A process for the preparation of 1-(2,3-dichlorophenyl)piperazine hydrochloride

Abstract

The application discloses a synthesis method of a compound 1-(2,3-dichlorophenyl)piperazine hydrochloride, which takes 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride as raw materials, and obtains 1-(2,3-dichlorophenyl)piperazine hydrochloride through a catalyst catalyzed condensation reaction. The synthesis method is simple, the product can be obtained at a high conversion rate, and the reaction safety is high; the raw material used in the application has a low environmental protection pressure, the reaction condition is mild, the requirement on equipment is low, and the application is suitable for industrial production requirements.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a synthetic method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride. BACKGROUND

[0002] Aripiprazole is a new atypical antipsychotic drug for the treatment of various acute and chronic schizophrenia and schizoaffective disorders, and its structural formula is as shown below:

[0003]

[0004] 1-(2,3-dichlorophenyl)piperazine hydrochloride is an important intermediate of aripiprazole, and its structural formula is as shown in formula I:

[0005]

[0006] So far, there are mainly two methods for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride: 1) 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride are used as raw materials to synthesize by condensation substitution in a polar aprotic solvent, and high-boiling solvents such as NMP and sulfolane are usually used; 2) 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride are used as raw materials to synthesize by condensation substitution in a solvent-free method at high temperature (150-170°C). Both of the two methods have many side reactions, high reaction temperature, large heat release of material decomposition, and high potential explosion risk, which are not conducive to industrial production. SUMMARY

[0007] The present application provides a new method for preparing 1-(2,3-dichlorophenyl)piperazine hydrochloride, which comprises the following steps:

[0008] 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride are used as raw materials to synthesize 1-(2,3-dichlorophenyl)piperazine hydrochloride by condensation reaction in the presence of a catalyst, and the reaction formula is as follows:

[0009]

[0010] As a preferred, the reaction solvent is selected from one of xylene, N,N-dimethylformamide, N-methylpyrrolidone, isopropanol, n-butanol, propylene glycol, glycerol, ethylene glycol or ethylene glycol monoethyl ether, and further preferably xylene.

[0011] As preferred, the catalyst is selected from one of benzenesulfonic acid, o-methylbenzenesulfonic acid, m-methylbenzenesulfonic acid, p-methylbenzenesulfonic acid, o-chlorobenzenesulfonic acid, m-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, o-methylbenzenesulfonic acid, m-methylbenzenesulfonic acid, p-methylbenzenesulfonic acid, o-methoxybenzenesulfonic acid, m-methoxybenzenesulfonic acid, p-methoxybenzenesulfonic acid, o-nitrobenzenesulfonic acid, m-nitrobenzenesulfonic acid, p-nitrobenzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid or methanesulfonic acid.

[0012] As further preferred, the catalyst is one of o-chlorobenzenesulfonic acid, m-chlorobenzenesulfonic acid or p-chlorobenzenesulfonic acid. Still further, the catalyst is p-chlorobenzenesulfonic acid.

[0013] As preferred, the molar ratio of compound II and compound III in the reaction is 1.0: (1.0-2.0), preferably 1.0:1.5.

[0014] As preferred, the volume to weight ratio (mL:g) of the reaction solvent to compound II in the reaction is (2.0-3.0):1, preferably 2.5:1.

[0015] As preferred, the molar ratio of the catalyst to compound II is (0.05-0.1):1, preferably 0.075:1.

[0016] The reaction product prepared by the present application can be obtained as high-purity 1-(2,3-dichlorophenyl)piperazine hydrochloride after simple crystallization and filtration; the raw materials used in the present application are cheap and easy to obtain, no high-toxic or strong-smelling raw materials are used, the environmental pressure is small, and the present application is suitable for industrial mass production; the synthesis method of 1-(2,3-dichlorophenyl)piperazine hydrochloride provided by the present application is simple, the raw materials are cheap, the yield is high, the quality is high, and the side reactions are few. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 HPLC spectrum of 1-(2,3-dichlorophenyl)piperazine hydrochloride prepared in Example 6. DETAILED DESCRIPTION

[0018] The present application will be further described in detail below through specific examples, and the raw materials used in the examples can be commercially available.

