Preparation method of 4-[4-(aminomethyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a medical intermediate compound, in particular to a preparation method of 4-[4-(aminomethyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester. Comprising the following steps: S1, dissolving 4-fluorobenzaldehyde in a solvent, adding an acid-binding agent and an auxiliary material N-BOC piperazine, and heating and reacting under the protection of nitrogen to obtain 1-BOC-4-(4-formylphenyl) piperazine; s2, dissolving 1-BOC-4-(4-formylphenyl) piperazine in a solvent, adding potassium acetate and hydroxylamine hydrochloride as acid binding agents, and reacting to obtain 1-BOC-4-(4-oximido phenyl) piperazine; and S3, dissolving 1-BOC-4-(4-oximido phenyl) piperazine in a solvent, adding a reducing agent and a correspondingly matched inhibitor, and reacting to obtain the 4-[4-(aminomethyl) phenyl] piperazine-1-carboxylic acid tert-butyl ester. According to the invention, the process cost is saved, and the yield and purity of the intermediate and the target product are high.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and relates to a pharmaceutical intermediate compound, specifically a preparation method of tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate. Background Art

[0002] 4-[4-(Aminomethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester is an amino compound used in the synthesis of anthelmintics, and is also used in the production of surfactant products such as wetting agents, emulsifiers, dispersants, and the production of plastic processing aids and rubber additives such as antioxidants, preservatives, stabilizers, etc. The molecular formula is C 14 H 17 BO5, molecular weight is 276.09, the structural formula of tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate is shown in Formula A:

[0003]

[0004] In the prior art, in the route for synthesizing the above compounds, all the intermediates must be post-treated by column chromatography, which affects the yield of the compounds on the one hand and increases the synthesis cost on the other. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and obtain a method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate with mild reaction conditions, high yield and no need for column chromatography.

[0006] The preparation method of tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate of the present invention comprises the following steps:

[0007] S1, dissolving 4-fluorobenzaldehyde in a solvent, adding an acid binding agent and an auxiliary material N-BOC piperazine in sequence, heating and reacting under nitrogen protection for 10 hours, monitoring the completion of the reaction of 4-fluorobenzaldehyde by liquid phase, and treating to obtain 1-BOC-4-(4-formylphenyl)piperazine; the mass ratio of the 4-fluorobenzaldehyde to the solvent is 1:8-15; the molar ratio of the 4-fluorobenzaldehyde, the acid binding agent, and the N-BOC piperazine is 1:1.5-2.0:1.1-1.5;

[0008] S2, dissolving 1-BOC-4-(4-formylphenyl)piperazine in a solvent, adding acid binding agents potassium acetate and hydroxylamine hydrochloride, reacting at 25 degrees Celsius for 12 hours, and treating to obtain 1-BOC-4-(4-hydroxyphenyl)piperazine; the mass ratio of the 1-BOC-4-(4-formylphenyl)piperazine to the solvent is 1:8-12; the molar ratio of the 1-BOC-4-(4-formylphenyl)piperazine, potassium acetate, and hydroxylamine hydrochloride is: 1:2.0-3.0:1.5-2.5;

[0009] S3. Dissolve 1-BOC-4-(4-hydroxyphenyl)piperazine in a solvent, add a reducing agent and a corresponding inhibitor, react for 12 hours, and obtain tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate through suction filtration, rotary evaporation, and pulping processes; the mass ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to the solvent is 1:10-20, and the molar ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to the inhibitor is 1:1-3.

[0010] The synthetic route of the method is:

[0011]

[0012] Preferably, the solvent in S1 is at least one of dimethyl sulfoxide, N,N-dimethylformamide or nitrogen methyl pyrrolidone. Further, the solvent is at least one of dimethyl sulfoxide, nitrogen methyl pyrrolidone and DMAc; further, the solvent is at least one of nitrogen methyl pyrrolidone and DMAc; further, the solvent is DMAc.

[0013] Preferably, the acid binding agent in S1 is potassium carbonate or cesium carbonate. Further, the acid binding agent is potassium carbonate.

[0014] Preferably, the solvent in S2 is at least one of ethanol water, ethyl acetate water, and ethanol. Further, the solvent is ethyl acetate water. It has been verified that incompatible mixed solvents can reduce the generation of by-products.

[0015] Preferably, the solvent in S3 is at least one of ethyl acetate, 1,4-dioxane, ethanol, and acetic acid. Further, the solvent is at least one of ethyl acetate, 1,4-dioxane, and ethanol; further, the solvent is at least one of 1,4-dioxane and ethanol; further, the solvent is ethanol.

[0016] Preferably, the reducing agent in S3 is at least one of palladium carbon hydrogen, palladium hydroxide hydrogen, sodium borohydride, and Raney nickel hydrogen; further, the reducing agent is palladium carbon hydrogen or palladium hydroxide hydrogen, and the amount used is 0.1-0.3 times the mass of 1-BOC-4-(4-hydroxyphenyl)piperazine; further, the reducing agent is sodium borohydride, and the molar ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to sodium borohydride is 1:2; further, the reducing agent is palladium hydroxide hydrogen, and the amount used is 0.1 times the mass of 1-BOC-4-(4-hydroxyphenyl)piperazine.

