Preparation method of 1-cyclopropyl piperazine

Abstract

The invention provides a preparation method of 1-cyclopropylpiperazine, which comprises the following steps: reacting a compound II and / or a salt thereof with cyclopropylamine to obtain the 1-cyclopropylpiperazine, and the synthetic route is as follows: # imgabs0 #, in which X is CI and Br, and I and X can be the same or different, for example, X is Cl and Br at the same time, or X is Cl and the other is Br. The invention provides synthesis of 1-cyclopropylpiperazine, which is convenient to operate, short in route, easy in reaction control and high in yield, and is suitable for process amplification production.

Description

Technical Field

[0001] The invention relates to a preparation method of 1-cyclopropylpiperazine, and belongs to the technical field of medicine and chemistry. Background Art

[0002] 1-Cyclopropylpiperazine is an important intermediate compound, and its chemical structure is shown in formula (I):

[0003]

[0004] The prior art CN101611014A specification discloses two methods for preparing 1-cyclopropylpiperazine, and the synthesis routes are as follows:

[0005] Route 1:

[0006]

[0007] Route 2:

[0008]

[0009] Among them, route 1 uses piperazine-1-carboxylic acid tert-butyl ester as a raw material, undergoes reduction amination, deprotection to form a salt, and frees to obtain 1-cyclopropylpiperazine, and the three-step yield of route 1 is 53%. Route 2 uses piperazine-1-carboxylic acid tert-butyl ester as a raw material, undergoes reduction amination, deprotection to free to obtain 1-cyclopropylpiperazine, and the two-step yield of route 2 is 36%. The disadvantages of this preparation method are complex reaction operation, long steps, and low yield.

[0010] Therefore, the current method for preparing 1-cyclopropylpiperazine still needs to be improved, and it is necessary to develop a new method for preparing 1-cyclopropylpiperazine. Summary of the invention

[0011] In view of the shortcomings of the prior art, the present invention provides a method for preparing 1-cyclopropylpiperazine.

[0012] The first aspect of the present invention provides a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0013] Compound II and / or its salt is reacted with cyclopropylamine to obtain 1-cyclopropylpiperazine. The synthesis route is as follows:

[0014]

[0015] Wherein X is Cl, Br, I, and X may be the same or different, for example, X is both Cl and Br, or one X is Cl and the other is Br;

[0016] Furthermore, the present invention provides a preferred technical solution, a method for preparing 1-cyclopropylpiperazine, comprising the following steps:

[0017] Bis(2-chloroethyl)amine hydrochloride is reacted with cyclopropylamine to obtain 1-cyclopropylpiperazine. The synthetic route is as follows:

[0018]

[0019] Further, the molar feed ratio of the compound II (including compound II-1) to cyclopropylamine is 1:2 to 6, for example 1:2 to 3;

[0020] Further, the reaction temperature is 40 to 60°C, for example 45 to 50°C;

[0021] Further, the reaction time is 1 to 5 hours, for example 1 to 2 hours;

[0022] Furthermore, the compound II (including compound II-1) is preferably added by dissolving it in solvent A and then dropping it into cyclopropylamine, or the compound II is dissolved in solvent A and cyclopropylamine and then dropped into solvent B at the same time for reaction;

[0023] Further, the solvent A or solvent B may be independently selected from an alcohol solvent, and the alcohol solvent may be selected from one of ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol or any combination thereof, such as methanol or ethanol;

[0024] Further, after the reaction is completed, a base is added and the product 1-cyclopropylpiperazine is obtained by vacuum distillation with high purity;

[0025] Further, the temperature of the reduced pressure distillation is 70 to 90°C, such as 70 to 80°C or 80 to 90°C;

[0026] The molar ratio of the base to compound II is 2 to 5:1, for example 2 to 4:1, for example 2:1, 3:1, 4:1.

[0027] Further, the base is selected from an inorganic base or an organic base, preferably an organic base; an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or a metal alkoxide M(OR)n, M is selected from any one of an alkali metal or an alkaline earth metal, preferably, the alkali metal is sodium, potassium or lithium, the alkaline earth metal is magnesium, R is selected from an alkyl group having 1 to 5 carbon atoms, and n is 1 or 2; further, the metal alkoxide M(OR) n is selected from sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, magnesium methoxide, magnesium ethoxide, magnesium n-propoxide, sodium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, magnesium isobutoxide or magnesium tert-amyl oxide; preferably, the metal alkoxide M(OR)n is selected from sodium methoxide, sodium ethoxide, magnesium ethoxide, magnesium n-propoxide, magnesium tert-butoxide or magnesium isobutoxide; more preferably, the metal alkoxide M(OR)n is sodium methoxide, sodium ethoxide or magnesium tert-butoxide, and further, the sodium alkoxide can be added as a solid or a solution of sodium alkoxide alcohol, such as a 30% mass fraction of sodium methoxide methanol solution.

