A process for the synthesis of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

Abstract

The application discloses a synthesis method of 1-[2-(2-hydroxyethoxy)ethyl]piperazine. The synthesis method comprises the following steps: taking easily-obtained piperazine and diethylene glycol as reaction raw materials, taking water as a solvent, and synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine in the presence of an iridium catalyst and a specific ligand. The synthesis method has the characteristics of high selectivity, high environmental protection and simple post-treatment operation, and can obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine with high yield and high purity.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a synthesis method of 1-[2-(2-hydroxyethoxy)ethyl]piperazine. BACKGROUND

[0002] 1-[2-(2-hydroxyethoxy)ethyl]piperazine is an important organic intermediate for the synthesis of antipsychotic drug quetiapine fumarate, and is widely used in chemical pharmaceutical, high polymer material, dye and fine chemical industry. Its structural formula is as follows:

[0003]

[0004] At present, the synthesis methods of 1-[2-(2-hydroxyethoxy)ethyl]piperazine reported in the literature are as follows: (1) under alkaline conditions, piperazine is condensed with 2-(2-chloroethoxy) ethanol to prepare. But the reaction will produce a large amount of disubstituted by-products, resulting in low yield of target product. The reaction route is as follows:

[0005]

[0006] (2) taking piperazine as the starting material, first synthesizing 1-Boc-piperazine with Boc anhydride, then condensing with 2-(2-chloroethoxy) ethanol to obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine. The reaction route is as follows:

[0007]

[0008] This route protects one side of piperazine first, effectively solving the problem of disubstituted by-products, but the reaction route is relatively long, and in the hydrolysis decarboxylation process, other impurities will be introduced, which limits the industrial production.

[0009] In Chinese patent CN103224476A, diethanolamine is used as the starting material, and 1-[2-(2-hydroxyethoxy)ethyl]piperazine is prepared by halogen displacement, acylation, and cyclization of diethanolamine. The reaction route is as follows:

[0010]

[0011] This process has many reaction steps and low atom utilization rate.

[0012] In Chinese patent CN103254153A, piperazine and piperazine dihydrochloride are used to prepare piperazine monohydrochloride in a solvent, and piperazine monohydrochloride is reacted with 2-(2-chloroethoxy) ethanol to obtain high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine by evaporating the solvent and vacuum reducing pressure distillation. The reaction route is as follows:

[0013]

[0014] The process reaction is over, and piperazine dihydrochloride is recovered by filtration, and after drying, it can be reused, thereby reducing the cost. The reaction yield is about 75%, which needs to be further improved.

[0015] In Chinese patent CN107663183A, 1-Boc-piperazine is used as a starting material to undergo condensation reaction with 2-chloroethoxyethanol, hydrolysis decarboxylation, and post-treatment by adjusting the pH value with inorganic base to obtain the target product 1-[2-(2-hydroxyethoxy) ethyl] piperazine. The reaction route is as follows:

[0016]

[0017] The starting material 1-Boc-piperazine of the process is not easy to obtain, and the cost of raw materials is high. SUMMARY

[0018] The present application is to overcome the problems existing in the prior art, and to simply and efficiently synthesize 1-[2-(2-hydroxyethoxy) ethyl] piperazine. A synthesis method of 1-[2-(2-hydroxyethoxy) ethyl] piperazine is provided, which is simple in reaction system, environmentally friendly, simple in post-treatment operation, and suitable for industrial production of 1-[2-(2-hydroxyethoxy) ethyl] piperazine, thereby improving the purity and yield of 1-[2-(2-hydroxyethoxy) ethyl] piperazine.

