A method for preparing symmetrical double-terminal piperidinyl alkane

Abstract

The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing a symmetrical double-terminal piperidinyl alkane, wherein the preparation method comprises the following steps: under the protection of an inert gas, a double-terminal halogenated alkane reacts with triphenylphosphine to prepare a phosphonium salt, namely an intermediate A, and then the intermediate A reacts with a piperidinone derivative under alkaline conditions to produce an intermediate B by Wittig reaction; the intermediate B is subjected to hydrogenation reduction to obtain the symmetrical double-terminal piperidinyl alkane; the raw materials of the preparation method of the present invention are easily available, the yield is high, and the preparation method is conducive to industrial production. The purity of the symmetrical double-terminal piperidinyl alkane obtained by the preparation method of the present invention is greater than 99%, and the total yield is 75-80%; the yield and purity are relatively high.

Description

Technical Field

[0001] The invention relates to a method for preparing a symmetrical double-terminal piperidinyl alkane, belonging to the technical field of chemical synthesis. Background Art

[0002] Symmetrical double-terminal piperidinyl alkane is an important symmetrical double-terminal cyclic intermediate with a wide range of uses. Its structural formula is as follows: ; wherein n is a natural number of 1 to 10; the symmetrical double-terminal piperidine alkane can be used as an important organic intermediate in the fields of display materials, organic functional materials, pharmaceutical intermediates, etc.

[0003] Chinese patent application CN106232733A uses symmetrical double-terminal piperidinyl alkane as the main chain to synthesize a type of bifunctional polymerizable monomer, which can be used to prepare lateral electric field driven liquid crystal display elements with strong orientation control ability and excellent afterimage characteristics. Chinese patent application CN108467485A uses symmetrical double-terminal piperidinyl alkane and tetrahalomethyl-containing compounds as the main raw materials to carry out condensation polymerization to prepare a polymer film with high alkali resistance. The polymer film is currently widely used in the fields of fuel cells and polymer material synthesis. Chinese patent CN115335434A applied by BASF of Germany uses symmetrical double-terminal piperidinyl alkane to synthesize a copper electroplating composition of a polyaminoamide type leveling agent, and the polymer can be used in the semiconductor field. At present, symmetrical double-terminal piperidinyl alkanes are more widely used in the field of anti-tumor drugs. For example, Chinese patent applications CN106866978A, CN116322628A, US20040071654A1, and CN115697321A all state that symmetrical double-terminal piperidinyl alkanes can be used in the field of anti-tumor drugs. In addition, such drugs are widely used in targeted drugs and sustained-control drugs because of their biodegradability and efficient release.

[0004] At present, the synthesis method of symmetrical double-terminal piperidinyl alkanes disclosed in PCT patent application WO2023049790A2 and Japanese patent application JP62267263A is: symmetrical double-terminal pyridinyl alkanes are generated by coupling reaction of 4-methylpyridine with a double-terminal halide under alkaline conditions, and then the symmetrical double-terminal pyridinyl alkane is hydrogenated and reduced to prepare symmetrical double-terminal piperidinyl alkane. This method has harsh coupling reaction conditions, needs to be carried out under ultra-low temperature conditions, and has low yield, which is not conducive to industrial production. Summary of the invention

[0005] The invention aims at the deficiencies in the prior art and provides a method for preparing a symmetrical double-terminal piperidinyl alkane. The preparation method has stable process, simple operation, high yield and is conducive to industrial production.

[0006] The technical solution of the present invention to solve the above technical problems is as follows: a method for preparing a symmetrical double-terminal piperidinyl alkane, the preparation method comprising: reacting a double-terminal halogenated alkane with triphenylphosphine under inert gas protection to prepare a phosphonium salt, namely, an intermediate A, and then reacting the intermediate A with a piperidinone derivative under alkaline conditions to prepare an intermediate B; and hydrogenating and reducing the intermediate B to obtain the symmetrical double-terminal piperidinyl alkane;

[0007] The structural formula of the double-terminal halogenated alkane is: ;

[0008] The structural formula of the intermediate A is: ;

[0009] The structural formula of the piperidone derivative is: ;

[0010] The structural formula of the intermediate B is: ;

[0011] The structural formula of the symmetrical double-terminal piperidinyl alkane is: ;

[0012] n is a natural number ranging from 1 to 10; X is Cl, Br or I; R is Boc or Bn.

[0013] Further, when preparing intermediate A, the molar ratio of the double-terminal halogenated alkane to triphenylphosphine is 1:(2.0-3.0);

[0014] When preparing intermediate B, the molar ratio of intermediate A to piperidone derivative is 1:(1.8-2.5), and the molar ratio of intermediate A to base is 1:(1.8-2.5);

[0015] When preparing a symmetrical double-terminal piperidinyl alkane product, palladium carbon is used as a catalyst for a hydrogenation reduction reaction, and the mass ratio of the intermediate B to palladium carbon is 1: (0.02~0.05).