[0028] Beneficial technical effects of the present invention:

[0029] 1. The present invention provides a synthesis of 1-cyclopropylpiperazine which is convenient to operate, has a short route, is easy to control the reaction, and has a high yield, and is suitable for process scale-up production.

[0030] 2.1-Cyclopropylpiperazine is an important intermediate. Due to the high activity of the amino group, the next step reaction has particularly high requirements for the moisture control of the raw material. The preparation method of the present invention can obtain a high-yield and high-purity product.

[0031] 3. The present invention further improves the reaction yield by controlling the reaction temperature, the order of adding materials and special post-treatment, thereby greatly saving costs.

[0032] 4. In the prior art, route 1 in CN101611014A has a yield of 53% through three steps, and route 2 has a yield of 36% through two steps;

[0033] As for the method in reference patent CN101605767A, the total yield of the four steps of comparative example 4 is only 25%, and the two-step yield of comparative example 5 is 32.49%. The two-step yield of the reaction of the present application is as high as 74%, achieving an unexpected technical effect. DETAILED DESCRIPTION

[0034] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0035] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples are commercially available unless otherwise specified. The present invention will now be described in more detail with reference to examples and comparative examples.

[0036] Example 1

[0037] Bis(2-chloroethyl)amine hydrochloride was prepared as follows:

[0038] Under nitrogen atmosphere, thionyl chloride (1131.5 g, 9.52 mol) was added dropwise to a stirred solution of diethanolamine (500 g, 4.76 mol) in xylene (2500 mL), stirred at 40-50 ° C for 2 hours, filtered and dried to obtain bis(2-chloroethyl)amine hydrochloride (845.2 g, yield 99.56%).

[0039] Example 2

[0040] 1-Cyclopropylpiperazine was prepared as follows:

[0041] Under a nitrogen atmosphere, a methanol (100 mL) solution of bis(2-chloroethyl)amine hydrochloride (50.0 g, 0.28 mol) and cyclopropylamine (47.98 g, 0.84 mol) were simultaneously added dropwise to ethanol, stirred at 45°C for 1 hour, a 30% mass fraction of sodium methoxide methanol solution (151.3 g, 0.84 mol) was added dropwise, and 1-cyclopropylpiperazine (24.52 g, 69.36% yield, GC purity 99.8%, water content 0.6%) was obtained by distillation under reduced pressure at 70-80°C as a colorless transparent oil.

[0042] 1 HNMR (400MHz, CD3OD): δ2.72(dd,8H), δ1.64(ddd,1H), δ0.87-0.07(m,4H).

[0043] Example 3

[0044] 1-Cyclopropylpiperazine was prepared as follows:

[0045] Under nitrogen atmosphere, a solution of bis(2-chloroethyl)amine hydrochloride (300.0 kg, 1680.7 mol) in methanol (600.0 L) was added dropwise to a solution of cyclopropylamine (287.8 kg, 5042.1 mol) in methanol (600.0 L), stirred at 45 ° C for 1 hour, a 30% mass fraction of sodium methoxide methanol solution (907.6 kg, 5042.1 mol) was added dropwise, and 1-cyclopropylpiperazine (157.1 kg, 74.1% yield, GC purity 99.5%, water content 0.6%) was obtained by distillation under reduced pressure at 80-90 ° C as a colorless transparent oil.

[0046] Comparative Example 1:

[0047] 1-Cyclopropylpiperazine was prepared as follows:

[0048] Under nitrogen atmosphere, a solution of bis(2-chloroethyl)amine hydrochloride (100.0 g, 0.56 mol) in water (100 mL) was slowly added dropwise to a stirred cyclopropylamine (95.95 g, 1.68 mol), and stirred at 45-55° C. for 1 hour. Sodium hydroxide (67.23 g, 1.68 mol) was added, and the crude 1-cyclopropylpiperazine was obtained by vacuum distillation in the form of a colorless transparent oil with a water content of 55.2%. Sodium hydroxide flakes were added for separation, and the water content was reduced to 5.1%. Activated molecular sieves were added for drying to obtain 24.76 g of 1-cyclopropylpiperazine with a yield of 35.02%.

