Preparation method of 1-cyclopropyl piperazine

Abstract

The invention discloses a preparation method of 1-cyclopropylpiperazine, which belongs to the technical field of pharmaceutical chemicals, and comprises the following steps: taking diethanol amine as a starting material, and carrying out substitution reaction with a sulfonyl reagent to generate an intermediate I; reacting the intermediate I with cyclopropylamine to generate an intermediate II; the intermediate II is subjected to a sulfonyl removal reaction, and 1-cyclopropyl piperazine is generated; compared with the prior art, the synthesis route provided by the invention has the advantages that the initial raw materials are simple and easy to obtain, and the 1-cyclopropylpiperazine is simply, conveniently and efficiently obtained by adopting the inorganic base as the acid-binding agent in the reaction; the problems of high danger and toxicity, high production cost and low production efficiency in the existing preparation process of the 1-cyclopropylpiperazine are solved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for preparing 1-cyclopropylpiperazine. Background Art

[0002] Histamine, as an important chemical transmitter, is widely present in the human body. It is formed by the decarboxylation of histidine. Its synthesis and storage process mainly occurs in mast cells, basophils, lungs, skin and gastrointestinal mucosa, and is involved in multiple central and peripheral physiological functions.

[0003] Apodaca et al. (US20040110746) discovered that piperazine benzamides are a class of biologically active molecules that can block or regulate histamine receptor activity, in which the 1-cyclopropylpiperazine structure plays a key role in the structure of the active molecule; in addition, the 1-cyclopropylpiperazine structure is also widely present in other active biological molecules.

[0004] There are many methods for synthesizing 1-cyclopropylpiperazine reported so far, such as:

[0005]

[0006] Giuseppe and Romano et al. (WO2003066621A1) reported that cyclopropylamine and N-Boc-acetaldehydeamine were used as starting materials, and (2-(cyclopropylamino)-ethylamino) tert-butyl formate was synthesized by reduction with sodium borohydride, and then acylated with bromoacetyl bromide and alkaline ring closed under the action of sodium hydrogen to synthesize tert-butyl 4-cyclopropyl-3-oxopiperazine-1-carboxylate. The sodium borohydride and sodium hydrogen used in this method are highly dangerous.

[0007]

[0008] Janssen pharmaceuticaNV reported (WO2008002816A1) that Boc-piperazine and (ethoxycyclopropyloxy)trimethylsilane were used as starting materials, and sodium cyanoborohydride was used for reduction to obtain tert-butyl 4-cyclopropylpiperazine-1-carboxylate; and then a 1,4-dioxane solution of hydrogen chloride was used for de-Boc reaction to obtain 1-cyclopropylpiperazine. This method uses (ethoxycyclopropyloxy)trimethylsilane with poor stability as the cyclopropyl source, and sodium cyanoborohydride has high danger and toxicity, which is not convenient for production and use.

[0009]

[0010] JanssenpharmaceuticaNV reported (WO2008076685A2) that di(ethanol)amine is used as the starting material, the amine group is first protected by trifluoroacetylation, and then reacted with methanesulfonyl chloride to form a di(methanesulfonic acid) ester, the disulfonic acid ester reacts with cyclopropylamine to close the ring, and finally deprotects to obtain 1-cyclopropylpiperazine. The raw materials of this reaction are simple and easy to obtain, but this route uses two different protecting groups, which increases the number of reaction steps, and the cyclization reaction time is long, and the amount of cyclopropylamine used is large, which is not conducive to reducing production costs and improving production efficiency. Summary of the invention

[0011] In view of this, the present invention provides a method for preparing 1-cyclopropylpiperazine to solve the problems of high risk and toxicity, high production cost and low production efficiency in the existing preparation process of 1-cyclopropylpiperazine.

[0012] In order to solve the above technical problems, the technical solution of the present invention is:

[0013] The present invention provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0014] (1) Using diethanolamine as the starting material, a substitution reaction is carried out with a sulfonyl reagent to generate intermediate I;

[0015]

[0016] (2) intermediate I reacts with cyclopropylamine to generate intermediate II;

[0017]

[0018] (3) intermediate II undergoes a desulfonylation reaction to generate 1-cyclopropylpiperazine;

[0019]

[0020] Wherein, in step (1), the sulfonyl reagent is a sulfonyl halide or a sulfonic anhydride, R is a C1-C4 alkyl, a phenyl, or an alkyl-substituted phenyl; and the X group is a chlorine group, a bromine group, or a sulfonyl group.