[0019] In order to achieve the above-mentioned purpose, the following technical solutions are adopted in the present application:

[0020] The present application provides a synthesis method of 1-[2-(2-hydroxyethoxy) ethyl] piperazine, which comprises: taking piperazine and diethylene glycol as raw materials, water as a reaction solvent, and carrying out nitrogen alkylation reaction under the action of an iridium catalyst and a ligand in a sealed pressure-resistant container, a protective atmosphere (oxygen-free atmosphere, in the embodiments of the present application, nitrogen atmosphere), at 120-150 DEG C (preferably 150 DEG C) for 1-15 h (preferably 10 h), and then carrying out post-treatment on the obtained reaction liquid to obtain the 1-[2-(2-hydroxyethoxy) ethyl] piperazine; the molar ratio of the piperazine, diethylene glycol, iridium catalyst and ligand is 2-4.5: 1: 0.01-0.04: 0.01-0.04 (preferably 4: 1: 0.01-0.04: 0.01-0.04, and particularly preferably 4: 1: 0.03: 0.03); and the reaction route is as follows:

[0021]

[0022] The catalyst is one of [IrCl(cod)]2, Cp*Ir(NH3)3(Cl)2, [Cp*IrCl2]2 or a mixture of two or more thereof (preferably [Cp*IrCl2]2);

[0023] The ligand is one of the compounds shown in formula L or a mixture of two or more thereof:

[0024]

[0025] wherein R1, R2 are the same and are C1-10 alkyl; or R1 is H and R2 is phenyl substituted with C1-4 alkyl; preferably R1, R2 are the same and are C1-10 alkyl.

[0026] The ligand shown in formula L is prepared by replacing didecylamine in Example 1 with the corresponding dialkylamine or substituted aniline.

[0027] The present application explores Py2NPPh2 and a series of structurally similar imidazole ligands, and it is found that the ligand in which the N of imidazole is substituted with a fatty acid ester (such as L3) has no promoting effect on the reaction or may even have an adverse effect, while the ligand in which the N of imidazole is substituted with an amide generally has a promoting effect. The following ligands are used as examples in the examples of the present application:

[0028]

[0029] Further, the ligand is preferably one of the compounds shown in formula L1, L2, L4 or a mixture of two or more thereof, and is particularly preferably the compound shown in formula L4.

[0030] Further, the volume of water is 0.5-3 mL / mmol (1 mL / mmol in the examples of the present application) based on the amount of substance of diethylene glycol.

[0031] Further, the post-treatment is as follows: dichloromethane is added to the reaction solution for extraction, the obtained organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and a mixture solution of ethyl acetate, methanol and triethylamine in a volume ratio of 60:40:1 is used as an eluent for silica gel column chromatography, the eluent containing the target compound is collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine.

[0032] The present application particularly recommends that the synthesis method is as follows: piperazine and diethylene glycol are used as raw materials, water is used as a reaction solvent, and nitrogen alkylation is carried out under the action of an iridium catalyst and a ligand in a sealed pressure-resistant container in a nitrogen atmosphere at 150℃ for 10 h, and the obtained reaction solution is subjected to post-treatment to obtain the 1-[2-(2-hydroxyethoxy)ethyl]piperazine; the molar ratio of the piperazine, diethylene glycol, iridium catalyst and ligand is 4:1:0.03:0.03; the catalyst is [Cp*IrCl2]2, and the ligand is the compound shown in formula L4.

[0033] Further, the post-treatment is: the reaction solution is added into dichloromethane for extraction, the obtained organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography on silica gel is carried out with a mixed solution of ethyl acetate, methanol and triethylamine in a volume ratio of 60:40:1 as an eluent, the eluent containing the target compound is collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine.

[0034] Compared with the prior art, the present application has the beneficial effects that: the present application uses easily available piperazine and diethylene glycol as reaction raw materials, water as a solvent, and synthesizes 1-[2-(2-hydroxyethoxy)ethyl]piperazine in the presence of an iridium catalyst and a specific ligand. The prior art mediates the reaction of amine and alcohol through an iridium catalyst and a basic substance, but this reaction system cannot achieve higher yield in the selective mono-n-alkylation reaction of piperazine. The synthesis method of the present application not only has the characteristics of strong selectivity, strong environmental protection and simple post-treatment operation, but also can obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine with high yield and high purity. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the ligand L4.