[0049] Comparative Example 2:

[0050] 1-Cyclopropylpiperazine was prepared as follows:

[0051] Under nitrogen atmosphere, a solution of bis(2-chloroethyl)amine hydrochloride (100.0 g, 0.56 mol) in water (100 mL) was slowly added dropwise to the stirred cyclopropylamine (95.95 g, 1.68 mol), and stirred at 45°C for 1 hour. Sodium hydroxide (67.23 g, 1.68 mol) was added, and the temperature was slowly raised to evaporate the excess cyclopropylamine. Sodium hydroxide (50.0 g, 0.5 w / w) was added at a temperature of 15-25°C, and stirred for 30 minutes. The mixture was allowed to stand for separation, and the organic phase was collected and distilled to obtain crude 1-cyclopropylpiperazine in the form of a colorless transparent oil with a water content of 4.5%. Activated molecular sieves were added for drying to obtain 31.90 g of 1-cyclopropylpiperazine with a yield of 45.12%.

[0052] Comparative Example 3:

[0053] 1-Cyclopropylpiperazine was prepared as follows:

[0054] Under nitrogen atmosphere, water (100 mL), bis(2-chloroethyl)amine hydrochloride (100.0 g, 0.56 mol), toluene (500 mL) solution, cyclopropylamine (95.95 g, 1.68 mol) were added to the reaction kettle, and the temperature was raised to 80±5°C and stirred for 16 hours. A 30% mass fraction of sodium methoxide methanol solution (302.4 g, 1.68 mol) was added dropwise, the temperature was lowered to 25±5°C, stirred for 1 hour, the solid was filtered, the pure fractions in the mother liquor were evaporated to dryness, and 17.45 g of 1-cyclopropylpiperazine was obtained by distillation in the form of a light yellow transparent oil, with a yield of 24.69%.

[0055] Comparative Example 4:

[0056] Reference CN101605767A

[0057]

[0058] 1-Cyclopropylpiperazine was prepared as follows:

[0059] Trifluoro-N,N-di-(2-hydroxy-ethyl)-acetamide was prepared as follows:

[0060] Under nitrogen atmosphere, methyl trifluoroacetate (25 g, 195.3 mmol) was added dropwise to a stirred solution of diethanolamine (20.5 g, 195 mmol) in tetrahydrofuran (100 mL), stirred for 16 hours, and concentrated to obtain an oily liquid.

[0061] Methanesulfonic acid 2-[(2-methylsulfonyl chloride-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-ethyl ester was prepared as follows:

[0062] Under nitrogen atmosphere, tetrahydrofuran (100 mL) and triethylamine (39.46 g, 390 mmol) were added to the above oily liquid, and the temperature was lowered to 5±5°C. Methanesulfonyl chloride (44.67 g, 390 mmol) was added dropwise to the system. After the addition was completed, the temperature was controlled at 5±5°C and stirred for 1 hour. The temperature was raised to 25±5°C and stirred for 16 hours. The solid in the system was filtered, the mother liquor was collected, and concentrated to obtain an oily liquid.

[0063] 1-Cyclopropylpiperazine dihydrochloride was prepared as follows:

[0064] Under nitrogen atmosphere, tetrahydrofuran (100 mL) and cyclopropylamine (11.13 g, 195 mmol) were added to the above oily liquid, and the temperature was raised to 45±5° C. and stirred for 16 hours. The system was concentrated to obtain a brown oily liquid, isopropanol (50 mL) was added, and a hydrogen chloride isopropanol solution (4-5 mol / L, 25 mL) was added dropwise, and stirred for 5 hours. The solid in the system was filtered, and the filter cake was rinsed twice with isopropanol (10 mL). After drying, 1-cyclopropylpiperazine dihydrochloride (11.57 g) was obtained, and the three-step yield was 30%.

[0065] 1-Cyclopropylpiperazine was prepared as follows:

[0066] 1-Cyclopropylpiperazine dihydrochloride (5.0 g, 25.4 mmol) was dissolved in water (15.00 mL) and methanol (15.00 mL) and converted into its free base by ion exchange chromatography using an SCX column. The desired product was eluted from the column using a 3.5 mol / L ammonia / methanol solution, and each pure fraction was evaporated to dryness to give 2.63 g of 1-cyclopropylpiperazine as an oil, with a yield of 82% and a four-step yield of 25%.