[0016] Furthermore, when preparing intermediate A, the temperature in the reaction system is 100-150° C.; and the insulation reaction time is 4-16 hours.

[0017] Furthermore, when preparing intermediate B, firstly dissolve intermediate A and piperidone derivatives in a solvent, control the temperature in the system to 0-50°C, add alkaline solution dropwise, and after the addition is completed, keep the reaction at 0-50°C for 4-12 hours.

[0018] Furthermore, when preparing intermediate B, firstly, intermediate A and piperidone derivatives are dissolved in a solvent, the temperature in the system is controlled to be 0-30°C, and an alkali solution is added dropwise. After the addition is completed, the reaction is kept at 0-30°C.

[0019] Furthermore, when preparing the symmetrical double-terminal piperidinyl alkane product, the hydrogenation reduction reaction temperature is 60-100°C, and the hydrogenation reduction reaction time is 12-24h.

[0020] Furthermore, when preparing intermediate A, the solvent selected for the reaction system is at least one of toluene, xylene, DMSO, DMF or DMAc;

[0021] When preparing intermediate B, the solvent selected by the system is at least one of toluene, dichloromethane, 2-methyltetrahydrofuran and tetrahydrofuran;

[0022] When preparing the symmetrical double-terminal piperidinyl alkane product, the solvent selected for the hydrogenation reduction reaction system is at least one of methanol, ethanol, isopropanol, tetrahydrofuran and toluene.

[0023] Furthermore, when preparing intermediate B, the base used is potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, butyl lithium or lithium hexamethyldisilazide.

[0024] Furthermore, the post-treatment operation for preparing the intermediate A is as follows: after the double-terminal halogenated alkane reacts with triphenylphosphine, the system is cooled to 20-25° C. and then filtered, the wet product is eluted with THF, and dried under reduced pressure to obtain the intermediate A;

[0025] The post-treatment operation for preparing the intermediate B is as follows: after the Wittig reaction is completed, hydrolysis and stratification are first performed, the aqueous phase is extracted and then the organic phase is combined, the organic phase is dehydrated, petroleum ether is added for pulping, and the solvent is dehydrated from the filtrate after pulping to obtain the intermediate B;

[0026] The post-treatment process for preparing the double-terminal piperidinyl alkane product is as follows: filtering after the hydrogenation reduction reaction is completed, removing the solvent from the filtrate, then recrystallizing using a mixed solution of n-heptane and toluene, filtering, and drying under reduced pressure to obtain the double-terminal piperidinyl alkane product.

[0027] Furthermore, the symmetrical double-terminal piperidinyl alkane is selected from any one of the following structural formulas:

[0028] .

[0029] The beneficial effects of the present invention are:

[0030] The preparation method of the symmetrical double-terminal piperidinyl alkane of the present invention comprises the following reaction process:

[0031] ;

[0032] The preparation method has simple process, readily available raw materials, short time, high product yield, and stable industrial production. The alkylcyclohexylbenzidine prepared by the preparation method of the present invention has a purity of more than 99% and a yield of 60-80%; both the yield and purity are high.

[0033] In the preparation method of the symmetrical double-terminal piperidinyl alkane of the present invention, first, under the protection of inert gas, the double-terminal halogenated alkane reacts with triphenylphosphine to prepare a phosphonium salt (intermediate A), and then Wittig reaction with a piperidone derivative under alkaline conditions to prepare (intermediate B), after the reaction is completed, the intermediate is hydrogenated and reduced to obtain the symmetrical double-terminal piperidinyl alkane. The synthesis process is simple to operate, has good process stability, and has high product purity and yield. In addition, the reaction conditions of the preparation method of the present invention are easier to control, do not require harsh reaction conditions, and do not require the use of special equipment, and are more suitable for industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the H NMR spectrum of intermediate A1 in Example 1;

[0035] Figure 2 is the NMR carbon spectrum of intermediate A1 in Example 1;

[0036] Figure 3 is the GC-MS spectrum of intermediate B1 in Example 1;

[0037] Figure 4 is the H NMR spectrum of intermediate B1 in Example 1;

[0038] Figure 5 is the NMR carbon spectrum of intermediate B1 in Example 1;

[0039] Figure 6 is the GC-MS spectrum of 1,3-di(4-piperidinyl)propane (Compound 1) in Example 1;

[0040] Figure 7 is the H NMR spectrum of 1,3-di(4-piperidinyl)propane (Compound 1) in Example 1;

[0041] Figure 8 This is the carbon NMR spectrum of 1,3-di(4-piperidinyl)propane (Compound 1) in Example 1. DETAILED DESCRIPTION

[0042] The specific implementation of the present invention is described in detail below. The present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used are only for describing specific embodiments and are not intended to limit the present invention.

