Preparation method of 1-tert-butyl carbamate piperazine

Abstract

The present invention provides a method for preparing 1-tert-butyl carbamate piperazine, belongs to the technical field of compound preparation, and the preparation method comprises the following steps: step S1, reacting N-Boc-O-toluenesulfonylhydroxylamine with Boc-piperazine to obtain 4-tert-butyl carbamate-Boc-piperazine; step S2, removing a Boc protecting group from the 4-tert-butyl carbamate-Boc-piperazine under the action of a deprotecting agent to obtain 1-tert-butyl carbamate piperazine. According to the preparation method of an embodiment of the present invention, cheaper Boc-piperazine is selected to introduce a piperazine ring, and the operation of subsequent reduction and hydrogenation is avoided, which not only reduces the production cost, but also improves the reaction safety factor.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and in particular to a method for preparing 1-tert-butyl carbamate piperazine. Background Art

[0002] Piperazine is a multifunctional core structure, and the two opposing nitrogen atoms in the piperazine ring have a large polar surface area, relative structural rigidity, and more hydrogen bond acceptors and donors. These properties usually lead to higher water solubility, oral bioavailability and ADME properties, as well as higher target affinity and specificity.

[0003] Piperazine can form different types of mono- or di-substituted derivatives at the nitrogen site, so piperazine derivatives can be easily modified to obtain the desired pharmacological activity, and its diverse derivatives have opened up a broad space for the development of innovative bioactive molecules for a variety of diseases. Currently, a series of piperazine derivatives have been widely used in the fields of anti-depression, anti-cancer, anti-bacterial, and anti-inflammatory.

[0004] N-aminopiperazine derivatives are a class of modifying groups and connecting bridges used in the development of drug molecules. They show good biological activity and low cytotoxicity in the fields of anti-tuberculosis drugs and anthelmintics. 1-tert-butyl carbamate piperazine is one of the basic structures. Currently, only one literature has reported the synthesis method (the synthesis route is shown in the following formula (1)). N-Boc-O-p-toluenesulfonylhydroxylamine is used as the raw material, reacted with Cbz-piperazine, and then palladium carbon reduction hydrogenation was performed to obtain the target product (Arch. Pharm. 2023, 356, e2200491);

[0005]

[0006] However, this method uses palladium-carbon hydrogenation to remove the Cbz protecting group, which is highly risky. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a method for preparing 1-tert-butyl carbamate piperazine, which has mild reaction conditions, simple operation, and strong feasibility and safety of the route.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] The preparation method of 1-tert-butyl carbamate piperazine according to an embodiment of the present invention comprises the following steps:

[0010] The preparation method of 1-tert-butyl carbamate piperazine is characterized in that it comprises the following steps:

[0011] Step S1, reacting N-Boc-O-p-toluenesulfonylhydroxylamine with Boc-piperazine to obtain tert-butyl 4-carbamate-Boc-piperazine;

[0012] Step S2, removing a Boc protecting group from the 4-tert-butyl carbamate-Boc-piperazine under the action of a deprotecting agent to obtain 1-tert-butyl carbamate piperazine.

[0013] Furthermore, the preparation method further comprises the following steps:

[0014] Step S01, reacting Boc-hydroxylamine and p-toluenesulfonyl chloride to obtain the N-Boc-O-p-toluenesulfonylhydroxylamine.

[0015] Furthermore, the reaction of step S01 is carried out in a first solvent under the action of a first base, wherein the first solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, tetrahydrofuran, and acetonitrile, and the first base is selected from any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA.

[0016] Furthermore, in the step S01, the molar ratio of Boc-hydroxylamine: p-toluenesulfonyl chloride: first base is 1:(1.0~1.5):(1.0~1.5); the reaction temperature is -5~40°C; and the reaction time is 2~8 h.

[0017] Furthermore, step S1 is carried out in a second solvent under the action of a second base, wherein the second solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, and tetrahydrofuran, and the second base is selected from any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA.

[0018] Furthermore, in the step S1, the molar ratio of N-Boc-O-toluenesulfonylhydroxylamine: Boc-piperazine: the second base is 1: (1.0-1.5): (1.0-1.5), the reaction temperature is -5-40°C, and the reaction time is 3-12 h.

[0019] Furthermore, in step S2, the deprotection reagent is selected from any one or more of zinc bromide, hydrochloric acid, trifluoroacetic acid, and magnesium perchlorate hexahydrate.

[0020] Furthermore, in the step S2, the molar ratio of 4-tert-butyl carbamate-Boc-piperazine: deprotection reagent is 1:(0.1-10.0), the reaction temperature is -10-40°C, and the reaction time is 1-12 h.

