A method for preparing (2R,5S)-4-Boc-2,5-dimethylpiperazine

Abstract

The application discloses a preparation method of (2R, 5S)-4-Boc-2, 5-dimethyl piperazine. Trans-2, 5-dimethyl piperazine is used as raw material, reacts with di-tert-butyl dicarbonate to generate N-Boc-2, 5-dimethyl piperazine, then is subjected to splitting by L-(+)-mandelic acid to obtain (2R, 5S)-4-Boc-2, 5-dimethyl piperazine mandelic acid salt, and then is separated to obtain 2R, 5S)-4-Boc-2, 5-dimethyl piperazine. The raw material used in the application is cheap and easy to obtain, the reaction condition is mild, the operation is simple, the total reaction yield is high, and the application is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to a method for preparing (2R,5S)-4-Boc-2,5-dimethylpiperazine. Background Technology

[0002] (2R,5S)-4-Boc-2,5-dimethylpiperazine is an important chemical intermediate. In the prior art, many patents and documents have disclosed the synthesis methods of (2R,5S)-4-Boc-2,5-dimethylpiperazine, and disclosed multiple synthetic routes.

[0003] Synthetic Route 1: Patent WO2002042992 discloses a method using 2,5-dimethyl-1-benzylpiperazine as a starting material, which, after resolution, reacts with di-tert-butyl dicarbonate followed by hydrogenation to remove the benzyl group, yielding (2R,5S)-4-Boc-2,5-dimethylpiperazine. The synthetic route is as follows:

[0004]

[0005] However, this route uses expensive raw materials and unconventional catalysts in the hydrogenation step, resulting in high costs and making it unsuitable for industrial production.

[0006] Synthetic Route 2: Patent CN102438991A discloses a method using readily available and inexpensive trans-2,5-dimethylpiperazine as a starting material. The reaction with di-tert-butyl dicarbonate followed by silica gel column purification yields (2R,5S)-4-Boc-2,5-dimethylpiperazine. The synthetic route is as follows:

[0007]

[0008] Synthetic Route 3: Patent CN102438991 discloses a method using (2R,5S)-1-Boc-4-benzyl-2,5-dimethylpiperazine as a starting material, followed by hydrogenation to remove the benzyl group, to obtain (2R,5S)-4-Boc-2,5-dimethylpiperazine. The synthetic route is as follows:

[0009]

[0010] However, this route uses expensive raw materials and is costly, making it unsuitable for industrial production. Summary of the Invention

[0011] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing (2R,5S)-4-Boc-2,5-dimethylpiperazine. The raw materials are inexpensive and readily available, the synthesis process is simple and mild, and conventional equipment can meet the requirements for industrial production. The operation process is simple, and the chiral purity of (2R,5S)-4-Boc-2,5-dimethylpiperazine prepared by the method of this invention reaches over 99%.

[0012] The technical solution of the present invention is as follows:

[0013] A method for preparing (2R,5S)-4-Boc-2,5-dimethylpiperazine includes the following steps:

[0014] (1) Using trans-2,5-dimethylpiperazine as raw material, N-Boc-2,5-dimethylpiperazine is generated by reacting with ditert-butyl dicarbonate under the action of an acid-binding agent.

[0015] Step 1) The structural formula of N-Boc-2,5-dimethylpiperazine is:

[0016]

[0017] (2) N-Boc-2,5-dimethylpiperazine was resolved with L-mandelic acid to obtain (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate.

[0018] (3) (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate was freed with a base to give (2R,5S)-4-Boc-2,5-dimethylpiperazine;

[0019] The structure of the (2R,5S)-4-Boc-2,5-dimethylpiperazine is shown in Formula I:

[0020]

[0021] Step 1) The synthetic reaction formula for N-Boc-2,5-dimethylpiperazine is as follows:

[0022]

[0023] Preferably, in step 1), the acid-binding agent is diethylamine, triethylamine, or diisopropylethylamine; the reaction is carried out in a solvent, which is ethyl acetate, isopropyl acetate, dichloromethane, toluene, or dimethyltetrahydrofuran.

[0024] Preferably, in step 1), the reaction temperature is 10–30°C and the reaction time is 4–10 h.

[0025] The synthetic reaction formula for step 2)(2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate is as follows:

[0026]

[0027] Preferably, the solvent used in step 2) is ethanol, isopropanol, acetone or ethyl acetate.

[0028] As a preferred method, during the separation in step 2), L-mandelic acid is added first, the temperature is raised to 50-60℃ and stirred for 2-4 hours, and then the temperature is lowered to -10-0℃ to crystallize, thereby obtaining (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelic acid salt.