[0044] A method for preparing a symmetrical double-terminal piperidinyl alkane, the preparation method comprising: under the protection of an inert gas, a double-terminal halogenated alkane reacts with triphenylphosphine to prepare a phosphonium salt, namely an intermediate A, and then the intermediate A reacts with a piperidinone derivative under alkaline conditions to produce an intermediate B by Wittig reaction; the intermediate B is subjected to hydrogenation reduction to obtain the symmetrical double-terminal piperidinyl alkane;

[0045] The structural formula of the double-terminal halogenated alkane is: ;

[0046] The structural formula of the intermediate A is: ;

[0047] The structural formula of the piperidone derivative is: ;

[0048] The structural formula of the intermediate B is: ;

[0049] The structural formula of the symmetrical double-terminal piperidinyl alkane is: ;

[0050] n is a natural number from 1 to 10; X is Cl, Br or I; R is Boc or Bn;

[0051] The specific reaction process is as follows:

[0052] .

[0053] Specifically, when preparing intermediate A, the molar ratio of the double-terminal halogenated alkane to triphenylphosphine is 1:(2.0-3.0); the mass ratio of the double-terminal halogenated alkane to the solvent is 1:(10.0-15.0);

[0054] When preparing intermediate B, the molar ratio of intermediate A to piperidone derivative is 1:(1.8-2.5), and the molar ratio of intermediate A to base is 1:(1.8-2.5); the mass ratio of intermediate A to solvent is 1:(2.2-2.5), and the mass ratio of base to solvent is 1:(5.0-10.0);

[0055] When preparing a symmetrical double-terminal piperidinyl alkane product, palladium carbon is used as a catalyst for hydrogenation reduction reaction, and the mass ratio of intermediate B to palladium carbon is 1: (0.02-0.05); the mass ratio of intermediate B to solvent is 1: (5.0-10.0).

[0056] Preferably, when preparing intermediate A, the molar ratio of the double-terminal halogenated alkane to triphenylphosphine is 1:2.5, and the mass ratio of the double-terminal halogenated alkane to the solvent is 1:12.3;

[0057] When preparing intermediate B, the molar ratio of intermediate A to piperidone derivative is 1:1.8, the molar ratio of intermediate A to base is 1:2.4, the mass ratio of intermediate A to solvent is 1:2.2, and the mass ratio of base to solvent is 1:5.0;

[0058] When preparing the symmetrical double-terminal piperidinyl alkane product, the mass ratio of the intermediate B to the solvent is 1:5.0, and the mass ratio of the intermediate B to palladium carbon is 1:0.02.

[0059] Specifically, when preparing intermediate A, the temperature in the reaction system is 100-150° C.; and the insulation reaction time is 4-16 hours.

[0060] Preferably, the temperature in the reaction system during preparation of intermediate A is 125°C.

[0061] Preferably, when preparing intermediate A, the insulation reaction time is 6 to 10 hours.

[0062] Specifically, when preparing intermediate B, firstly dissolve intermediate A and piperidone derivatives in a solvent, control the temperature in the system to 0-50°C, add alkaline solution dropwise, and after the addition is completed, keep the reaction at 0-50°C for 4-12 hours.

[0063] Preferably, when preparing intermediate B, intermediate A and piperidone derivatives are first dissolved in a solvent, the temperature in the system is controlled to be 0-30°C, an alkali solution is added dropwise, and after the addition is completed, the reaction is kept at 0-30°C.

[0064] Preferably, when preparing intermediate B, the insulation reaction time is 8 to 10 hours.

[0065] Specifically, when preparing the symmetrical double-terminal piperidinyl alkane product, the hydrogenation reduction reaction temperature is 60-100° C., and the hydrogenation reduction reaction time is 12-24 hours.

[0066] Preferably, when preparing the symmetrical double-terminal piperidinyl alkane product, the hydrogenation reduction reaction temperature is 80°C.

[0067] Preferably, when preparing the symmetrical double-terminal piperidinyl alkane product, the hydrogenation reduction reaction time is 12 to 16 hours.

[0068] Specifically, when preparing intermediate A, the solvent selected for the reaction system is at least one of toluene, xylene, DMSO, DMF or DMAc;

[0069] When preparing intermediate B, the solvent selected by the system is at least one of toluene, dichloromethane, 2-methyltetrahydrofuran and tetrahydrofuran;

[0070] When preparing the symmetrical double-terminal piperidinyl alkane product, the solvent selected for the hydrogenation reduction reaction system is at least one of methanol, ethanol and isopropanol.