[0036] Figure 2 The nuclear magnetic resonance carbon spectrum of the ligand L4.

[0037] Figure 3 The nuclear magnetic resonance hydrogen spectrum of 1-[2-(2-hydroxyethoxy)ethyl]piperazine.

[0038] Figure 4 The nuclear magnetic resonance carbon spectrum of 1-[2-(2-hydroxyethoxy)ethyl]piperazine.

[0039] Figure 5 The nuclear magnetic resonance hydrogen spectrum of the ligand L1.

[0040] Figure 6 The nuclear magnetic resonance carbon spectrum of the ligand L1.

[0041] Figure 7 The nuclear magnetic resonance hydrogen spectrum of the ligand L2.

[0042] Figure 8 The nuclear magnetic resonance carbon spectrum of the ligand L2.

[0043] Figure 9 The nuclear magnetic resonance hydrogen spectrum of the ligand L3.

[0044] Figure 10 The nuclear magnetic resonance carbon spectrum of the ligand L3. DETAILED DESCRIPTION

[0045] The technical solutions of the present application will be further described in detail below with specific examples and in conjunction with the drawings, but the present application is not limited thereto.

[0046] Example 1:

[0047] Preparation of 2-chloro-N,N didecylacetamide

[0048] Into a three-necked flask, ethanol 15 mL and didecylamine (0.956 g, 5 mmol) were added, and a mixed solution of chloroacetyl chloride (0.56 g, 5 mmol) and 10 mL of ethanol was slowly dropped by a constant pressure dropping funnel under ice bath condition, stirred for 2 h, filtered, the filter cake was washed with ethanol, the filtrate was collected, 30 mL of water was added, and DCM (30 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA: PE: TEA volume ratio = 8:92:1) was used for separation to obtain an eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain the product (2-chloro-N,N didecylacetamide) 0.579 g, with a yield of 44% and an HPLC purity of 99%.

[0049] Preparation of ligand L4

[0050] Into a three-necked flask, imidazole (68 mg, 1 mmol), 2-chloro-N,N didecylacetamide (0.522 g, 2 mmol), sodium bicarbonate (84 mg, 1 mmol) and 25 mL of EA were added, and the reaction was carried out at 60°C for 24 h. After the reaction was completed, filtration was performed, and the filtrate was concentrated. Column chromatography (DCM: MeOH: TEA volume ratio = 90:10:1) was used for separation to obtain an eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain a white viscous liquid 0.272 g, with a yield of 35% and an HPLC purity of 99%.

[0051] The compound obtained in Example 1 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum is shown in FIG. 1, Figure 1 1 H NMR (500 MHz, DMSO) δ 7.52 (s, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 4.94 (s, 4H), 3.33-3.09 (m, 8H), 1.55 (s, 4H), 1.47 (m, 4H), 1.26 (m, 56H), 0.89-0.77 (m, 12H). The carbon spectrum is shown in FIG. 2, Figure 2 13 ​​C NMR (126 MHz, DMSO) d 166.08 (2C), 138.17, 127.47, 120.59, 47.00 (4C), 46.57 (2C), 45.58 (4C), 31.30 (4C), 28.98 (4C), 28.77 (4C), 28.71 (4C), 28.36 (2C), 27.16 (2C), 26.38 (2C), 26.23 (2C), 22.08 (4C), 13.77 (4C).

[0052] Example 2:

[0053] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0054] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water, after nitrogen replacement, heated to 150 °C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used to separate the eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.321 g of a colorless liquid, with a yield of 83.1% and an HPLC purity of 98.8%.

[0055] The compound obtained in Example 2 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum is shown in FIG. 1, and its carbon spectrum is shown in FIG. 2. Figure 3 1 H NMR (500 MHz, CDCl3) d 7.28 (s, 1H), 3.50-3.45 (m, 2H), 3.42 (t, J = 5.1 Hz, 2H), 3.38-3.33 (m, 2H), 3.18 (s, 1H), 2.70 (t, J = 4.3 Hz, 4H), 2.41-2.21 (m, 6H). The carbon spectrum is shown in FIG. 2. Figure 4 13 C NMR (126 MHz, CDCl3) d 67.45, 61.21, 58.29, 54.14 (2C), 46.32, 45.30 (2C).