[0029] The synthetic reaction formula for step 3)(2R,5S)-4-Boc-2,5-dimethylpiperazine is as follows:

[0030]

[0031] Preferably, the alkali used in step 3) is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate; and the solvent used is ethyl acetate, dichloromethane, or toluene.

[0032] Preferably, in step 3), the reaction temperature is 20–30°C and the reaction time is 2–4 h.

[0033] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0034] This invention uses L-mandelic acid as a resolving agent and a special solvent as a resolving medium to obtain (2R,5S)-4-Boc-2,5-dimethylpiperazine with higher chiral purity; and it eliminates the need for silica gel column purification, making the operation simpler. Attached Figure Description

[0035] Figure 1 The chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 1;

[0036] Figure 2 The chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 2;

[0037] Figure 3 The chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 3;

[0038] Figure 4 The chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 4;

[0039] Figure 5 The chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 5;

[0040] Figure 6 The image shows the chiral purity spectrum of (2R,5S)-4-Boc-2,5-dimethylpiperazine obtained in Example 6. Detailed Implementation

[0041] In this invention, experimental methods without specific conditions are generally performed under conventional conditions or as recommended by the manufacturer, and the raw materials used are all chemically pure.

[0042] Example 1

[0043] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0044]

[0045] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (132.9 g, 1313.3 mmol) were dissolved in 1000 mL of dichloromethane. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (210.5 g, 963.2 mmol) was slowly added. After the addition was complete, the mixture was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture separated into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 175.6 g of a pale yellow oil, with a yield of 93.6%.

[0046] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate (II)

[0047]

[0048] Compound III (100 g, 466.6 mmol) was added to 1000 ml of isopropanol, followed by L-mandelic acid (35.5 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to -10-0 °C, filtered, and dried to obtain 54.2 g of white solid, with a yield of 40%.

[0049] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0050]

[0051] Compound II (100 g, 272.8 mmol) was added to 800 mL of dichloromethane, followed by 300 mL of 1 N NaOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 52.6 g of white solid, with a yield of 90% and a chiral purity of 99.3%.

[0052] Example 2

[0053] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0054]

[0055] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (124.1 g, 1225.8 mmol) were dissolved in 1000 mL of ethyl acetate. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (200.9 g, 919.4 mmol) was slowly added. After the addition was complete, the solution was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture was allowed to separate into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 172.2 g of a pale yellow oil, with a yield of 91.8%.

[0056] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate (II)

[0057]

[0058] Compound III (100 g, 466.6 mmol) was added to 1000 ml of ethanol, followed by L-mandelic acid (35.5 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to -10-0 °C, filtered, and dried to obtain 51.5 g of white solid, with a yield of 38%.

[0059] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0060]

[0061] Compound II (100 g, 272.8 mmol) was added to 800 mL of dichloromethane, followed by 300 mL of 1N KOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 49.7 g of white solid, with a yield of 85% and a chiral purity of 97.6%.

[0062] Example 3

[0063] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0064]

[0065] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (119.7 g, 1182.9 mmol) were dissolved in 1000 mL of dichloromethane. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (210.3 g, 963.6 mmol) was slowly added. After the addition was complete, the mixture was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture was allowed to separate into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 172.4 g of a pale yellow oil, with a yield of 91.9%.

[0066] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate (II)

[0067]

[0068] Compound III (100 g, 466.6 mmol) was added to 1000 ml of acetone, followed by L-mandelic acid (35.5 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to -10-0 °C, filtered, and dried to obtain 50.6 g of white solid, with a yield of 37.4%.

[0069] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0070]

[0071] Compound II (100 g, 272.8 mmol) was added to 800 mL of dichloromethane, followed by 300 mL of 1N KOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 45.3 g of colorless oil, with a yield of 77.5% and a chiral purity of 89.2%.

[0072] Example 4

[0073] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0074]

[0075] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (124.3 g, 1228.4 mmol) were dissolved in 1000 mL of dichloromethane. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (200.7 g, 919.6 mmol) was slowly added. After the addition was complete, the mixture was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture was allowed to separate into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 170.6 g of a pale yellow oil, with a yield of 90.9%.

[0076] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate (II)

[0077]

[0078] Compound III (100 g, 466.6 mmol) was added to 1000 ml of isopropanol, followed by L-tartaric acid (24.7 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to -10-0 °C, filtered, and dried to give 70.3 g of white solid, with a yield of 52.0%.

[0079] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0080]

[0081] Compound II (100 g, 272.8 mmol) was added to 800 mL of toluene, followed by 300 mL of 1 N KOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 48.6 g of colorless oil, with a yield of 83.1% and a chiral purity of 51.0%.

