A preparation method of 2-(1-piperazinyl)pyrimidine

Abstract

The present invention relates to a preparation method of 2-(1-piperazinyl)pyrimidine in the field of biopharmaceutical synthesis, which uses 2-hydrazinopyrimidine and 1-chloropiperazine as raw materials, DMSO as solvent, copper chloride as metal catalyst, m-chloroperbenzoic acid ( m The present invention uses a novel method for preparing 2-(1-piperazinyl)pyrimidine by using a free radical coupling reaction with 2-(1-piperazinyl)pyrimidine (CPBA) as an oxidant. The method provides a simple, mild, and high-yield route.

Description

Technical Field

[0001] The present invention belongs to the field of biopharmaceutical synthesis, and specifically relates to a new method for synthesizing 2-(1-piperazinyl)pyrimidine. Background Art

[0002] Piribedil, chemically known as 2-(4-piperazinyl-1-pyrimidine), is a non-ergot dopamine receptor agonist clinically used to treat Parkinson's disease. 2-(1-piperazinyl)pyrimidine is a key intermediate used in the synthesis of piribedil. Currently, the following methods have been reported in the literature for the synthesis of 2-(1-piperazinyl)pyrimidine:

[0003] (1) Matthew AJ Duncton et al. used 2-chloropyrimidine as the starting material and reacted it with 1-tert-butyloxycarbonylpiperazine in a nucleophilic substitution reaction to obtain an N-alkylated intermediate. The Boc group was then removed using an ion exchange resin in an adsorption-dissociation manner to obtain 1-(2-pyrimidinyl)piperazine. This reaction procedure is cumbersome and not suitable for large-scale production.

[0004]

[0005] (2) Patent PL167397 (1995) used unmodified piperazine to carry out N-alkylation reaction with 2-chloropyrimidine. The reaction had poor selectivity and the risk of disubstitution.

[0006]

[0007] (3) Patent CN 102786497, 2-aminopyrimidine undergoes a cyclization reaction with bis(2-chloroethyl)amine hydrochloride to obtain 1-(2-pyrimidinyl)piperazine.

[0008]

[0009] Chlorination with thionyl chloride will cause certain corrosiveness to the reaction equipment. Summary of the Invention

[0010] In order to overcome the shortcomings of the above methods, such as harsh reaction conditions and complicated synthesis steps, the present invention provides a method for preparing 2-(1-piperazinyl)pyrimidine, which has short reaction steps, mild reaction conditions, low synthesis cost and high yield.

[0011] The technical solution adopted by the present invention is as follows: a method for preparing 2-(1-piperazinyl)pyrimidine, which uses 2-hydrazinopyrimidine and 1-chloropiperazine as raw materials, dimethyl sulfoxide as solvent, copper chloride as metal catalyst, and m-chloroperbenzoic acid (m-CPBA) as oxidant to prepare 2-(1-piperazinyl)pyrimidine through a free radical coupling reaction; the reaction formula is as follows:

[0012]

[0013] Furthermore, the molar amount of the copper chloride is 0.05-0.2 times, preferably 0.1 times, the molar amount of 2-hydrazinopyrimidine.

[0014] Furthermore, the reaction temperature is 80-100°C, preferably 90°C.

[0015] Furthermore, the molar amount of the oxidizing agent m-chloroperbenzoic acid is 1.5-2.5 times the molar amount of 2-hydrazinopyrimidine, preferably 2 times.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] (1) The present invention provides a new route for the synthesis of 2-(1-piperazinyl)pyrimidine, which uses 2-hydrazinopyrimidine and 1-chloropiperazine as raw materials to prepare 2-(1-piperazinyl)pyrimidine through a free radical coupling reaction; the yield is high, reaching more than 45%.

[0018] (2) The preparation route of the present invention is simple, the catalyst is cheap metal copper chloride, and the oxidant is m-chloroperbenzoic acid, which has the advantage of being cheap and easily available.

[0019] (3) The route provided by the present invention has mild reaction conditions, simple operation, and good promotion and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the H NMR spectrum of the target compound;

[0021] Figure 2 is the NMR carbon spectrum of the target compound; DETAILED DESCRIPTION

[0022] Analytical instruments and equipment used in the examples: nuclear magnetic resonance spectrometer (AVANCE DMXⅡⅠ400M, Bruker); triple-purpose ultraviolet analyzer (ZF-6).