[0021] Wherein, the R is methyl, and the X is chlorine.

[0022] Wherein, in step (1), the solvent is any one or two of acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; before the reaction, a base is added to adjust the pH value to 9-11, and the base is any one or two of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate.

[0023] Wherein, in step (2), the solvent is any one or two of acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide, and the molar ratio of the base added to the reaction to the cyclopropylamine is 1:(2.5-3.5); the added base is one or two of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylamine, and diisopropylethylamine.

[0024] Wherein, in step (3), the reaction temperature is reflux, and the solvent used is hydrobromic acid and carboxylic acid in a volume ratio of (1.5-2.5):1.

[0025] Wherein, the carboxylic acid is any one or more of formic acid, acetic acid and propionic acid.

[0026] Wherein, step (1) is specifically as follows:

[0027]

[0028] Add diethanolamine and acetone to the reaction bottle, protect with nitrogen, cool to 5°C in an ice-water bath, slowly drop methanesulfonyl chloride and 50% sodium hydroxide into the reaction solution at the same time, adjust the pH value to 9-11, adjust the internal temperature to 2-8°C, and add the solution within about 1.0h; after the addition is complete, keep the temperature for 4.0hrs. Move to room temperature and keep the temperature overnight. After the reaction is completed, add water, filter, dry the filter cake, and purify it with ethyl acetate-n-hexane to obtain di(methylsulfonyloxyethyl) methanesulfonamide.

[0029] Wherein, step (2) is specifically as follows:

[0030]

[0031] Cyclopropylamine, potassium carbonate and acetonitrile were added to the reaction flask. Under nitrogen protection, the acetonitrile solution of di(methylsulfonyloxyethyl)methanesulfonamide was added dropwise at room temperature, the internal temperature was 25-30°C, and the addition was completed within 25-35 minutes. After the addition was completed, the temperature was kept for 2.0 hours. The temperature was raised to reflux for reaction for 12.0 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. 1-cyclopropyl-4-(methylsulfonyl)piperazine was obtained by column chromatography.

[0032] The concentration of the acetonitrile solution of di(methylsulfonyloxyethyl)methanesulfonamide (10.18 g, 30.00 mmol) was 1 mmol / ml.

[0033] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0034] The synthetic route of the invention uses diethanolamine as a starting material, performs a substitution reaction with a sulfonyl reagent, then reacts with cyclopropylamine, and finally performs a desulfonylation reaction to obtain 1-cyclopropylpiperazine.

[0035] Compared with the conventional process, the synthetic route provided by the invention has simple and readily available starting materials, and an inorganic base is used as an acid-binding agent in the reaction, so that 1-cyclopropylpiperazine is obtained simply and efficiently; the problems of high risk and toxicity, high production cost and low production efficiency in the existing preparation process of 1-cyclopropylpiperazine are solved. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The mass spectrum of 1-cyclopropylpiperazine obtained in Example 1;

[0037] Figure 2 This is the hydrogen spectrum of 1-cyclopropylpiperazine obtained in Example 2. DETAILED DESCRIPTION

[0038] The following embodiments are provided for a better understanding of the present invention, but are not limited to the best mode of implementation, and do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0039] Example 1

[0040] This embodiment provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0041] Step (1):

[0042]

[0043] Diethanolamine (5.26 g, 50.00 mmol) and acetone (20 ml) were added to the reaction flask, nitrogen was protected, and the temperature was cooled to 5°C in an ice-water bath. Methanesulfonyl chloride (20.05 g, 3.50 equiv.) and 50% sodium hydroxide aqueous solution (18.00 g, 4.50 equiv.) were slowly added dropwise to the reaction solution at the same time, pH = 10, internal temperature 2-8°C, and the addition was completed within 1.0 h; after the addition was completed, the temperature was kept for 4.0 hrs. The mixture was moved to room temperature and kept overnight; after the reaction was completed, water (200 mL) was added, filtered, the filter cake was dried, and purified with ethyl acetate-n-hexane to obtain di(methylsulfonyloxyethyl)methanesulfonamide (15.61 g, 92%).

