propylenediyl)bipyridine in step (2) is 1:2.5; the base is sodium hydroxide; the solvent of the reaction is tetrahydrofuran; the reaction temperature is 60°C and the reaction time is 3 hours.

[0028] Furthermore, after the reaction for preparing 1,3-di(4-piperidinyl)propane is completed, the following purification step is also included: filtering the reaction solution, concentrating the filtrate under reduced pressure, adding n-heptane and stirring, cooling to 0° C., and filtering to obtain 1,3-di(4-piperidinyl)propane.

[0029] The present invention also provides a method for preparing 1,3-di(4-piperidinyl)propane, the method comprising the following steps:

[0030]

[0031] (i) reacting the intermediate with the catalyst to obtain a mixture;

[0032] (ii) The mixture is reacted with a base to obtain 1,3-di(4-piperidinyl)propane.

[0033] Furthermore, in step (i), the mass ratio of the intermediate to the catalyst is 1:0.1-0.5; the catalyst is 10% palladium carbon; the solvent of the reaction is an organic solvent; the reaction temperature is 60-80°C, the pressure is 4-8MPa, and the reaction time is 10-15 hours;

[0034] In step (ii), the mass ratio of the base to the intermediate of step (i) is 1:2-3; the base is an organic base or an inorganic base; the solvent of the reaction is an organic solvent; the reaction temperature is 55-65° C., and the reaction time is 2-4 hours.

[0035] Furthermore, in step (i), the mass ratio of the intermediate to the catalyst is 1:0.2; the solvent of the reaction is acetic acid; the reaction temperature is 70°C, the pressure is 4-8MPa, and the reaction time is 12 hours;

[0036] In step (ii), the mass ratio of the base to the intermediate of step (i) is 1:2.5; the base is sodium hydroxide; the solvent of the reaction is tetrahydrofuran; the reaction temperature is 60° C. and the reaction time is 3 hours.

[0037] Furthermore, after the reaction for preparing 1,3-di(4-piperidinyl)propane is completed, the following purification step is also included: filtering the reaction solution, concentrating the filtrate under reduced pressure, adding n-heptane and stirring, cooling to 0° C., and filtering to obtain 1,3-di(4-piperidinyl)propane.

[0038] Experimental results show that the present invention uses 4-pyridinecarboxaldehyde and acetylpyridine as starting materials to prepare 4,4'-(1,3-propylenediyl)bipyridine and 1,3-di(4-piperidyl)propane according to the synthesis concept of green chemistry. 4,4'-(1,3-propylenediyl)bipyridine can be first obtained by a step-by-step method, and then 1,3-di(4-piperidyl)propane can be obtained. Alternatively, 1,3-di(4-piperidyl)propane can be directly prepared using an intermediate. Compared with the method for preparing 4,4'-(1,3-propylenediyl)bipyridine and 1,3-di(4-piperidyl)propane in the prior art, the present invention avoids the use of highly toxic and hazardous substances, has less harm to humans and the environment, has a relatively simple synthesis process, has a higher yield, and is suitable for industrial scale-up production.

[0039] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0040] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0041] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0042] According to the following synthetic route, 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane can be prepared by first obtaining 4,4'-(1,3-propanediyl)bipyridine and then obtaining 1,3-di(4-piperidinyl)propane through a step-by-step method, or by directly using an intermediate to obtain 1,3-di(4-piperidinyl)propane:

[0043]

[0044] In Examples 1 and 2, 4,4'-(1,3-propanediyl)bipyridine is first obtained by a stepwise method, and then 1,3-di(4-piperidinyl)propane is obtained.

[0045] Example 1. Preparation of 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane

[0046] Step 1: Preparation of intermediates

[0047] 4-Acetylpyridine (50 g, 412.76 mmol, 1.0 eq), 4-pyridinecarboxaldehyde (44.21 g, 412.76 mmol, 1.0 eq), isopropanol (100 mL, 2 V), piperidine (5.0 g, 0.1 w) were added to a 250 mL three-necked flask, heated to 80 ° C for 4 h, heptane (400 mL, 8 V) was added while hot, cooled to 25 ± 5 ° C, slurried for 0.5 h, filtered, washed with n-heptane, and dried to obtain 73.7 g of a light yellow solid, i.e., an intermediate, with a purity of 95% and a yield of 85%. [M+1] = 211.2. 1 H NMR (400MHz, DMSO-d6) δ8.86–8.78(m,2H),8.69–8.63(m,2H),8.06(d,J=15.7Hz,1H),8.01–7.94(m,2H),7.86–7.79(m,2H),7.70(d,J=15.9Hz,1H).