[0021] The above technical solution of the present invention has at least one of the following beneficial effects:

[0022] According to the preparation method of the embodiment of the present invention, cheaper Boc-piperazine is used to introduce the piperazine ring, thereby avoiding the subsequent reduction and hydrogenation operation, which not only reduces the production cost but also improves the reaction safety factor;

[0023] Furthermore, in the present application, N-Boc-O-toluenesulfonylhydroxylamine is obtained by reacting Boc-hydroxylamine and p-toluenesulfonyl chloride, thereby further reducing the production cost;

[0024] The method of the embodiment of the present invention has mild reaction conditions and is easy to operate. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0026] First, the preparation method of 1-tert-butyl carbamate piperazine according to an embodiment of the present invention is described in detail below.

[0027] The preparation method of 1-tert-butyl carbamate piperazine according to an embodiment of the present invention comprises the following steps:

[0028] Step S1, reacting N-Boc-O-p-toluenesulfonylhydroxylamine with Boc-piperazine to obtain tert-butyl 4-carbamate-Boc-piperazine;

[0029] Step S2, removing a Boc protecting group from the 4-tert-butyl carbamate-Boc-piperazine under the action of a deprotecting agent to obtain 1-tert-butyl carbamate piperazine.

[0030] According to the preparation method of the embodiment of the present invention, cheaper Boc-piperazine is used to introduce the piperazine ring, thereby avoiding the subsequent reduction and hydrogenation operation, which not only reduces the production cost but also improves the reaction safety factor.

[0031] Wherein, N-Boc-O-toluenesulfonylhydroxylamine can be directly used as a commercial product, or can be prepared by the following method, that is, the preparation method according to the embodiment of the present invention can also include the following steps:

[0032] Step S01, reacting Boc-hydroxylamine and p-toluenesulfonyl chloride to obtain the N-Boc-O-p-toluenesulfonylhydroxylamine.

[0033] By adopting Boc-hydroxylamine and p-toluenesulfonyl chloride to react to obtain N-Boc-O-p-toluenesulfonylhydroxylamine, the production cost is further reduced.

[0034] The following is a description of the homemade N-Boc-O-toluenesulfonylhydroxylamine as an example, but the preparation method of the present invention is not limited thereto.

[0035] (I) Preparation of N-Boc-O-p-toluenesulfonylhydroxylamine (I)

[0036] According to an embodiment of the present application, Boc-hydroxylamine and p-toluenesulfonyl chloride are reacted to obtain the N-Boc-O-p-toluenesulfonylhydroxylamine (I).

[0037] Specifically, the reaction formula is shown in the following formula (2):

[0038]

[0039] In one embodiment of the present invention, the above reaction is carried out in a first solvent under the action of a first base.

[0040] Wherein, the first solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, tetrahydrofuran, and acetonitrile. Among them, tetrahydrofuran is preferred, which can not only dissolve each reaction reagent better, but also has simple post-processing, high safety, and can be recycled after processing.

[0041] The first base is selected from any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA. The first base can act as an acid binding agent to absorb the hydrogen chloride produced by the reaction, which is conducive to promoting the above reaction. Among them, triethylamine is preferred, and triethylamine and its salts are soluble in water and can be removed by washing with water.

[0042] In some embodiments of the present invention, the molar ratio of Boc-hydroxylamine: p-toluenesulfonyl chloride: first base is 1: (1.0-1.5): (1.0-1.5). A slight excess of the first base can completely absorb the hydrogen chloride produced by the reaction, thereby promoting the reaction to proceed in the forward direction. Preferably, the molar ratio of Boc-hydroxylamine: p-toluenesulfonyl chloride: base is 1: 1.05: 1.2.

[0043] The reaction temperature is -5~40℃; the reaction time is 2~8 h. The reaction conditions are mild and easy to control. The reaction temperature is preferably 0~5℃, at which a higher yield can be obtained. The reaction time is preferably 3 h. If the reaction time is too long, the effect of improving the yield is limited, and if it is too short, the reaction cannot be completed.

[0044] Preferably, after the reaction is completed, the following steps are further performed: extracting and separating the liquids, drying, and evaporating the solvent. That is, after the reaction is completed, N-Boc-O-toluenesulfonylhydroxylamine can be obtained by simple solid-liquid separation treatment for use in the next reaction.

[0045] (II) Preparation of tert-butyl 4-carbamate-Boc-piperazine (II)

[0046] In the present invention, N-Boc-O-p-toluenesulfonylhydroxylamine (I) is reacted with Boc-piperazine under the action of a second base to obtain 4-tert-butylcarbamate-Boc-piperazine (II).