[0044] Step (2):

[0045]

[0046] Cyclopropylamine (1.71 g, 30.00 mmol), potassium carbonate (12.44 g, 75 mmol, 3.00 equiv.) and acetonitrile (30 mL) were added to the reaction flask. Under nitrogen protection, a solution of di(methylsulfonyloxyethyl)methanesulfonamide (10.18 g, 30.00 mmol) in acetonitrile (30 mL) was added dropwise at room temperature. The internal temperature was 25-30°C and the addition was completed in about 30 min. After the addition was completed, the mixture was kept warm for 2.0 hrs. The mixture was heated to reflux for 12.0 hrs. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. 1-cyclopropyl-4-(methylsulfonyl)piperazine (4.47 g, 73%) was obtained by column chromatography.

[0047] Step (3):

[0048]

[0049] 1-Cyclopropyl-4-(methylsulfonyl)piperazine (4.08 g, 20 mmol), phenol (2.26 g, 1.20 equiv.), 48% hydrobromic acid (19.5 mL) and glacial acetic acid (13 mL) were added to a reaction flask, heated to reflux for reaction, and kept warm for 8.0 hrs. After the reaction was completed, the temperature was lowered to room temperature, concentrated to dryness under reduced pressure, dissolved in water (100 mL), extracted twice with ethyl acetate, the separated aqueous phase was neutralized with liquid alkali (50%) to pH = 11-12, extracted 5 times with chloroform, the organic phases were combined, concentrated to dryness, and distilled under reduced pressure to obtain 1-cyclopropylpiperazine (2.04 g, 81%). 1 HNMR(500MHz, CDCl3)δ2.85(t,J=4.9Hz,4H),2.59(s,4H),1.91(s,1H),1.61(d dd,J=8.6,6.5,3.8Hz,1H),0.42(dddd,J=10.4,4.3,2.3,1.6Hz,4H).LCMS[M+H] + =127.2.

[0050] Example 2

[0051] This embodiment provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0052] Step (1):

[0053]

[0054] Diethanolamine (5.26 g, 50.00 mmol) and acetonitrile were added to the reaction flask, nitrogen was protected, and the temperature was cooled to 5°C in an ice-water bath. Methanesulfonyl bromide (27.82 g, 3.50 equiv.) and 50% potassium hydroxide aqueous solution (25.25 g, 4.50 equiv.) were slowly added to the reaction solution at the same time, pH = 9, internal temperature 2-8°C, and the addition was completed within 1.0 h; after the addition was completed, the temperature was kept for 4.0 hrs. The mixture was moved to room temperature and kept overnight; after the reaction was completed, water (200 mL) was added, filtered, the filter cake was dried, and purified with ethyl acetate-n-hexane to obtain di(ethylsulfonyloxyethyl)ethanesulfonamide (16.25 g, 93%).

[0055] Step (2):

[0056]

[0057] Cyclopropylamine (1.71 g, 30.00 mmol), potassium carbonate (10.36 g, 75.00 mmol, 2.50 equiv.) and acetone (30 mL) were added to the reaction flask. Under nitrogen protection, a solution of di(methylsulfonyloxyethyl)methanesulfonamide (10.18 g, 30.00 mmol) in acetone (30 mL) was added dropwise at room temperature. The internal temperature was 25-30°C and the addition was completed over about 30 min. After the addition was completed, the mixture was kept warm for 2.0 hrs. The mixture was heated to reflux for 12.0 hrs. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. 1-cyclopropyl-4-(ethylsulfonyl)piperazine (4.85 g, 74%) was obtained by column chromatography.