[0048] Step 2: Preparation of 4,4'-(1,3-propanediyl)bipyridine

[0049] The intermediate (300 g, 1.43 mol, 1.0 eq) and anhydrous formic acid (1800 mL, 6 V) of the previous step were added to a 3L three-necked flask, heated to 90°C and stirred, and zinc powder (513.21 g, 7.85 mol, 5.5 eq) was added in batches. After the addition was completed, the reaction was continued for 1 hour, filtered through diatomaceous earth, rinsed with 2L ethanol, concentrated to dryness under reduced pressure at 70°C, and then 1000 mL of water was added, potassium hydroxide (240.19 g, 4.28 mol, 3.0 eq) was added, extracted with 2L ethyl acetate, separated, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain 240 g of a white solid, i.e., 4,4'-(1,3-propanediyl)bipyridine, with a purity of 98% and a yield of 85%. [M+1] = 199.3. 1 H NMR (400MHz, Chloroform-d) δ 8.64–8.37 (m, 4H), 7.08 (d, J = 5.1Hz, 4H), 2.62 (t, J = 7.7Hz, 4H), 1.97 (td, J = 8.0, 7.6, 1.9Hz, 2H).

[0050] Step 3: Preparation of 1,3-di(4-piperidinyl)propane

[0051] 4,4'-(1,3-propanediyl)bipyridine (133g, 670.83mmol, 1.0eq), 10% palladium carbon (26g, 0.2w), acetic acid (1.3L, 10V) were added to a 2L autoclave, 3MPa hydrogen, 60℃ reaction for 16 hours, diatomaceous earth was used for filtration to remove palladium carbon, the filtrate was concentrated under reduced pressure until no more was produced, tetrahydrofuran (1330mL, 10V) and sodium hydroxide (53.67g, 2.0eq) were added, the temperature was raised to 60℃ and the reaction was carried out for 3 hours, a small amount of diatomaceous earth was used for filtration to remove inorganic salts, the filtrate was concentrated under reduced pressure to dryness, 150mL of n-heptane was added, the temperature was cooled to 0℃ with stirring, and a white solid powder was obtained after filtration. After drying, 127g of white solid, i.e., 1,3-di(4-piperidinyl)propane, was obtained, with a purity of 98% and a yield of 90%. [M+1]=211.4. 1 H NMR(400MHz, DMSO-d6)δ2.83(dt,J=12.2,3.3Hz,4H),2.34(td,J=12.0,2.5Hz,4H),1.56–1.45(m, 4H), 1.20 (ddt, J=11.2, 7.2, 4.1Hz, 4H), 1.09 (q, J=6.8, 6.4Hz, 4H), 0.89 (qd, J=12.0, 4.0Hz, 4H).

[0052] Example 2: Preparation of 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane

[0053] Step 1: Preparation of intermediates

[0054] 4-Acetylpyridine (50 g, 412.76 mmol, 1.0 eq), 4-pyridinecarboxaldehyde (44.21 g, 412.76 mmol, 1.0 eq), ethanol (100 mL, 2 V), piperidine (2.5 g, 0.05 w) were added to a 250 mL three-necked flask, heated to 75 ° C for 4 h, heptane (400 mL, 8 V) was added while hot, cooled to 25 ± 5 ° C, slurried for 0.5 h, filtered, rinsed with n-heptane, and dried to obtain 65.9 g of a light yellow solid, i.e., an intermediate, with a purity of 95% and a yield of 76%. [M+1] = 211.2. 1 H NMR (400MHz, DMSO-d6) δ8.86–8.78(m,2H),8.69–8.63(m,2H),8.06(d,J=15.7Hz,1H),8.01–7.94(m,2H),7.86–7.79(m,2H),7.70(d,J=15.9Hz,1H).