[0023] Example 1: Preparation of 2-(1-piperazinyl)pyrimidine

[0024] In a 50 ml round-bottom flask, 2-hydrazinopyrimidine (1.1 g, 10 mmol), 25 mL DMSO, 1-chloropiperazine (1.44 g, 12 mmol), copper chloride (0.134 g, 1.0 mmol) and m-chloroperbenzoic acid were added in sequence.

[0025] (m-CPBA, 3.44 g, 20 mmol), heated at 90°C for 12 h (TLC to track the reaction progress);

[0026] The reaction formula is:

[0027]

[0028] After the reaction, the reaction system was concentrated using a rotary evaporator, and the concentrate was extracted with purified water (100 ml) and ethyl acetate (20 ml * 3). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product; 0.76 g of the pure product was obtained by column chromatography, with a yield of 46.5%.

[0029] 1 H NMR (400MHz, CDCl3) δ8.25 (d, J = 4.7Hz, 2H), 6.42 (t, J = 4.7Hz, 1H), 3.76–3.71 (m, 4H), 2.90–2.85 (m, 4H), 1.99 (s, 1H).

[0030] 13 C NMR (100MHz, CDCl3) δ161.80,157.72,109.79,46.03,44.91.

[0031] Example 2: Screening of metal catalysts

[0032] The experimental conditions and feed amounts of this embodiment are the same as those of Example 1. Different metal catalysts are selected for the experiment, as shown in Table 1:

[0033] Table 1

[0034]

[0035] As shown in Table 1, when ferric chloride, ferrous chloride, and cobalt chloride were used as metal catalysts, the reaction yields were 41.5%, 36.5%, 29.2%, and 29.2%, respectively. When cupric chloride and cuprous chloride were used as metal catalysts, the reaction yields were 46.5% and 40%, respectively. In summary, the present invention uses cupric chloride as the reaction metal catalyst.

[0036] Example 3: Screening of cupric chloride dosage

[0037] The experimental conditions and feeding amount of this embodiment are the same as those of Example 1. Different doses of copper chloride are selected for the experiment, as shown in Table 2:

[0038] Table 2

[0039]

[0040]

[0041] As shown in Table 2, when the amount of copper chloride is 0.3 mmol, the reaction yield is only 24.1%; when the amount is 1.0 mmol, the reaction yield is 46.5%. However, further increasing the amount of copper chloride does not significantly improve the reaction yield. In summary, the amount of copper chloride used in the present invention can be selected from 0.5 mmol to 2.0 mmol, preferably 1 mmol.

[0042] Example 4: Screening of oxidants

[0043] The experimental conditions and feeding amount of this embodiment are the same as those of embodiment 1. Different reaction oxidants are selected for the experiment, as shown in Table 3:

[0044] Table 3

[0045] Metal catalysts oxidants solvent Temperature (℃) Yield (%) 1 <![CDATA[CuCl2(10mol%)]]> m-CPBA DMSO 90 46.5 2 <![CDATA[CuCl2(10mol%)]]> TBHP DMSO 90 36.5 3 <![CDATA[CuCl2(10mol%)]]> <![CDATA[H2O2]]> DMSO 90 Trace 4 <![CDATA[CuCl2(10mol%)]]> <![CDATA[K2S2O8]]> DMSO 90 25.6 5 <![CDATA[CuCl2(10mol%)]]> <![CDATA[Na2S2O8]]> DMSO 90 27.0

[0046] As can be seen from Table 3, when tert-butyl peroxide (TBHP), hydrogen peroxide (H2O2), potassium persulfate (K2S2O8), and sodium persulfate (Na2S2O8) are selected as oxidants, the reaction yields are 36.5%, 0%, 25.6%, and 27.0%, respectively; when meta-chloroperbenzoic acid (m-CPBA) is selected as the oxidant, the reaction yield is the highest, which is 46.5%; in summary, the present invention selects meta-chloroperbenzoic acid (m-CPBA) as the oxidant.