[0058] Step (3):

[0059]

[0060] 1-Cyclopropyl-4-(methylsulfonyl)piperazine (4.08 g, 20 mmol), phenol (2.26 g, 1.20 equiv.), 48% hydrobromic acid (25 mL) and formic acid (13 mL) were added to a reaction flask, heated to reflux for reaction, and kept warm for 8.0 hrs. After the reaction was completed, the temperature was lowered to room temperature, concentrated to dryness under reduced pressure, dissolved in water (100 mL), extracted twice with ethyl acetate, the separated aqueous phase was neutralized with liquid alkali (50%) to pH = 11-12, extracted 5 times with chloroform, the organic phases were combined, concentrated to dryness, and distilled under reduced pressure to obtain 1-cyclopropylpiperazine (2.01 g, 80%). 1 HNMR(500MHz, CDCl3)δ2.85(t,J=4.9Hz,4H),2.59(s,4H),1.91(s,1H),1.61(d dd,J=8.6,6.5,3.8Hz,1H),0.42(dddd,J=10.4,4.3,2.3,1.6Hz,4H).LCMS[M+H]+ =127.2.

[0061] Example 3

[0062] This embodiment provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0063] Step (1):

[0064]

[0065] Diethanolamine (5.26 g, 50.00 mmol), potassium carbonate (31.10 g, 4.50 equiv.) and N,N-dimethylformamide were added to the reaction flask under nitrogen protection, cooled to 5°C in an ice-water bath, and benzenesulfonyl chloride (30.91 g, 3.50 equiv.) was slowly added dropwise to the reaction solution at an internal temperature of 2-8°C within 1.0 h; after the addition was completed, the temperature was kept for 4.0 hrs. The mixture was moved to room temperature and kept overnight; after the reaction was completed, water (200 mL) was added, filtered, the filter cake was dried, and purified using ethyl acetate-n-hexane to obtain di(benzenesulfonyloxyethyl)benzenesulfonamide (24.18 g, 92%).

[0066] Step (2):

[0067]

[0068] Cyclopropylamine (1.71 g, 30.00 mmol), sodium bicarbonate (8.82 g, 105.00 mmol, 3.50 equiv.) and N,N-dimethylformamide (30 mL) were added to the reaction flask. Under nitrogen protection, a solution of di(methylsulfonyloxyethyl)methanesulfonamide (15.77 g, 30.00 mmol) in N,N-dimethylformamide (30 mL) was added dropwise at room temperature. The internal temperature was 25-30°C and the addition was completed in about 30 minutes. After the addition was completed, the temperature was kept for 2.0 hrs. The temperature was raised to reflux for reaction for 12.0 hrs. After the reaction was completed, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. 1-cyclopropyl-4-(phenylsulfonyl)piperazine (5.91 g, 74%) was obtained by column chromatography.

[0069] Step (3):

[0070]

[0071] 1-Cyclopropyl-4-(methylsulfonyl)piperazine (5.33 g, 20 mmol), phenol (2.26 g, 1.20 equiv.), 48% hydrobromic acid (32.5 mL) and propionic acid (13 mL) were added to a reaction flask, heated to reflux for reaction, and kept warm for 8.0 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated to dryness under reduced pressure, dissolved in water (100 mL), extracted twice with ethyl acetate, the separated aqueous phase was neutralized with liquid alkali (50%) to pH = 11-12, extracted 5 times with chloroform, the organic phases were combined, concentrated to dryness, and distilled under reduced pressure to obtain 1-cyclopropylpiperazine (2.10 g, 83%). 1 HNMR(500MHz, CDCl3)δ2.85(t,J=4.9Hz,4H),2.59(s,4H),1.91(s,1H),1.61(d dd,J=8.6,6.5,3.8Hz,1H),0.42(dddd,J=10.4,4.3,2.3,1.6Hz,4H).LCMS[M+H] + =127.2.

[0072] Example 4

[0073] This embodiment provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0074] Step (1):

[0075]

[0076] Diethanolamine (5.26 g, 50.00 mmol), sodium carbonate (23.85 g, 4.50 equiv.) and tetrahydrofuran (60 mL) were added to the reaction flask, nitrogen was protected, the temperature was cooled to 5°C in an ice-water bath, toluenesulfonyl chloride (33.36 g, 3.50 equiv.) was slowly added dropwise to the reaction solution, the internal temperature was 2-8°C, and the addition was completed within 1.0 h; after the addition was completed, the temperature was kept for 4.0 hrs. The mixture was moved to room temperature and kept overnight; after the reaction was completed, water (200 mL) was added, filtered, the filter cake was dried, and purified with ethyl acetate-n-hexane to obtain di(toluenesulfonyloxyethyl)toluenesulfonamide (25.83 g, 91%).