[0055] Step 2: Preparation of 4,4'-(1,3-propanediyl)bipyridine

[0056] The intermediate (300 g, 1.43 mol, 1.0 eq) and anhydrous formic acid (1800 mL, 6 eq) of the previous step were added to a 3L three-necked flask, heated to 75°C and stirred, and zinc powder (513.21 g, 7.85 mol, 5.5 eq) was added in batches. After the addition was completed, the reaction was continued for 1 hour, filtered through diatomaceous earth, rinsed with 2L ethanol, concentrated to dryness under reduced pressure at 70°C, and then 1000 mL of water was added, potassium hydroxide (240.19 g, 4.28 mol, 3.0 eq) was added, extracted with 2L ethyl acetate, separated, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain 225 g of a white solid, i.e., 4,4'-(1,3-propanediyl)bipyridine, with a purity of 98% and a yield of 80%. [M+1] = 199.3. 1 H NMR (400MHz, Chloroform-d) δ 8.64–8.37 (m, 4H), 7.08 (d, J = 5.1Hz, 4H), 2.62 (t, J = 7.7Hz, 4H), 1.97 (td, J = 8.0, 7.6, 1.9Hz, 2H).

[0057] Step 3: Preparation of 1,3-di(4-piperidinyl)propane

[0058] 4,4'-(1,3-propanediyl)bipyridine (133g, 670.83mmol, 1.0eq), 10% palladium carbon (26g, 0.2w), acetic acid (1.3L, 10V) were added to a 2L autoclave, 5MPa hydrogen, 80℃ reaction for 16 hours, diatomaceous earth was used for filtration to remove palladium carbon, the filtrate was concentrated under reduced pressure until no more was produced, tetrahydrofuran (1330mL, 10v) and sodium hydroxide (53.67g, 2.0eq) were added, the temperature was raised to 60℃ for reaction for 3 hours, a small amount of diatomaceous earth was used for filtration to remove inorganic salts, the filtrate was concentrated under reduced pressure to dryness, 150mL of n-heptane was added, the temperature was cooled to 0℃ with stirring, and a white solid powder was obtained after filtration. After drying, 127g of white solid, i.e., 1,3-di(4-piperidinyl)propane, was obtained, with a purity of 98% and a yield of 90%. [M+1]=211.4. 1 H NMR(400MHz, DMSO-d6)δ2.83(dt,J=12.2,3.3Hz,4H),2.34(td,J=12.0,2.5Hz,4H),1.56–1.45(m, 4H), 1.20 (ddt, J=11.2, 7.2, 4.1Hz, 4H), 1.09 (q, J=6.8, 6.4Hz, 4H), 0.89 (qd, J=12.0, 4.0Hz, 4H).

[0059] Example 3 is to directly utilize the intermediate to prepare 1,3-di(4-piperidinyl)propane.

[0060] Example 3. Preparation of 1,3-di(4-piperidinyl)propane

[0061] Step 1: Preparation of intermediates

[0062] Add 4-acetylpyridine (50 g, 412.76 mmol, 1.0 eq), 4-pyridinecarboxaldehyde (44.21 g, 412.76 mmol, 1.0 eq), methanol (100 mL, 2 V), piperidine (5.0 g, 0.1 w) into a 250 mL three-necked flask, heat to 65 ° C for 4 h, add heptane (400 mL, 8 V) while hot, cool to 25 ± 5 ° C, beat for 0.5 h, filter, rinse with n-heptane, and dry to obtain 73.5 g of light yellow solid, i.e., intermediate, with a purity of 95% and a yield of 85%. [M+1] = 211.2. 1 H NMR (400MHz, DMSO-d6) δ8.86–8.78(m,2H),8.69–8.63(m,2H),8.06(d,J=15.7Hz,1H),8.01–7.94(m,2H),7.86–7.79(m,2H),7.70(d,J=15.9Hz,1H).

[0063] Step 2: Preparation of 1,3-di(4-piperidinyl)propane

[0064] The intermediate (133g, 670.83mmol, 1.0eq), 10% palladium carbon (26g, 0.2w), acetic acid (1.3L, 10v) were added to a 2L autoclave, 6MPa hydrogen, 70℃ reaction for 12 hours, diatomaceous earth was used for filtration to remove palladium carbon, the filtrate was concentrated under reduced pressure until no more was produced, tetrahydrofuran (1330mL, 10V) and sodium hydroxide (53.67g, 2.0eq) were added, the temperature was raised to 60℃ for reaction for 3 hours, a small amount of diatomaceous earth was used for filtration to remove inorganic salts, the filtrate was concentrated under reduced pressure to dryness, 150mL of n-heptane was added, the temperature was cooled to 0℃ with stirring, and a white solid powder was obtained after drying, 113g of white solid was obtained, i.e., 1,3-di(4-piperidinyl)propane, with a purity of 98% and a yield of 85%. [M+1]=211.4. 1 H NMR(400MHz, DMSO-d6)δ2.83(dt,J=12.2,3.3Hz,4H),2.34(td,J=12.0,2.5Hz,4H),1.56–1.45(m, 4H), 1.20 (ddt, J=11.2, 7.2, 4.1Hz, 4H), 1.09 (q, J=6.8, 6.4Hz, 4H), 0.89 (qd, J=12.0, 4.0Hz, 4H).