[0056] Comparative Example 1: Cat. 3 + no ligand

[0057] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0058] ​​To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used for separation to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain a colorless liquid 0.213 g, with a yield of 55.6% and an HPLC purity of 98.9%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0059] Comparative Example 2: Cat. 1 + no ligand

[0060] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0061] To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used for separation to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain a colorless liquid 0.213 g, with a yield of 55.6% and an HPLC purity of 98.9%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0062] Comparative Example 3: Cat. 2 + no ligand

[0063] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0064] To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used for separation to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain a colorless liquid 0.213 g, with a yield of 55.6% and an HPLC purity of 98.9%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0065] Comparative Example 4: Cat. 3 + comparative ligand

[0066] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0067] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), Py2NPPh2(0.0931 g, 0.12 mmol) and 4 mL of water, and after nitrogen replacement, heated to 150°C for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.219 g of a colorless liquid, with a yield of 56.8% and an HPLC purity of 98%. (Boiling point: 112-114°C, density: 1.037±0.06 g / cm3)

[0068] Example 3:

[0069] Synthesis of 2-chloro-N,N-diethylacetamide

[0070] Into a three-necked flask were added 45 mL of ethanol and diethylamine (7.1 g, 0.1 mol), and a mixed solution of chloroacetyl chloride (5.6 g, 0.05 mol) and 15 mL of ethanol was slowly added dropwise through a constant-pressure dropping funnel under ice-bath conditions. After stirring for 2 h, the mixture was filtered, the filter cake was washed with ethanol, and the filtrate was collected. Then, 30 mL of water was added, and DCM (30 mL x 3) was added for extraction. The combined organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:PE:TEA = 8:92:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 10.579 g of the product as a yellowish liquid, with a yield of 71% and an HPLC purity of 99%.

[0071] Synthesis of ligand L1

[0072] Into a three-necked flask were added imidazole (0.544 g, 8 mmol), 2-chloro-N,N-diethylacetamide (2.35 g, 16 mmol), sodium bicarbonate (0.672 g, 8 mmol) and 25 mL of EA, and the mixture was reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was separated by column chromatography (DCM:MeOH:TEA = 90:10:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 1.16 g of the product as a white viscous liquid, with a yield of 44% and an HPLC purity of 99%.

[0073] The compound obtained in Example 3 was analyzed by nuclear magnetic resonance, and the hydrogen spectrum thereof is shown in FIG. 1.Figure 5 as shown, 1 H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 7.74 (d, J = 1.5 Hz, 2H), 5.49 (s, 4H), 3.37 (q, J = 7.1 Hz, 4H), 3.31 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H), 1.04 (t, J = 4.2 Hz, 6H). Carbon spectrum as attached Figure 6 as shown, 13 C NMR (126 MHz, DMSO) δ 164.01 (2C), 138.74, 123.25 (2C), 49.90 (2C), 40.71 (2C), 40.09 (2C), 13.82 (2C), 12.83 (2C).

[0074] Example 4

[0075] Synthesis of 2-chloro-N-(2,6-dimethylphenyl)acetamide

[0076] Into a three-necked flask, 45 mL of ethanol and 2,6-dimethylaniline (19.8 g, 0.1 mol) were put and stirred uniformly in an ice water bath, chloroacetyl chloride (5.6 g, 0.05 mol) and 15 mL of ethanol were taken in a constant pressure dropping funnel and slowly dropped. After stirring for 2 h, the filter cake was washed with ethanol, the filtrate was collected, 30 mL of water was added, and DCM (30 mL x 3) was extracted. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was separated (EA: PE: TEA volume ratio = 8:92:1) to obtain the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain the product 5.89 g, with a yield of 59.6%, and an HPLC purity of 99%.