[0071] Preferably, the solvent selected for the reaction system when preparing intermediate A is DMF;

[0072] When preparing intermediate B, the solvents selected in the system are toluene and tetrahydrofuran;

[0073] When preparing the symmetrical double-terminal piperidinyl alkane product, the solvent selected for the hydrogenation reduction reaction system is isopropanol.

[0074] Specifically, when preparing intermediate B, the base used is potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, butyl lithium or lithium hexamethyldisilazide.

[0075] Preferably, when preparing intermediate B, the base used is potassium tert-butoxide.

[0076] Specifically, the post-treatment operation for preparing the intermediate A is as follows: after the double-terminal halogenated alkane reacts with triphenylphosphine, the system is cooled to 20-25°C and then filtered, the wet product is eluted with tetrahydrofuran, wherein the mass ratio of the wet product to tetrahydrofuran is 1:(0.5-2.0), and the intermediate A is obtained by drying under reduced pressure;

[0077] The post-treatment operation for preparing the intermediate B is as follows: after the Wittig reaction is completed, hydrolysis and stratification are first performed, the aqueous phase is extracted and then the organic phase is combined, the organic phase is dehydrated, petroleum ether is added for pulping, and the solvent is dehydrated from the filtrate after pulping to obtain the intermediate B;

[0078] The post-treatment process for preparing the double-terminal piperidinyl alkane product is as follows: filtering after the hydrogenation reduction reaction is completed, removing the solvent from the filtrate, and then using a mixed solution of n-heptane and toluene for recrystallization, filtering, and drying under reduced pressure to obtain the double-terminal piperidinyl alkane product, wherein the mass ratio of n-heptane to toluene is (19.0~21.0):1, the dissolution temperature during recrystallization is 45~50°C, and the crystallization filtration temperature is -30~-25°C.

[0079] Specifically, the symmetrical double-terminal piperidinyl alkane is selected from any one of the following structural formulas:

[0080] .

[0081] Example 1

[0082] Step 1: Preparation of phosphonium salt intermediate A1

[0083] Take 295.1g of triphenylphosphine and add it to 893.0g of DMF. Heat it to 125℃ and the system becomes colorless and clear. Add 1,3-dibromopropane DMF solution dropwise (take 90.8g of 1,3-dibromopropane and add it to 223.3g of DMF). After the addition is complete, keep the temperature for 10 hours, cool it to room temperature and filter it. The filter cake is washed with tetrahydrofuran to obtain a white solid. Control the bath temperature to ≤80℃ and dry it under reduced pressure for 6 hours to obtain intermediate A1, HPLC: 99.94%, yield 91.3%.

[0084] Step 2: Preparation of intermediate B1 by Wittig reaction

[0085] Take 145.6g of intermediate A1, 68g of N-benzyl-4-piperidone, and 320g of toluene and mix them evenly. Cool down to 0~10℃, start to drip potassium tert-butoxide THF solution (53.9g potassium tert-butoxide, add 269.5g THF and mix evenly), keep the dripping temperature at 0~10℃, and keep the temperature at 0~10℃ for 8 hours. After the insulation is completed, add 200g of water to quench, let stand and separate, separate the aqueous phase, extract it once with 50g of toluene, and merge it into the organic phase. The organic phase is controlled to have a bath temperature of ≤60℃ and desolventize under reduced pressure. After the desolventization is completed, use 200g of petroleum ether to beat twice, combine the filtrate, control the bath temperature of ≤55℃, desolventize under reduced pressure, and obtain a colorless oily liquid after the desolventization is completed, GC: 97.11%, yield 89.3%.

[0086] Step 3: Hydrogenation and deprotection to prepare compound 1

[0087] Add 2.2g (wet) 5% Pd / C and intermediate B1 solution (51.6g intermediate B1 and 258g isopropanol) to the hydrogenation kettle, replace with nitrogen 3 times, and replace with hydrogen 3 times. Turn on the stirring, heat to the kettle temperature of 70°C, charge with hydrogen to 0.9MPa for reaction, and discharge after about 12 hours of reaction. Filter to remove Pd / C, and after filtration, the bath temperature is ≤55°C, and the vacuum degree is -0.09~-0.1MPa to remove the solvent under reduced pressure to obtain a light yellow solid. Add 56.2g n-heptane and 2.8g toluene to the system, recrystallize, and filter to obtain an off-white filter cake. The filter cake is controlled to have a bath temperature of ≤50°C, a vacuum degree of -0.09~-0.1MPa, and a reduced pressure drying to obtain an off-white solid compound 1, GC: 99.11%, yield 93.3%.

[0088] The NMR spectrum of intermediate A1 is as follows Figure 1 Figure 2 As shown, the conditions for NMR spectrum determination are: 1 H-NMR (400MHz, Chloroform-d).