[0047] According to the preparation method of the embodiment of the present invention, Boc-piperazine is selected to introduce the piperazine ring, which is cheaper than Cbz-piperazine, and the removal of the Boc protecting group avoids the operation of using Pd / C reduction hydrogenation, and the reaction is safer.

[0048] Specifically, the reaction formula is shown in the following formula (3):

[0049]

[0050] In some embodiments of the present invention, the reaction is carried out in a second solvent under the action of a second base. Wherein, the second solvent is selected from any one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, and tetrahydrofuran. Among them, dichloromethane is preferred, which has high solubility and is poorly soluble in water, simplifying post-processing operations.

[0051] The second base is selected from any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA. Including any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA. Among them, triethylamine is preferred, and triethylamine and its salts are soluble in water and can be removed by washing with water.

[0052] In some embodiments of the present invention, the molar ratio of N-Boc-O-toluenesulfonylhydroxylamine: Boc-piperazine: the second base is 1: (1.0~1.5): (1.0~1.5); preferably, the molar ratio of N-Boc-O-toluenesulfonylhydroxylamine: Boc-piperazine: base is 1:1.05:1.2.

[0053] The reaction temperature of this step is -5~40°C, preferably 25°C; the reaction time is 3~12 h, preferably 8 h.

[0054] Preferably, after the reaction is completed, the following steps may be further performed: extracting and separating the liquids, drying, and evaporating the solvent. That is, after the reaction is completed, 4-tert-butyl carbamate-Boc-piperazine can be obtained by simple solid-liquid separation for the next reaction.

[0055] (III) Preparation of tert-butyl 1-carbamate piperazine (III)

[0056] 4-tert-butyl carbamate-Boc-piperazine (II) selectively removes a Boc protecting group under the action of a deprotecting agent to obtain 1-tert-butyl carbamate-piperazine (III).

[0057] That is, after obtaining the intermediate 4-tert-butyl carbamate-Boc-piperazine (II), it is necessary to selectively remove a Boc protecting group under the action of a deprotecting agent to obtain the target product 1-tert-butyl carbamate-piperazine (III).

[0058] Specifically, the reaction formula is shown in the following formula (4):

[0059]

[0060] The deprotection reaction can be carried out in a third solvent, and the third solvent can be selected from any one or more of dichloromethane, tetrahydrofuran, methanol, acetonitrile, and dioxane, wherein acetonitrile is preferred.

[0061] The deprotection reagent includes any one or more of zinc bromide, hydrochloric acid, trifluoroacetic acid, and magnesium perchlorate hexahydrate. Among them, zinc bromide is preferred, which has mild reaction conditions and good selectivity and can selectively remove the Boc protecting group of the secondary amine in the presence of the Boc protected primary amine.

[0062] In some embodiments of the present invention, the molar ratio of tert-butyl 4-carbamate-Boc-piperazine: deprotection agent is 1:(0.1-10.0); preferably, the molar ratio of tert-butyl 4-carbamate-Boc-piperazine: deprotection agent is 1:2.0.

[0063] The reaction temperature of this step is -10~40°C, preferably 10~15°C; the reaction time is 1~12 h, preferably 4 h.

[0064] In addition, as post-treatment steps, after the reaction is completed, the following steps may also be included: filtration, concentration, extraction and separation, drying, and evaporation.

[0065] It can be seen from the above description that the present invention can provide a simple and effective preparation method of 1-tert-butyl carbamate piperazine. In addition, the reaction conditions in the preparation method of the present invention are mild, the operation is simple, and the feasibility and safety of the route are stronger.

[0066] The preparation method of 1-tert-butyl carbamate piperazine according to the present invention is further described below in conjunction with specific examples.

[0067] It should be noted here that in the following embodiments, steps (1), (2) and (3) are independent of each other, that is, different steps in different embodiments can be combined with each other without restriction. For example, (1) in Embodiment 1 can be combined with (2) and (3) in Embodiment 2 to form a new embodiment, or (1) in Embodiment 1, (3) in Embodiment 2, and (2) in Embodiment 3 can be combined to form a new embodiment, and so on.

[0068] Example 1

[0069] (I) Preparation of N-Boc-O-p-toluenesulfonylhydroxylamine (I)

[0070] In a 500 mL round-bottom flask, add 150 mL tetrahydrofuran, 15 g Boc-hydroxylamine, and 13.68 g triethylamine, cool to 0-5°C, add dropwise 100 mL tetrahydrofuran solution containing 22.55 g p-toluenesulfonyl chloride, and keep warm for 3 h.