[0067] Comparative Example 5:

[0068] Reference CN101605767A

[0069]

[0070] 1-Cyclopropylpiperazine was prepared as follows:

[0071] Under nitrogen atmosphere, diethanolamine (10.0 g, 97.66 mmol) was added to the reaction kettle, sulfuric acid (20 mL) was added, the mixture was stirred and heated to 180 ± 5 ° C, stirred for 6 hours, cooled to 25 ± 5 ° C, water (50 mL) and cyclopropylamine (20 mL) were added, the mixture was stirred and heated to 50 ± 5 ° C, stirred for 16 hours, cooled to 25 ± 5 ° C, and converted into its free base by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 3.5 mol / L ammonia / methanol, and each pure fraction was evaporated to dryness to obtain 3.17 g of 1-cyclopropylpiperazine in an oily state, with a two-step yield of 32.49%.

Claims

1. A method for preparing 1-cyclopropylpiperazine, comprising the following steps: Compound II and / or its salt is reacted with cyclopropylamine to obtain 1-cyclopropylpiperazine. The synthesis route is as follows: Wherein X is Cl, Br, I, and X may be the same or different, for example, X is both Cl and Br, or one X is Cl and the other is Br.

2. A method for preparing 1-cyclopropylpiperazine, comprising the following steps: Bis(2-chloroethyl)amine hydrochloride is reacted with cyclopropylamine to obtain 1-cyclopropylpiperazine. The synthetic route is as follows:

3. The method according to claim 1 or 2, characterized in that: The preparation method of the compound I satisfies one or more of the following conditions: In step (1), the molar feed ratio of the compound II or compound II-1 to cyclopropylamine is 1:2 to 6, for example, 1:2 to 3; In step (2), the reaction temperature is 40 to 60° C., for example, 45 to 50° C.; (3) The reaction time is 1 to 5 hours, for example 1 to 2 hours.

4. The method according to claim 1 or 2, characterized in that: The compound II or compound II-1 is added in a manner of dissolving in solvent A and then dropwise added to cyclopropylamine, or the compound II is dissolved in solvent A and cyclopropylamine and then dropwise added to solvent B at the same time for reaction.

5. The method according to claim 4, characterized in that: The solvent A or solvent B can be independently selected from alcohol solvents, and the alcohol solvent can be selected from ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol or any combination thereof, such as methanol or ethanol.

6. The method according to claim 1 or 2, characterized in that: After the reaction is completed, a base is added and the mixture is distilled under reduced pressure to obtain a high-purity product, 1-cyclopropylpiperazine.

7. The method according to claim 6, characterized in that: The temperature of the reduced pressure distillation is 70-90°C, for example 70-80°C or 80-90°C.

8. The method according to claim 6, characterized in that: The molar ratio of the base to compound II is 2 to 5:1, for example 2 to 4:1, for example 2:1, 3:1, 4:

1.

9. The method according to claim 6, characterized in that: The base is selected from an inorganic base or an organic base, preferably an organic base.

10. The method according to claim 6, characterized in that: The organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or a metal alkoxide M(OR)n, M is selected from any one of an alkali metal or an alkaline earth metal, preferably, the alkali metal is sodium, potassium or lithium, the alkaline earth metal is magnesium, R is selected from an alkyl group having 1 to 5 carbon atoms, and n is 1 or 2; further, the metal alkoxide M(OR)n is selected from sodium methoxide, potassium methoxide, Lithium ethoxide, sodium ethoxide, magnesium methoxide, magnesium ethoxide, magnesium n-propoxide, sodium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide, magnesium isobutoxide or magnesium tert-amyl oxide; preferably, the metal alkoxide M(OR)n is selected from sodium methoxide, sodium ethoxide, magnesium ethoxide, magnesium n-propoxide, magnesium tert-butoxide or magnesium isobutoxide; more preferably, the metal alkoxide M(OR)n is sodium methoxide, sodium ethoxide or magnesium tert-butoxide, and further, the sodium alkoxide can be added as a solid or a solution of sodium alkoxide alcohol, such as a 30% mass fraction of sodium methoxide methanol solution.

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