[0017] Preferably, the temperature condition in S3 is 40-80° C. Further, the temperature condition is 70° C.

[0018] Preferably, the inhibitor in S3 is at least one of ammonia water, triethylamine, and N,N-diisopropylethylamine; further, it is at least one of ammonia water and N,N-diisopropylethylamine; further, it is N,N-diisopropylethylamine, and the amount of N,N-diisopropylethylamine is 1.1 times the molar amount of 1-BOC-4-(4-hydroxyphenyl)piperazine

[0019] The preparation method of 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester of the present invention is to obtain 1-BOC-4-(4-oxime phenyl)piperazine for subsequent reduction operation. The method of reducing cyano group to aminomethyl group adopted by the traditional process is: using Raney nickel as a reducing agent, adding ammonia water as a polymerization inhibitor hydrogenation method, by changing different solvent systems and increasing or decreasing ammonia water equivalent, etc., the generation of byproduct 1-BOC-4-(4-methylphenyl)piperazine and unknown impurities cannot be well controlled, and the content ratio is relatively large, and the crude product needs to be purified by steps to achieve the purpose of purification. Relative to the traditional process, the present invention effectively solves the problem of large byproduct content, and solves the dilemma of column chromatography.

[0020] The positive effects of the present invention are as follows: (1) the method of the present invention prepares tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate through nucleophilic substitution, condensation and reduction reactions, and no column chromatography is required in the entire preparation process and post-treatment process, thereby saving process costs; (2) the yield and purity of the intermediate and target product of the method are both high, and the method is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the 1H-NMR spectrum of tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate prepared by the method described in Example 1 of the present application. DETAILED DESCRIPTION

[0022] The abbreviations and Chinese meanings involved in the examples of the present application are: DMF: N,N-dimethylformamide; NMP: nitrogen methyl pyrrolidone; DMAc: N,N-dimethylacetamide; BOC: tert-butyloxycarbonyl; DIPEA: N,N-diisopropylethylamine.

[0023] Example 1

[0024] Step 1: In a three-liter four-necked flask, 1 mol of 4-fluorobenzaldehyde was dissolved in 1 liter of DMAC, and 1.1 mol of N-BOC piperazine and 1.5 mol of potassium carbonate were added in sequence. The mixture was refluxed for 24 hours under nitrogen protection, and the reaction of 4-fluorobenzaldehyde was completed by liquid phase monitoring.

[0025] Post-treatment: After cooling, the reaction solution was poured into 2L of water, separated, the organic layer was retained, and the aqueous layer was extracted twice with 1L of ethyl acetate. The organic phases were combined, washed once with 1L of water and once with 1L of saturated brine, dried, and spin-dried. The crude product was added to 0.5L of n-hexane and slurried for 1h, filtered, and the filter cake was rinsed twice with n-hexane and vacuum-dried to obtain 246g of off-white solid with a purity of 97% and a yield of 95%.

[0026] Step 2: In a two-liter four-necked flask, 29 g of 1-BOC-4-(4-formylphenyl)piperazine, 125 ml of ethyl acetate, and 125 ml of water were added in sequence. Potassium acetate (the amount used was 2 times the molar amount of 1-BOC-4-(4-formylphenyl)piperazine) and hydroxylamine hydrochloride (the amount used was 1.5 times the molar amount of 1-BOC-4-(4-formylphenyl)piperazine) were added. The mixture was stirred at room temperature for 12 hours. The reaction was completed by monitoring the liquid phase.

[0027] Post-treatment: directly separate the layers, wash the organic layer once with saturated brine, dry, and spin-dry to obtain 27.5 g of an off-white solid with a purity of 97% and a yield of 90%.

[0028] Step 3, in a 500mL single-mouth bottle, add 27.5g of 1-BOC-4-(4-hydroxyphenyl)piperazine in ethanol, 2.75g of palladium hydroxide, and DIPEA (1.1 times the molar amount of 1-BOC-4-(4-hydroxyphenyl)piperazine) in sequence, replace the atmosphere with nitrogen three times and then with hydrogen, react at 70 degrees for 12 hours, and monitor the reaction completion with liquid phase, with by-products of 9-10% and 1-BOC-4-(4-hydroxyphenyl)piperazine remaining at about 2-2.5%, and stop the reaction.