[0089] The GC-MS spectrum of intermediate B1 is as follows Figure 3 As shown, the NMR spectrum is Figure 4-Figure 5As shown, the conditions for NMR spectrum determination are: 1 H-NMR (400MHz, Chloroform-d).

[0090] The GC-MS spectrum of compound 1 is as follows Figure 6 As shown, the NMR spectrum is Figure 7-Figure 8 As shown, the conditions for NMR spectrum determination are: 1 H-NMR (400MHz, Chloroform-d).

[0091] The structural formula of intermediate A1 is: ;

[0092] The structural formula of intermediate B1 is: ;

[0093] The structural formula of compound 1 is: .

[0094] Example 2

[0095] Step 1: Preparation of intermediate A2

[0096] Take 295.1g of triphenylphosphine and add it to 893.0g of DMF. Heat it to 125℃ and the system becomes colorless and clear. Add 1,4-dibromobutane in DMF dropwise (take 97.1g of 1,4-dibromobutane and add it to 223.3g of DMF). Keep the temperature for 10 hours after the addition is complete. Cool it to room temperature and filter it. Wash the filter cake with tetrahydrofuran to obtain a white solid. Control the bath temperature to ≤80℃ and dry it under reduced pressure for 6 hours to obtain intermediate A2. HPLC: 99.92%, yield 92.8%.

[0097] Step 2: Preparation of intermediate B2 by Wittig reaction

[0098] Take 148.4g of intermediate A2, 68g of N-benzyl-4-piperidone, and 320g of toluene and mix them evenly. Cool down to 10~20℃, start to drip potassium tert-butoxide THF solution (53.9g potassium tert-butoxide, add 269.5g THF and mix evenly), keep the dripping temperature at 10~20℃, and keep the reaction at 10~20℃ for 8 hours. After the insulation is completed, add 200g of water to quench, let stand and separate, separate the aqueous phase, extract it once with 50g of toluene, and merge it into the organic phase. The organic phase controls the bath temperature to ≤60℃, and desolventizes under reduced pressure. After the desolventization is completed, use 200g of petroleum ether to beat twice, combine the filtrate, control the bath temperature of the organic phase to ≤55℃, desolventize under reduced pressure, and obtain a colorless oily liquid after the desolventization is completed, GC: 97.45%, yield 90.1%.

[0099] Step 3: Hydrogenation and deprotection to prepare compound 2

[0100] Add 2.2g (wet) 5% Pd / C and intermediate B2 solution (53.5g intermediate B2 and 258g isopropanol) to the hydrogenation kettle, replace with nitrogen 3 times, and replace with hydrogen 3 times. Turn on the stirring, heat to the kettle temperature of 70°C, charge with hydrogen to 0.9MPa for reaction, and discharge after about 12 hours of reaction. Filter to remove Pd / C, and after filtration, the bath temperature is ≤55°C, and the vacuum degree is -0.09~-0.1MPa to remove the solvent under reduced pressure to obtain a light yellow solid. Add 56.2g n-heptane and 2.8g toluene to the system, recrystallize, and filter to obtain an off-white filter cake. The filter cake is controlled to have a bath temperature of ≤50°C, a vacuum degree of -0.09~-0.1MPa, and a reduced pressure drying to obtain an off-white solid compound 2, GC: 99.23%, yield 93.8%.

[0101] The structural formula of intermediate A2 is: ;

[0102] The structural formula of intermediate B2 is: ;

[0103] The structural formula of compound 2 is: .

[0104] Example 3

[0105] Step 1: Preparation of intermediate A3

[0106] Take 295.1g triphenylphosphine and add it to 893.0g DMF. Heat it to 125℃ and the system becomes colorless and clear. Add 1,5-dibromopentane DMF solution (take 103.4g 1,4-dibromopentane and add it to 223.3g DMF) dropwise. Keep warm for 10 hours after the addition is completed. Cool it to room temperature and filter it. Wash the filter cake with tetrahydrofuran to obtain a white solid. Control the bath temperature to ≤80℃ and dry it under reduced pressure for 6 hours to obtain intermediate A2. HPLC: 99.94%, yield 92.8%.

[0107] Step 2: Preparation of intermediate B3 by Wittig reaction

[0108] Take 154.1g of intermediate A3, 68g of N-benzyl-4-piperidone, and 320g of toluene and mix them evenly. Cool down to 20-30°C, start adding potassium tert-butoxide THF solution (53.9g potassium tert-butoxide is added to 269.5g THF and mixed evenly), keep the dropping temperature at 20-30°C, and keep the reaction at 20-30°C for 8 hours. After the insulation is completed, add 200g of water to quench, let stand and separate, separate the aqueous phase, extract it once with 50g of toluene, and merge it into the organic phase. The organic phase is controlled to have a bath temperature of ≤60°C and desolventize under reduced pressure. After the desolventization is completed, use 200g of petroleum ether to beat twice, combine the filtrate, control the bath temperature of ≤55°C, desolventize under reduced pressure, and obtain a colorless oily liquid after the desolventization is completed, GC: 98.13%, yield 92.1%.