[0065] In summary, the present invention provides a method for synthesizing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane. The present invention uses 4-pyridinecarboxaldehyde and acetylpyridine as starting materials to prepare 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane. 4,4'-(1,3-propanediyl)bipyridine can be first obtained by a step-by-step method, and then 1,3-di(4-piperidinyl)propane can be obtained. 1,3-di(4-piperidinyl)propane can also be directly prepared from an intermediate. Compared with the method for preparing 4,4'-(1,3-propanediyl)bipyridine and 1,3-di(4-piperidinyl)propane in the prior art, the present invention avoids the use of highly toxic and hazardous substances, has less harm to humans and the environment, has a relatively simple synthesis process, has a higher yield, and is suitable for industrialized scale-up production.

Claims

1. A method for preparing 4,4'-(1,3-propanediyl)bipyridine, characterized in that: The method comprises the following steps: The intermediate reacts with a reducing agent to obtain 4,4'-(1,3-propanediyl)bipyridine; The molar ratio of the intermediate to the reducing agent is 1:4-6; the reducing agent is zinc powder; the solvent of the reaction is anhydrous formic acid; the temperature of the reaction is 70-100° C., and the time is 0.5-2 hours.

2. The method according to claim 1, characterized in that The molar ratio of the intermediate to the reducing agent is 1:5.5; the reaction temperature is 75-90° C. and the reaction time is 1 hour.

3. The method according to claim 1, characterized in that: The preparation method of the intermediate comprises the following steps: 4-acetylpyridine and 4-pyridinecarboxaldehyde react to obtain an intermediate; the reaction is carried out under the action of a base, and the base is an organic base or an inorganic base; the mass ratio of the 4-acetylpyridine, 4-pyridinecarboxaldehyde and the base is 1:0.6-1:0.01-0.2; the solvent of the reaction is an organic solvent; the temperature of the reaction is 70-90°C, and the time is 3-5 hours.

4. The method according to claim 3, characterized in that: The base is piperidine; the mass ratio of 4-acetylpyridine, 4-pyridinecarboxaldehyde and base is 1:0.8-0.9:0.05-0.1; the solvent of the reaction is methanol, ethanol or isopropanol; the reaction temperature is 80°C and the reaction time is 4 hours.

5. A method for preparing 1,3-di(4-piperidinyl)propane, characterized in that: The method comprises the following steps: (1) preparing 4,4'-(1,3-propanediyl)bipyridine by the method according to any one of claims 1 to 4; (2) reacting 4,4'-(1,3-propanediyl)bipyridine with a catalyst to obtain a mixture; (3) The mixture is reacted with a base to obtain 1,3-di(4-piperidinyl)propane.

6. The method according to claim 5, characterized in that In step (2), the mass ratio of 4,4'-(1,3-propanediyl)bipyridine to the catalyst is 1:0.1-0.5; the catalyst is 10% palladium carbon; the solvent of the reaction is an organic solvent; the reaction temperature is 50-90°C, the pressure is 2-6MPa, and the reaction time is 12-18 hours; In step (3), the mass ratio of the base to the 4,4'-(1,3-propylenediyl)bipyridine in step (2) is 1:2-3; the base is an organic base or an inorganic base; the solvent of the reaction is an organic solvent; the reaction temperature is 55-65°C and the reaction time is 2-4 hours.

7. The method according to claim 6, characterized in that In step (2), the mass ratio of 4,4'-(1,3-propylenediyl)bipyridine to the catalyst is 1:0.2; the solvent of the reaction is acetic acid; the reaction temperature is 60-80°C, the pressure is 3-5MPa, and the reaction time is 16 hours; In step (3), the mass ratio of the base to the 4,4'-(1,3-propylenediyl)bipyridine in step (2) is 1:2.5; the base is sodium hydroxide; the solvent of the reaction is tetrahydrofuran; the reaction temperature is 60°C and the reaction time is 3 hours.

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