[0077] Synthesis of ligand L2

[0078] Into a three-necked flask, 2-chloro-N-(2,6-dimethylphenyl)acetamide (3.16 g, 16 mmol) and imidazole (0.544 g, 8 mmol), sodium bicarbonate (0.672 g, 8 mmol), and 25 mL of EA were put, and reacted at 60°C for 24 h. Column chromatography was separated (DCM: MeOH: TEA volume ratio = 90:10:1) to obtain the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain the product L2, a total of 1.01 g, with a yield of 44%, an HPLC purity of 99%, and as a white viscous liquid.

[0079] The compound obtained in Example 4 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum is as attached Figure 7 as shown, 1H NMR (500 MHz, DMSO) δ 9.88 (s, 2H), 9.26 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.15 - 7.00 (m, 6H), 5.07 (s, 2H), 4.17 (s, 2H), 2.19 (s, 12H). Carbon spectrum as attached Figure 8 as shown, 13 C NMR (126 MHz, DMSO) δ 169.23, 163.61, 138.64, 135.22 (4C), 134.30 (2C), 127.80 (4C), 126.82 (2C), 123.48 (2C), 50.83, 44.28, 18.24 (4C).

[0080] Example 5

[0081] Synthesis of Ligand L3

[0082] Into a three-necked flask was charged with ethyl chloroacetate (1.96 g, 16 mmol), imidazole (0.544 g, 8 mmol), sodium bicarbonate (0.672 g, 8 mmol) and 25 mL EA, reacted at 60 °C for 24 h. After the reaction was completed, it was filtered, the filtrate was concentrated, and column chromatography (DCM:MeOH:TEA = 80:20:5 by volume) was used to separate the eluent containing the target compound, and the solvent was removed under reduced pressure to obtain 0.908 g of ligand L3, with a yield of 41%, HPLC purity of 98.9%, as a white viscous liquid.

[0083] The compound obtained in Example 5 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum is as attached Figure 9 as shown, 1 H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 7.90 (s, 2H), 5.43 (s, 4H), 4.28 - 3.97 (m, 4H), 1.15 (t, J = 7.1 Hz, 6H). Carbon spectrum as attached Figure 10 as shown, 13 C NMR (126 MHz, DMSO) δ 167.08 (2C), 138.69, 123.78 (2C), 62.47 (2C), 50.31 (2C), 14.38 (2C).

[0084] Example 6: Cat. 3 + L1

[0085] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0086] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L1 ligand (0.0396 g, 0.12 mmol) and 4 mL of water. After nitrogen replacement, it was heated to 150 °C and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.246 g of a colorless liquid, with a yield of 63.7% and an HPLC purity of 98.4%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0087] Example 7: Cat. 3 + L2

[0088] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0089] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L2 ligand (0.0512 g, 0.12 mmol) and 4 mL of water. After nitrogen replacement, it was heated to 150 °C and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction. The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.246 g of a colorless liquid, with a yield of 63.7% and an HPLC purity of 98.4%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0090] Comparative Example 5: Cat. 1 + L3

[0091] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0092] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L3 ligand (0.0332 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.172 g of a colorless liquid, with a yield of 44.3% and an HPLC purity of 98.4%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0093] Example 8: Cat. 1 + L4

[0094] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0095] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [IrCl(cod)]2(0.081 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.219 g of a colorless liquid, with a yield of 56.6% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0096] Example 9: Cat. 2 + L4

[0097] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0098] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), Cp*Ir(NH3)3(Cl)2(0.054 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150°C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.235 g of a colorless liquid, with a yield of 60.9% and an HPLC purity of 98.9%. (Boiling point: 112-114°C, density: 1.037±0.06 g / cm3)