[0109] Step 3: Hydrogenation and deprotection to prepare compound 3

[0110] Add 2.2g (wet) 5% Pd / C and intermediate B1 solution (57.4g intermediate B3 and 258g isopropanol) to the hydrogenation kettle, replace with nitrogen 3 times, and replace with hydrogen 3 times. Turn on the stirring, heat to the kettle temperature of 70°C, charge with hydrogen to 0.9MPa for reaction, and discharge after about 12 hours of reaction. Filter to remove Pd / C, and after filtration, the bath temperature is ≤55°C, and the vacuum degree is -0.09~-0.1MPa to remove the solvent under reduced pressure to obtain a light yellow solid. Add 56.2g n-heptane and 2.8g toluene to the system, recrystallize, and filter to obtain an off-white filter cake. The filter cake is controlled to have a bath temperature of ≤50°C, a vacuum degree of -0.09~-0.1MPa, and a reduced pressure drying to obtain an off-white solid compound 2, GC: 99.43%, yield 94.5%.

[0111] The structural formula of intermediate A3 is: ;

[0112] The structural formula of intermediate B3 is: ;

[0113] The structural formula of compound 3 is: .

[0114] Example 4

[0115] Step 1: Preparation of phosphonium salt intermediate A4

[0116] Take 295.1g of triphenylphosphine and add it to 893.0g of DMF. Heat it to 125℃ and the system becomes colorless and clear. Add 1,3-diiodopropane solution dropwise (take 133.1g of 1,3-diiodopropane and add it to 223.3g of DMF). After the addition is complete, keep the temperature for 10 hours, cool it to room temperature and filter it. The filter cake is washed with tetrahydrofuran to obtain a white solid. Control the bath temperature to ≤80℃ and dry it under reduced pressure for 6 hours to obtain intermediate A4, HPLC: 99.94%, yield 96.3%.

[0117] Step 2: Preparation of intermediate B1 by Wittig reaction

[0118] Take 164.4g of intermediate A4, 68g of N-benzyl-4-piperidone, and 320g of toluene and mix them evenly. Cool down to 10~20℃, start to drip potassium tert-butoxide THF solution (53.9g potassium tert-butoxide, add 269.5g THF and mix evenly), keep the dripping temperature at 10~20℃, and keep the reaction at 10~20℃ for 6 hours. After the insulation is completed, add 200g of water to quench, let stand and separate, separate the aqueous phase, extract it once with 50g of toluene, and merge it into the organic phase. The organic phase controls the bath temperature to ≤60℃, and desolventizes under reduced pressure. After the desolventization is completed, use 200g of petroleum ether to beat twice, combine the filtrate, control the bath temperature of the organic phase to ≤55℃, desolventize under reduced pressure, and obtain a colorless oily liquid after the desolventization is completed, GC: 97.42%, yield 95.1%.

[0119] Step 3: Hydrogenation and deprotection to prepare compound 1

[0120] This step is the same as Example 1, the product purity GC: 99.08%, the yield is 92.9%.

[0121] The structural formula of intermediate A4 is: ;

[0122] The structural formula of intermediate B1 is: ;

[0123] The structural formula of compound 1 is: .

[0124] Example 5

[0125] Step 1: Preparation of intermediate A1

[0126] The method is the same as Example 1.

[0127] Step 2: Preparation of intermediate B5 by Wittig reaction

[0128] Take 145.6g of intermediate A1, 71.6g of N-BOC-4-piperidone, and 320g of toluene and mix them evenly. Cool down to 40~50℃, start to drip potassium tert-butoxide THF solution (53.9g potassium tert-butoxide, add 269.5g THF and mix evenly), keep the dripping temperature at 40~50℃, and keep the temperature at 40~50℃ for 8 hours. After the insulation is completed, add 200g of water to quench, let stand and separate, separate the aqueous phase, extract it once with 50g of toluene, and merge it into the organic phase. The organic phase controls the bath temperature to ≤60℃, and desolventizes under reduced pressure. After the desolventization is completed, use 200g of petroleum ether to beat twice, combine the filtrate, control the bath temperature of the organic phase to ≤55℃, desolventize under reduced pressure, and obtain a light yellow oily intermediate B5 after the desolventization is completed, GC: 96.53%, yield 77.8%.