[0047] Furthermore, the amount of the oxidant m-chloroperbenzoic acid (m-CPBA) was screened, as shown in Table 4:

[0048] Table 4

[0049]

[0050]

[0051] As shown in Table 4, the dosage of the oxidant m-CPBA can be selected from 15-25 mmol, preferably 20 mmol. Continuing to increase the dosage of the oxidant does not significantly improve the reaction yield.

[0052] Example 5: Screening of reaction solvents

[0053] The experimental conditions and feeding amount of this embodiment are the same as those of Example 1. Different reaction solvents are selected for the experiment, as shown in Table 5:

[0054] Table 5

[0055] Metal catalysts oxidants solvent Temperature (℃) Yield (%) 1 <![CDATA[CuCl2(10mol%)]]> m-CPBA EtOH 90 13.0 2 <![CDATA[CuCl2(10mol%)]]> m-CPBA <![CDATA[CH3CN]]> 90 16.5 3 <![CDATA[CuCl2(10mol%)]]> m-CPBA DCM 90 15.0 4 <![CDATA[CuCl2(10mol%)]]> m-CPBA THF 90 31.0 5 <![CDATA[CuCl2(10mol%)]]> m-CPBA DMSO 90 46.5 6 <![CDATA[CuCl2(10mol%)]]> m-CPBA <![CDATA[H2O]]> 90 trace

[0056] As can be seen from Table 5, when the reaction solvent is pure water, the reaction yield is the lowest; when the reaction solvent is ethanol, acetonitrile, dichloromethane, and tetrahydrofuran, the reaction yields are 13.0%, 16.5%, 15.0%, and 31.0%, respectively; when DMSO is selected as the solvent, the reaction yield is the highest, which is 46.5%. In summary, the present invention selects DMSO as the solvent.

[0057] Example 6: Screening of reaction temperature

[0058] The experimental conditions and feed amount of this embodiment are the same as those of Example 1. Different reaction temperatures are selected for the experiments. The specific conditions are shown in Table 6.

[0059] Table 6

[0060]

[0061]

[0062] As shown in Table 6, when the reaction temperature is 65°C, the reaction yield is extremely low; when the reaction temperature is 80°C, the reaction yield is 39.4%; when the reaction temperature is 90°C, the reaction yield is the highest, at 46.5%. However, further increasing the reaction temperature does not significantly improve the reaction yield. In summary, the reaction temperature of the present invention can be selected from 80-100°C, preferably 90°C.

[0063] It should be noted that the above-mentioned specific embodiments are intended to demonstrate the practical application of the technical solutions provided by the present invention and should not be construed as limiting the scope of protection of the present invention. A person skilled in the art of the present invention may make several simple deductions or substitutions without departing from the concept of the present invention, and all of these should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing 2-(1-piperazinyl)pyrimidine, characterized in that: 2-Hydrazinopyrimidine and 1-chloropiperazine are used as raw materials, dimethyl sulfoxide is used as solvent, copper chloride is used as metal catalyst, and m-chloroperbenzoic acid ( m -CPBA) as an oxidant, and 2-(1-piperazinyl)pyrimidine was prepared through a free radical coupling reaction; The reaction formula is as follows: ； The molar amount of the copper chloride is 0.05-0.2 times the molar amount of 2-hydrazinopyrimidine; and the reaction temperature is 80-100°C.

2. The method for preparing 2-(1-piperazinyl)pyrimidine according to claim 1, wherein: The molar amount of the copper chloride is 0.1 times the molar amount of 2-hydrazinopyrimidine.

3. The method for preparing 2-(1-piperazinyl)pyrimidine according to claim 1, wherein: The reaction temperature was 90°C.

4. The method for preparing 2-(1-piperazinyl)pyrimidine according to claim 1, wherein: The molar amount of m-chloroperbenzoic acid is 1.5-2.5 times the molar amount of 2-hydrazinopyrimidine.

5. The method for preparing 2-(1-piperazinyl)pyrimidine according to claim 4, wherein: The molar amount of m-chloroperbenzoic acid is twice the molar amount of 2-hydrazinopyrimidine.

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