[0099] Example 10: Large amount of catalyst

[0100] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0101] Into a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.1275 g, 0.16 mmol), L4 ligand (0.124 g, 0.16 mmol) and 4 mL of water, after nitrogen replacement, heated to 150°C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.235 g of a colorless liquid, with a yield of 60.9% and an HPLC purity of 98.9%. (Boiling point: 112-114°C, density: 1.037±0.06 g / cm3)

[0102] Example 11: Small amount of catalyst

[0103] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0104] To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0319 g, 0.04 mmol), L4 ligand (0.031 g, 0.04 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.237 g of a colorless liquid, with a yield of 61.4% and an HPLC purity of 98.4%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0105] Example 12: Short reaction time

[0106] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0107] To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL of water, after nitrogen replacement, heated to 150 °C, and reacted for 5 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.29 g of a colorless liquid, with a yield of 75.6% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0108] Example 13: Long reaction time

[0109] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0110] Piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water were added into a pressure tube, which was heated to 150 °C after nitrogen replacement, and reacted for 15 h. After the reaction was completed, dichloromethane (80 mL x 3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.267 g of a colorless liquid, with a yield of 69.5% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0111] Continued extension of the reaction time can cause the monosubstituted target product to continue to react to generate disubstituted byproducts, ultimately leading to a decrease in yield.

[0112] Example 14: Low temperature

[0113] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0114] Piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water were added into a pressure tube, which was heated to 150 °C after nitrogen replacement, and reacted for 15 h. After the reaction was completed, dichloromethane (80 mL x 3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (EA:MeOH:TEA = 60:40:1 by volume) to obtain an eluent containing the target compound. The solvent was removed by rotary evaporation under reduced pressure to obtain 0.267 g of a colorless liquid, with a yield of 69.5% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3)

[0115] Comparative Example 6: Large feed ratio

[0116] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0117] To a pressure tube was added piperazine (1.72 g, 20 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water, after nitrogen replacement, heated to 150 °C, reaction for 10 h. After reaction, dichloromethane (8 mL x 3) was added to extract, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used to separate the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.199 g of colorless liquid, with a yield of 51.8% and a HPLC purity of 98.5%. (Boiling point: 112-114 °C, density: 1.037±0.06 g / cm3)

[0118] Comparative Example 7: Small ratio of raw materials

[0119] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0120] To a pressure tube was added piperazine (0.334 g, 4 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water, after nitrogen replacement, heated to 150 °C, reaction for 10 h. After reaction, dichloromethane (8 mL x 3) was added to extract, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used to separate the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.122 g of colorless liquid, with a yield of 31.6% and a HPLC purity of 98.4%. (Boiling point: 112-114 °C, density: 1.037±0.06 g / cm3)

[0121] Comparative Example 8: No catalyst

[0122] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0123] To a pressure tube was added piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), L4 ligand (0.0956 g, 0.12 mmol) and 4 mL water, after nitrogen replacement, heated to 150 °C, reaction for 10 h. TLC monitoring showed no product was detected.

[0124] Comparative Example 9: No catalyst + no ligand

[0125] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0126] Piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol) and 4 mL of water were added to a pressure tube, which was heated to 150 °C after nitrogen replacement, and reacted for 10 h. No product was detected by TLC monitoring.

[0127] Comparative Example 10

[0128] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0129] Piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), KOH (0.246 g, 4.4 mmol) and 4 mL of water were added to a pressure tube, which was heated to 150 °C under nitrogen protection, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used to separate the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.223 g of colorless liquid, with a yield of 57.8% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037±0.06 g / cm3)

[0130] As can be seen from Comparative Example 10 and Comparative Example 1, in the reaction of piperazine and diethylene glycol, the basic substance has little promoting effect on the selective mono-n-alkylation of the piperazine amine group. As can be seen from Comparative Example 5, the ligand L3 (1,3-diester imidazole chloride salt) has an adverse effect on the selective mono-n-alkylation of the piperazine amine group.