[0129] Step 3: Hydrogenation and deprotection to prepare compound 1

[0130] Add 2.2g (wet) 5% Pd / C and intermediate B1 solution (51.6g intermediate B1 and 258g isopropanol) to the hydrogenation kettle, replace with nitrogen 3 times, and replace with hydrogen 3 times. Turn on the stirring, heat to the kettle temperature of 70°C, charge with hydrogen to 0.9MPa for reaction, and discharge after about 12 hours of reaction. Filter to remove Pd / C, and after filtration, the bath temperature is ≤55°C, and the vacuum degree is -0.09~-0.1MPa to remove the solvent under reduced pressure to obtain a light yellow solid. Add 56.2g n-heptane and 2.8g toluene to the system for recrystallization, and after filtration, an off-white filter cake is obtained. The filter cake is controlled to have a bath temperature of ≤50°C, a vacuum degree of -0.09~-0.1MPa, and a reduced pressure drying to obtain an off-white solid compound 1, GC: 99.11%, yield 93.3%.

[0131] The structural formula of intermediate A1 is: ;

[0132] The structural formula of intermediate B5 is: ;

[0133] The structural formula of compound 1 is: .

[0134] Example 6

[0135] The intermediate A1 was prepared by the same method as in Example 1, except that the material ratio of dibromopropane to triphenylphosphine was changed from 1:2.5 to 1:3.0.

[0136] In this Example 6, the intermediate A1 obtained had a HPLC value of 99.94% and a yield of 92.8%.

[0137] It can be seen from the data results of Example 1 and Example 6 that in the experimental process of this Example 6, increasing the material ratio of triphenylphosphine can improve the yield to a certain extent.

[0138] Example 7-Example 10

[0139] The intermediate A1 was prepared by the same method as in Example 1, except that different solvents were used. The HPLC purity and yield of the intermediate A1 are shown in Table 1 below.

[0140] Table 1 Yield and purity data of intermediate A1 prepared under different solvent conditions

[0141]

[0142] It can be seen from the data in Table 1 that solvents with different boiling points will result in different product yields. From the data, it can be seen that solvents with higher boiling points, such as DMSO, DMAc, and DMF, are more conducive to obtaining intermediate A1 with high yield and high purity.

[0143] Embodiment 11

[0144] When the intermediate B1 is prepared by the same method as in Example 1, the difference is that the molar ratio of the intermediate A to the piperidone derivative is 1:2.5.

[0145] In this Example 11, the GC of the intermediate B1 obtained was 97.32% and the yield was 68.2%.

[0146] It can be seen from the data of Example 1 and Example 11 that increasing the material ratio of piperidone derivatives can effectively improve the GC purity of the product, but the remaining piperidone raw materials are large, which is not conducive to purification.

[0147] Example 12-Example 15

[0148] The same method as in Example 1 was used to prepare Compound 1, except that the hydrogenation reduction reaction temperature was changed. The GC purity and yield of Compound 1 obtained by changing the hydrogenation reduction reaction temperature and the time required for the hydrogenation reduction reaction are shown in Table 2 below.

[0149] Table 2 Experimental data of changing the temperature of hydrogenation reduction reaction

[0150]

[0151] From the comparison of the data in the above table, it can be seen that increasing the hydrogenation reduction reaction temperature can significantly reduce the reaction time, but the reaction purity is slightly reduced. Based on this, the preferred reaction temperature is 70°C.

[0152] Example 16-Example 17, Comparative Example 1-Comparative Example 2

[0153] Compound 1 was prepared by the same method as in Example 1, except that the solvent for the hydrogenation reduction reaction was changed. The GC purity and yield of the product of Compound 1 are shown in Table 3 below.

[0154] Table 3 Experimental data of changing the solvent for hydrogenation reduction reaction

[0155]

[0156] From the data in the above table, it can be seen that the hydrogenation purity and yield are different when changing different solvents, and proton-containing solvents are relatively better.

[0157] Comparative Example 3

[0158] The intermediate B1 was prepared by the same method as in Example 1, except that the reaction temperature of step 2 was increased. In this comparative example 3, the reaction temperature of step 2 was 60°C.

[0159] The GC purity of the intermediate B1 in this comparative example 3 is 86.7%, and the yield is 60.2%.

[0160] From the comparison of the data of Comparative Example 3 and Example 1, it can be seen that if the reaction temperature of step 2 is increased, the purity and yield of intermediate B1 are significantly reduced, which may be caused by the rapid decomposition of the generated ylide reagent due to the high temperature and the side reaction. The temperature conditions defined in the present invention are more conducive to obtaining high-yield and high-purity products.

[0161] Comparative Example 4

[0162] Compound 3 was prepared using the currently disclosed method WO2023049790A2. The specific preparation process is as follows:

[0163] ;

[0164] First, 4-methylpyridine and 1,3-dibromopropane were coupled under n-butyl lithium conditions to generate 1,5-dipyridylpentane with a single-step yield of 40.0%. Then, 1,5-dipyridylpentane was hydrogenated under palladium-carbon conditions to obtain a light yellow product with a single-step yield of 85% and an overall yield of 34.0%.