[0029] Post-treatment: The reaction liquid was cooled, filtered, the filter cake was recovered and discarded, the organic phase was evaporated to dryness, 3 times the volume of n-hexane was added for washing, filtered, and the filter cake was recrystallized twice with 1.5 times the volume of isopropanol to obtain 15.7g of pure product, off-white solid, purity 98%, yield 60%. The NMR spectrum is shown as Figure 1 As shown, the analysis results are as follows:

[0030] 1 H-NMR spectrum (400MHz, CDCl3)δ:7.22(2H,d,J=7.5Hz),6.89(2H,d,J=7.5Hz),3.79(2H,s),3.6-3.55(4H,m),3.15-3.08(4H,m),2.35(2H,s),1.47(9H,s)

[0031] Example 2

[0032] The difference between this embodiment and embodiment 1 is that: NMP is selected as the solvent in the first step, and the reaction time is 10 hours; palladium carbon combined with ammonia water is selected as the palladium catalyst.

[0033] In this example, the purity of 1-BOC-4-(4-formylphenyl)piperazine is 95%, and the yield is 88%.

[0034] In this example, the purity of 1-BOC-4-(4-hydroxyphenyl)piperazine is 95%, and the yield is 85%.

[0035] The purity of the target product 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester in this embodiment is 95%, and the yield is 40%. 1 The H-NMR spectrum was consistent with that of Example 1.

[0036] Example 3

[0037] The difference between this embodiment and embodiment 1 is that DMF is selected as the solvent in the first step, and sodium borohydride, calcium chloride and ethanol are used for reduction in the last step.

[0038] In this example, the purity of 1-BOC-4-(4-formylphenyl)piperazine is 90%, the yield is 55%, and a lot of by-products are produced, which are mainly caused by the decomposition of DMF.

[0039] In this example, the purity of 1-BOC-4-(4-hydroxyphenyl)piperazine is 95%, and the yield is 85%.

[0040] The purity of the target product 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester in this embodiment is 90%, and the yield is 20%. 1 The H-NMR spectrum was consistent with that of Example 1.

Claims

1. A method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate, Its characteristics are: Includes the following step, S1, dissolving 4-fluorobenzaldehyde in a solvent, adding an acid binding agent and an auxiliary material N-BOC piperazine in sequence, heating and reacting under nitrogen protection for 10 hours, monitoring the completion of the reaction of 4-fluorobenzaldehyde by liquid phase, and treating to obtain 1-BOC-4-(4-formylphenyl)piperazine; the mass ratio of the 4-fluorobenzaldehyde to the solvent is 1:8-15; the molar ratio of the 4-fluorobenzaldehyde, the acid binding agent, and the N-BOC piperazine is 1:1.5-2.0:1.1-1.5; S2, dissolving 1-BOC-4-(4-formylphenyl)piperazine in a solvent, adding acid binding agents potassium acetate and hydroxylamine hydrochloride, reacting at 25 degrees Celsius for 12 hours, and treating to obtain 1-BOC-4-(4-hydroxyphenyl)piperazine; the mass ratio of the 1-BOC-4-(4-formylphenyl)piperazine to the solvent is 1:8-12; the molar ratio of the 1-BOC-4-(4-formylphenyl)piperazine, potassium acetate, and hydroxylamine hydrochloride is: 1:2.0-3.0:1.5-2.5; S3. Dissolve 1-BOC-4-(4-hydroxyphenyl)piperazine in a solvent, add a reducing agent and a corresponding inhibitor, react at 40-80°C for 12 hours, and obtain tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate through suction filtration, rotary evaporation, and pulping processes; the mass ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to the solvent is 1:10-20, and the molar ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to the inhibitor is 1:1-3.

2. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its characteristics are: The solvent in S1 is at least one of dimethyl sulfoxide, N,N-dimethylformamide or nitrogen methyl pyrrolidone.

3. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its characteristics are: The acid binding agents in S1 are potassium carbonate and cesium carbonate.

4. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its characteristics are: The solvent in S2 is at least one of ethanol water, ethyl acetate water, and ethanol.

5. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its characteristics are: The solvent in S3 is at least one of ethyl acetate, 1,4-dioxane, ethanol and acetic acid.

6. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its features are: S3 The reducing agent is at least one of palladium carbon hydrogen gas, palladium hydroxide hydrogen gas, sodium borohydride, and Raney nickel hydrogen gas.

7. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 6, Its characteristics are: The reducing agent is palladium carbon hydrogen gas or palladium hydroxide hydrogen gas, and the amount used is 0.1-0.3 times the mass of 1-BOC-4-(4-oxime phenyl) piperazine.

8. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 6, Its characteristics are: The reducing agent is sodium borohydride, and the molar ratio of 1-BOC-4-(4-hydroxyphenyl)piperazine to sodium borohydride is 1:

2.

9. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 6, Its characteristics are: Furthermore, the reducing agent is palladium hydroxide hydrogen gas, and the amount used is 0.1 times the mass of 1-BOC-4-(4-hydroxyphenyl)piperazine.

10. The method for preparing tert-butyl 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylate according to claim 1, Its characteristics are: The inhibitor in S3 is at least one of ammonia water, triethylamine and N,N-diisopropylethylamine.

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