[0131] Example 15:

[0132] Preparation of 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0133] Piperazine (1.376 g, 16 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), KOH (0.246 g, 4.4 mmol) and 4 mL of water were added to a pressure tube, which was heated to 150 °C under nitrogen protection, and reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA = 60:40:1 by volume) was used to separate the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.223 g of colorless liquid, with a yield of 57.8% and an HPLC purity of 98%. (Boiling point: 112-114 °C, density: 1.037±0.06 g / cm3)

[0134] Example 16:

[0135] 1-[2-(2-hydroxyethoxy)ethyl]piperazine

[0136] To a pressure tube was added piperazine (0.688 g, 8 mmol), diethylene glycol (0.448 g, 4 mmol), [Cp*IrCl2]2(0.0956 g, 0.12 mmol), L4 ligand (0.0936 g, 0.12 mmol) and 4 mL water, after nitrogen replacement, heated to 150 °C, reacted for 10 h. After the reaction was completed, dichloromethane (8 mL x 3) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (EA:MeOH:TEA volume ratio = 60:40:1) was used to separate the eluent containing the target compound, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.233 g of a colorless liquid, with a yield of 60.4%, and an HPLC purity of 99%. (Boiling point: 112-114 °C, density: 1.037 ± 0.06 g / cm3).

Claims

1. A method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine, characterized in that... The synthesis method is as follows: using piperazine and diethylene glycol as raw materials, and water as the reaction solvent, a nitrogen alkylation reaction is carried out in a sealed pressure-resistant container, under a protective atmosphere, at 120-150°C for 1-15 hours in the presence of an iridium catalyst and ligand. The resulting reaction solution is then post-treated to obtain the 1-[2-(2-hydroxyethoxy)ethyl]piperazine; the molar ratio of piperazine, diethylene glycol, iridium catalyst, and ligand is 2-4.5:1:0.01-0.04:0.01-0.

04. The catalyst is [IrCl(cod)]2, Cp Ir(NH3)3(Cl)2、[Cp One or a mixture of two or more of IrCl2; The ligand is one or a mixture of two or more compounds represented by formula L: ； Where R1 and R2 are the same and are both C1-10 alkyl groups; or R1 is H and R2 is a phenyl group substituted with a C1-4 alkyl group.

2. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that: The protective atmosphere is a nitrogen atmosphere.

3. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that: The nitrogen alkylation reaction was carried out at a temperature of 150°C for 10 hours.

4. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that: The molar ratio of piperazine, diethylene glycol, iridium catalyst to ligand is 4:1:0.03:0.

03.

5. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that: The catalyst is [Cp] IrCl2]2.

6. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine according to any one of claims 1-5, characterized in that: The ligand is one or a mixture of two or more compounds represented by formulas L1, L2, and L4. 。 7. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 6, characterized in that: The ligand is a compound of formula L4.

8. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that: The volume of water, expressed as a molar amount of diethylene glycol, is 0.5-3 mL / mmol.

9. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that... The post-treatment is as follows: dichloromethane is added to the reaction solution for extraction, the resulting organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography with a mixed solution of ethyl acetate, methanol and triethylamine in a volume ratio of 60:40:1 as the eluent. The eluent containing the target compound is collected, and the solvent is removed under reduced pressure to obtain 1-[2-(2-hydroxyethoxy)ethyl]piperazine.

10. The method for synthesizing 1-[2-(2-hydroxyethoxy)ethyl]piperazine as described in claim 1, characterized in that... The synthesis method is as follows: using piperazine and diethylene glycol as raw materials, and water as the reaction solvent, a nitrogen alkylation reaction is carried out at 150°C for 10 hours in a sealed pressure-resistant container under a nitrogen atmosphere, with the aid of an iridium catalyst and a ligand. The resulting reaction solution is then post-treated to obtain the 1-[2-(2-hydroxyethoxy)ethyl]piperazine; the molar ratio of piperazine, diethylene glycol, iridium catalyst, and ligand is 4:1:0.03:0.03; the catalyst is [Cp IrCl2]2, wherein the ligand is a compound of formula L4. 。

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