[0165] From the data comparison between Comparative Example 4 and Example 3, it can be seen that the yield of the product of Example 3 using the preparation method of the present invention is higher, while the yield of the product of the method of Comparative Example 4 is relatively low. This is because the reaction conditions for preparing the intermediate 1,5-dipyridylpentane in WO2023049790A2 are too harsh, and it needs to be carried out at -78°C, which is greatly affected by the external environment and has poor process repeatability. Compared with the present invention, the conditions are milder, the repeatability is higher, and the system state is better.

[0166] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0167] For those skilled in the art, several modifications and improvements may be made without departing from the concept of the present invention, all of which belong to the protection scope of the present invention. The protection scope of the present invention shall be based on the attached claims.

Claims

1. A method for preparing a symmetrical double-terminal piperidinyl alkane, characterized in that: The preparation method comprises: under the protection of an inert gas, a double-terminal halogenated alkane reacts with triphenylphosphine to prepare a phosphonium salt, namely an intermediate A; then the intermediate A reacts with a piperidone derivative under alkaline conditions to produce an intermediate B by Wittig reaction; and the intermediate B is subjected to hydrogenation reduction to obtain the symmetrical double-terminal piperidinyl alkane; When preparing intermediate B, firstly dissolve intermediate A and piperidone derivatives in a solvent, control the temperature in the system to be 0-50°C, dropwise add alkaline solution, and after the dropwise addition is completed, keep the temperature at 0-50°C for reaction for 4-12 hours; When preparing the symmetrical double-terminal piperidinyl alkane product, the solvent selected for the hydrogenation reduction reaction system is at least one of methanol, ethanol and isopropanol; The structural formula of the double-terminal halogenated alkane is: ; The structural formula of the intermediate A is: ; The structural formula of the piperidone derivative is: ; The structural formula of the intermediate B is: The structural formula of the symmetrical double-terminal piperidinyl alkane is: ; n is a natural number ranging from 1 to 10; X is Cl, Br or I; R is Boc or Bn.

2. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing intermediate A, the molar ratio of the double-terminal halogenated alkane to triphenylphosphine is 1:(2.0~3.0); When preparing intermediate B, the molar ratio of intermediate A to piperidone derivative is 1:(1.8-2.5), and the molar ratio of intermediate A to base is 1:(1.8-2.5); When preparing a symmetrical double-terminal piperidinyl alkane product, palladium carbon is used as a catalyst for a hydrogenation reduction reaction, and the mass ratio of the intermediate B to palladium carbon is 1: (0.02~0.05).

3. A method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing intermediate A, the temperature in the reaction system is 100~150°C; the insulation reaction time is 4~16h.

4. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing intermediate B, firstly dissolve intermediate A and piperidone derivatives in a solvent, control the temperature in the system to 0-30°C, dropwise add alkaline solution, and after the dropwise addition is completed, keep the temperature at 0-30°C for reaction.

5. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing the symmetrical double-terminal piperidinyl alkane product, the hydrogenation reduction reaction temperature is 60-100°C, and the hydrogenation reduction reaction time is 12-24h.

6. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing intermediate A, the solvent selected for the reaction system is at least one of toluene, xylene, DMSO, DMF or DMAc; When preparing intermediate B, the solvent selected in the system is at least one of toluene, dichloromethane, 2-methyltetrahydrofuran and tetrahydrofuran.

7. A method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: When preparing intermediate B, the base used is potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, butyl lithium or lithium hexamethyldisilazide.

8. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: The post-treatment operation for preparing the intermediate A is as follows: after the double-terminal halogenated alkane and triphenylphosphine are reacted, the system is cooled to 20-25° C. and then filtered, the wet product is eluted with THF, and dried under reduced pressure to obtain the intermediate A; The post-treatment operation for preparing the intermediate B is as follows: after the Wittig reaction is completed, hydrolysis and stratification are first performed, the aqueous phase is extracted and then the organic phase is combined, the organic phase is dehydrated, petroleum ether is added for pulping, and the solvent is dehydrated from the filtrate after pulping to obtain the intermediate B.

9. The method for preparing a symmetrical double-terminal piperidinyl alkane according to claim 1, characterized in that: The post-treatment process for preparing the double-terminal piperidinyl alkane product is as follows: filtering after the hydrogenation reduction reaction is completed, removing the solvent from the filtrate, then recrystallizing using a mixed solution of n-heptane and toluene, filtering, and drying under reduced pressure to obtain the double-terminal piperidinyl alkane product.

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