[0082] Example 5

[0083] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0084]

[0085] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (122.8 g, 1213.6 mmol) were dissolved in 1000 mL of dichloromethane. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (201.3 g, 922.3 mmol) was slowly added. After the addition was complete, the mixture was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture separated into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 172.6 g of a pale yellow oil, with a yield of 92.0%.

[0086] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine tartrate (II)

[0087]

[0088] Compound III (100 g, 466.6 mmol) was added to 1000 ml of ethyl acetate, followed by L-tartaric acid (24.7 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to -10-0 °C, filtered, and dried to give 78.6 g of a white solid, with a yield of 58.1%.

[0089] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0090]

[0091] Compound II (100 g, 272.8 mmol) was added to 800 mL of dichloromethane, followed by 300 mL of 1 N KOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 50.0 g of colorless oil, with a yield of 85.5% and a chiral purity of 62.8%.

[0092] Example 6

[0093] Step 1: Preparation of N-Boc-2,5-dimethylpiperazine(III)

[0094]

[0095] Trans-2,5-dimethylpiperazine (100 g, 875.6 mmol) and triethylamine (124.6 g, 1231.3 mmol) were dissolved in 1000 mL of dichloromethane. The solution was cooled to 10–20 °C, and di-tert-butyl dicarbonate (201.2 g, 921.9 mmol) was slowly added. After the addition was complete, the mixture was stirred at 10–20 °C for 4 h. Gas chromatography showed that the reaction was complete. After the reaction was complete, 500 mL of water was added, and the mixture separated into layers. The organic phase was washed twice with 500 mL of 0.1 N dilute hydrochloric acid. The organic phase was concentrated to give 171.8 g of a pale yellow oil, with a yield of 91.6%.

[0096] Step 2: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine mandelate (II)

[0097]

[0098] Compound III (100 g, 466.6 mmol) was added to 1000 ml of isopropanol, followed by L-mandelic acid (35.5 g, 233.3 mmol). The mixture was heated to 50-60 °C and stirred for 2 h. The mixture was then slowly cooled to 20-30 °C, filtered, and dried to obtain 49.6 g of white solid, with a yield of 36.7%.

[0099] Step 3: Preparation of (2R,5S)-4-Boc-2,5-dimethylpiperazine (I)

[0100]

[0101] Compound II (100 g, 272.8 mmol) was added to 800 mL of toluene, followed by 300 mL of 1 N KOH (300 mmol) solution. The mixture was stirred at room temperature for 2 h, and the layers separated. The organic phase was washed twice with 300 mL of water and concentrated to dryness to give 50.2 g of colorless oil, with a yield of 85.9% and a chiral purity of 59.4%.

Claims

1. A method for preparing (2R, 5S)-4-Boc-2,5-dimethylpiperazine, characterized in that, Includes the following steps: (1) Using trans-2,5-dimethylpiperazine as raw material, N-Boc-2,5-dimethylpiperazine is generated by reacting with ditert-butyl dicarbonate under the action of an acid-binding agent. Step 1) The structural formula of N-Boc-2,5-dimethylpiperazine is: ； (2) N-Boc-2,5-dimethylpiperazine was resolved with L-mandelic acid to obtain (2R, 5S)-4-Boc-2,5-dimethylpiperazine mandelate. The solvent used in step 2) is isopropanol; During the separation in step 2), L-mandelic acid was added first, the temperature was raised to 50-60℃ and stirred for 2-4 hours, and then the temperature was lowered to -10-0℃ to crystallize, yielding (2R, 5S)-4-Boc-2,5-dimethylpiperazine mandelic acid salt. (3) (2R, 5S)-4-Boc-2,5-dimethylpiperazine mandelate was freed with a base to give (2R, 5S)-4-Boc-2,5-dimethylpiperazine; The structure of the (2R, 5S)-4-Boc-2,5-dimethylpiperazine is shown in Formula I: ； Step 3) The base used is sodium hydroxide or potassium hydroxide; the solvent used is dichloromethane.

2. The preparation method according to claim 1, characterized in that: In step 1), the acid-binding agent is diethylamine, triethylamine, or diisopropylethylamine; the reaction is carried out in a solvent, which is ethyl acetate, isopropyl acetate, dichloromethane, toluene, or dimethyltetrahydrofuran.

3. The preparation method according to claim 1, characterized in that: In step 1), the reaction temperature is 10~30℃ and the reaction time is 4~10h.

4. The preparation method according to claim 1, characterized in that: In step 3), the reaction temperature is 20~30℃ and the reaction time is 2~4h.

Images