[0019] Example 1

[0020] In a 250 ml reaction bottle, bis(2-chloroethyl)amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and xylene 45 ml, and a catalyst (0.0075 mol) were sequentially added, and the temperature was raised to 135±2℃, and the temperature was controlled at 135±2℃ for 29±1 hours. The product purity of the reaction liquid was detected by HPLC.

[0021] Table 1

[0022]

[0023]

[0024] Note: "Category" and "reaction solution purity" are the purity of 1-(2,3-dichlorophenyl)piperazine hydrochloride in the reaction solution detected by liquid chromatography.

[0025] From the above table data, the reaction solvent is xylene, and the catalyst is p-chlorobenzene sulfonic acid, which has the best effect.

[0026] Example 2

[0027] In a 250 ml reaction bottle, bis(2-chloroethyl)amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and solvent 45 ml, p-chlorobenzene sulfonic acid (1.45 g, 0.0075 mol) were added in turn, and the temperature was raised to 135±2℃, and the temperature was controlled at 135±2℃ for 29±1 hours. The purity of the product was detected by HPLC.

[0028] Table 2

[0029]

[0030]

[0031] Note: "Category" and "reaction solution purity" are the purity of 1-(2,3-dichlorophenyl)piperazine hydrochloride in the reaction solution detected by liquid chromatography.

[0032] From the above table, the reaction catalyst is p-chlorobenzene sulfonic acid, and the reaction solvent is xylene, which has the best effect.

[0033] Example 3

[0034] In a 250 ml reaction bottle, bis(2-chloroethyl)amine hydrochloride, 2,3-dichloroaniline (16.2 g, 0.1 mol) and solvent xylene 45 ml, p-chlorobenzene sulfonic acid (1.45 g, 0.0075 mol) were added in the proportion shown in Table 3, and the temperature was raised to 135±2℃, and the temperature was controlled at 135±2℃ for 29±1 hours. The purity of the product was detected by HPLC.

[0035] Table 3

[0036]

[0037] Note: "Category" and "reaction solution purity" are the purity of 1-(2,3-dichlorophenyl)piperazine hydrochloride in the reaction solution detected by liquid chromatography.

[0038] From the above table, it can be seen that when the reaction solvent is xylene and the catalyst is p-chlorobenzene sulfonic acid, the effect is best when the molar ratio of the compound II and the compound III is 1.0:1.5.

[0039] Example 4

[0040] In a 250 ml reaction bottle, bis (2-chloroethyl) amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and xylene in the proportion listed in Table 4, p-chlorobenzene sulfonic acid (1.45 g, 0.0075 mol) were sequentially added, and the temperature was raised to 135±2℃, and the reaction was carried out at 135±2℃ for 29±1 hours. The purity of the product was detected by HPLC.

[0041] Table 4

[0042]

[0043] Note: The values in the items of "category" and "reaction liquid purity" are the purity of 1-(2,3-dichlorophenyl) piperazine hydrochloride in the reaction liquid detected by liquid chromatography.

[0044] From the above table, it can be seen that when the reaction solvent is xylene and the catalyst is p-chlorobenzene sulfonic acid, the effect is best when the volume ratio of the reaction solvent to the weight of the compound II is 2.5:1.0.

[0045] Example 5

[0046] In a 250 ml reaction bottle, bis (2-chloroethyl) amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and xylene 45 ml, p-chlorobenzene sulfonic acid in the proportion listed in Table 5 were sequentially added, and the temperature was raised to 135±2℃, and the reaction was carried out at 135±2℃ for 29±1 hours. The purity of the product was detected by HPLC.

[0047] Table 5

[0048]

[0049]

[0050] Note: The values in the items of "category" and "reaction liquid purity" are the purity of 1-(2,3-dichlorophenyl) piperazine hydrochloride in the reaction liquid detected by liquid chromatography.

[0051] From the above table, it can be seen that when the reaction solvent is xylene and the catalyst is p-chlorobenzene sulfonic acid, considering the price and production cost of the catalyst, the effect is best when the molar ratio of the catalyst and the molar ratio of the compound II are selected as 0.075:1.0.