[0077] Step (2):

[0078]

[0079] Cyclopropylamine (1.71 g, 30.00 mmol), triethylamine (9.11 g, 90.00 mmol, 3.00 equiv.) and tetrahydrofuran (30 mL) were added to the reaction flask. Under nitrogen protection, a solution of di(methylsulfonyloxyethyl)methanesulfonamide (17.03, 30.00 mmol) in acetonitrile (30 mL) was added dropwise at room temperature. The internal temperature was 25-30°C and the addition was completed in about 30 min. After the addition was completed, the mixture was kept warm for 2.0 hrs. The mixture was heated to reflux for 12.0 hrs. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to dryness. 1-cyclopropyl-4-(tosyl)piperazine (6.14 g, 73%) was obtained by column chromatography.

[0080] Step (3):

[0081]

[0082] 1-Cyclopropyl-4-(methylsulfonyl)piperazine (5.61 g, 20 mmol), phenol (2.26 g, 1.20 equiv.), 48% hydrobromic acid (25 mL) and glacial acetic acid (13 mL) were added to a reaction flask, heated to reflux for reaction, and kept warm for 8.0 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated to dryness under reduced pressure, dissolved in water (100 mL), extracted twice with ethyl acetate, the separated aqueous phase was neutralized with liquid alkali (50%) to pH = 11-12, extracted 5 times with chloroform, the organic phases were combined, concentrated to dryness, and distilled under reduced pressure to obtain 1-cyclopropylpiperazine (2.07 g, 82%). 1 HNMR(500MHz, CDCl3)δ2.85(t,J=4.9Hz,4H),2.59(s,4H),1.91(s,1H),1.61(d dd,J=8.6,6.5,3.8Hz,1H),0.42(dddd,J=10.4,4.3,2.3,1.6Hz,4H).LCMS[M+H] + =127.2.

[0083] Although the embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and cannot be understood as limiting the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention without departing from the principles and purpose of the present invention. The protection scope of the present invention is defined by the claims and their equivalent technical solutions.

Claims

1. A method for preparing 1-cyclopropylpiperazine, characterized in that The steps include: (1) Using diethanolamine as the starting material, a substitution reaction is carried out with a sulfonyl reagent to generate intermediate I; (2) intermediate I reacts with cyclopropylamine to generate intermediate II; (3) intermediate II undergoes a desulfonylation reaction to generate 1-cyclopropylpiperazine; 2. A method for preparing 1-cyclopropylpiperazine according to claim 1, characterized in that: In step (1), the sulfonyl reagent is a sulfonyl halide or a sulfonic anhydride, R is a C1-C4 alkyl, a phenyl, or an alkyl-substituted phenyl; and the X group is a chlorine group, a bromine group, or a sulfonyl group.

3. A method for preparing 1-cyclopropylpiperazine according to claim 2, characterized in that: The R is methyl, and the X is chlorine.

4. A method for preparing 1-cyclopropylpiperazine according to claim 1, characterized in that: In step (1), the solvent is any one or two of acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; before the reaction, a base is added to adjust the pH value to 9-11, and the base is any one or two of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, and sodium carbonate.

5. A method for preparing 1-cyclopropylpiperazine according to claim 1, characterized in that: In step (2), the solvent is any one or two of acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide, and the molar ratio of the base added to the reaction to the cyclopropylamine is 1:(2.5-3.5); the added base is one or two of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylamine, and diisopropylethylamine.

6. A method for preparing 1-cyclopropylpiperazine according to claim 1, characterized in that: In step (3), the reaction temperature is reflux, and the solvent used is hydrobromic acid and carboxylic acid in a volume ratio of (1.5-2.5):

1.

7. A method for preparing 1-cyclopropylpiperazine according to claim 6, characterized in that: The carboxylic acid is any one or more of formic acid, acetic acid and propionic acid.

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