[0052] Example 6

[0053] In a 250 ml reaction flask, bis (2-chloroethyl) amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and dimethylformamide 45 ml, p-chlorobenzenesulfonic acid (1.45 g, 0.075 mol) were added in sequence. The temperature was raised to 135 ± 2 °C and maintained at 135 ± 2 °C for 29 ± 1 h.

[0054] Work-up: cooled to room temperature, ethanol 45 ml was added, slurried, filtered and dried to obtain compound I as white solid 23.5 g in 87.90% yield. HPLC: purity: 99.26%.

[0055] The reaction was evaluated as level 3 for reaction safety and was safe.

[0056] Example 7

[0057] In a 250 ml reaction flask, bis (2-chloroethyl) amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and dimethylformamide 45 ml, p-chlorobenzenesulfonic acid (1.45 g, 0.075 mol) were added in sequence. The temperature was raised to 135 ± 2 °C and maintained at 135 ± 2 °C for 29 ± 1 h.

[0058] Work-up: cooled to room temperature, ethanol 45 ml was added, slurried, filtered and dried to obtain compound I as white solid 20.53 g in 76.79% yield. HPLC: purity: 98.80%.

[0059] Example 8

[0060] In a 250 ml reaction flask, bis (2-chloroethyl) amine hydrochloride (25.8 g, 0.15 mol), 2,3-dichloroaniline (16.2 g, 0.1 mol) and dimethylformamide 45 ml, p-chlorobenzenesulfonic acid (1.45 g, 0.075 mol) were added in sequence. The temperature was raised to 135 ± 2 °C and maintained at 135 ± 2 °C for 29 ± 1 h.

[0061] Work-up: cooled to room temperature, ethanol 45 ml was added, slurried, filtered and dried to obtain compound I as white solid 19.24 g in 71.97% yield. HPLC: purity: 98.91%.

[0062] Example 9

[0063] In a 1 L reaction flask, add bis (2-chloroethyl) amine hydrochloride (103.2 g, 0.60 mol), 2,3-dichloroaniline (64.8 g, 0.4 mol) and dimethylformamide 180 ml, p-chlorobenzene sulfonic acid (5.8 g, 0.03 mol) in sequence. Warm up to 135 ± 2 °C, control temperature at 135 ± 2 °C for 29 ± 1 hours.

[0064] Work-up: cool down to room temperature, add ethanol 180 ml, slurry, filter, dry, get compound I white solid 92.84 g, yield 86.82%. HPLC: purity: 99.21%.

[0065] Comparative Example 1

[0066] In a 1 L reaction flask, add bis (2-chloroethyl) amine hydrochloride (103.2 g, 0.60 mol), 2,3-dichloroaniline (64.8 g, 0.4 mol) and NMP 45 ml in sequence. Warm up to 135 ± 2 °C, control temperature at 135 ± 2 °C for 29 ± 1 hours.

[0067] Work-up: cool down to room temperature, add ethanol 180 ml, slurry, filter, dry, get compound I white solid 85.72 g, yield 80.11%. HPLC: purity: 99.01%.

[0068] This reaction is evaluated as level 5 in reaction safety, with potential risk of violent decomposition and explosion.

Claims

1. A process for the preparation of 1-(2,3-dichlorophenyl)piperazine hydrochloride, characterized in that The method comprises the following steps: The reaction formula is as follows: 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride are used as raw materials, and 1-(2,3-dichlorophenyl)piperazine hydrochloride is obtained through condensation reaction in a reaction solvent with a catalyst. The reaction solvent is xylene, and the catalyst is p-chlorobenzenesulfonic acid.

2. The production method according to claim 1, characterized by The molar ratio of compound II to compound III in the reaction is 1.0:(1.0-2.0).

3. The method of claim 2, wherein The molar ratio of compound II to compound III in the reaction is 1.0:1.

5.

4. The method of claim 1, wherein The volume of the reaction solvent to the weight of compound II in the reaction is 2.0-3.0 mL / g.

5. The method of claim 4, wherein The volume of the reaction solvent to the weight of compound II in the reaction is 2.5 mL / g.

6. The method of claim 1, wherein The molar ratio of the catalyst to compound II is (0.05-0.1):

1.

7. The method of claim 6, wherein The molar ratio of the catalyst to compound II is 0.075:1.

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