[0071] Post-treatment: concentrate under reduced pressure to remove the solvent, add 120 mL of dichloromethane for extraction, wash twice with 60 mL of water, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 30.94 g of N-Boc-O-toluenesulfonylhydroxylamine with a yield of 95.6%.

[0072] (II) Preparation of tert-butyl 4-carbamate-Boc-piperazine (II)

[0073] In a 250 mL round-bottom flask, add 150 mL of dichloromethane, and then add 15 g of N-Boc-O-toluenesulfonylhydroxylamine, 6.34 g of triethylamine and 10.21 g of Boc-piperazine, and react at room temperature (25°C) for 8 h.

[0074] Post-treatment: add 80 mL of clean water to wash twice, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 12.95 g of 4-tert-butyl carbamate-Boc-piperazine with a yield of 82.3%.

[0075] (III) Preparation of tert-butyl 1-carbamate piperazine (III)

[0076] In a 250 mL round-bottom flask, add 150 mL acetonitrile and 15 g 4-tert-butyl carbamate-Boc-piperazine, cool to 10-15°C, add 22.42 g zinc bromide, and keep warm for 4 h.

[0077] Post-treatment: filtration, concentration of the filtrate, then addition of 80 mL of ethyl acetate, washing with 50 mL of sodium carbonate aqueous solution, and then washing with 50 mL of water, drying over anhydrous sodium sulfate, and evaporation to dryness to obtain 8.68 g of 1-tert-butyl carbamate piperazine, with a yield of 86.7%.

[0078] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows:

[0079] 1 H NMR (400 MHz, DMSO- d 6) δ 7.92(br, 1H), 2.70-2.63 (m, 4H), 2.60-2.56(m, 4H), 1.88(br, 1H), 1.40(s, 9H).

[0080] The test results were consistent with the structure of 1-tert-butyl piperazine carbamate.

[0081] The yield was calculated based on the theoretical value of the obtained product 1-tert-butyl carbamate piperazine (8.68 g). Example 2

[0082] (I) Preparation of N-Boc-O-p-toluenesulfonylhydroxylamine (I)

[0083] In a 500 mL round-bottom flask, add 150 mL tetrahydrofuran, 15 g Boc-hydroxylamine, and 13.68 g triethylamine, cool to 0-5°C, add dropwise 100 mL tetrahydrofuran solution containing 22.55 g p-toluenesulfonyl chloride, and warm to room temperature for reaction for 3 h.

[0084] Post-treatment: concentrate under reduced pressure to remove the solvent, add 120 mL of dichloromethane for extraction, wash twice with 60 mL of water, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 29.55 g of N-Boc-O-toluenesulfonylhydroxylamine with a yield of 91.3%.

[0085] (II) Preparation of tert-butyl 4-carbamate-Boc-piperazine (II)

[0086] In a 250 mL round-bottom flask, add 150 mL of dichloromethane, and then add 15 g of N-Boc-O-toluenesulfonylhydroxylamine, 6.34 g of N-methylmorpholine and 10.21 g of Boc-piperazine, and react at room temperature (25°C) for 8 h.

[0087] Post-treatment: add 80 mL of clean water to wash twice, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 12.08 g of 4-tert-butyl carbamate-Boc-piperazine with a yield of 76.8%.

[0088] (III) Preparation of tert-butyl 1-carbamate piperazine (III)

[0089] In a 250 mL round-bottom flask, add 120 mL of dichloromethane and 15 g of 4-tert-butyl carbamate-Boc-piperazine, cool to 10-15°C, add 36.89 g of zinc bromide, and keep warm for 4 h.

[0090] Post-treatment: The reaction solution was concentrated, then 100 mL of dichloromethane was added, washed with 100 mL of sodium carbonate aqueous solution, and then washed with 50 mL of clean water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 8.03 g of 1-tert-butyl carbamate piperazine with a yield of 80.2%.

[0091] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure. The result was the same as in Example 1, and its detailed description is omitted here. Example 3

[0092] (I) Preparation of N-Boc-O-p-toluenesulfonylhydroxylamine (I)

[0093] In a 500 mL round-bottom flask, add 150 mL tetrahydrofuran, 15 g Boc-hydroxylamine, and 10.69 g pyridine, cool to 0-5°C, add dropwise 100 mL tetrahydrofuran solution containing 22.55 g p-toluenesulfonyl chloride, and keep warm for 3 h.

[0094] Post-treatment: concentrate under reduced pressure to remove the solvent, add 120 mL of dichloromethane for extraction, wash twice with 60 mL of water, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 29.97 g of N-Boc-O-toluenesulfonylhydroxylamine with a yield of 92.6%.

[0095] (II) Preparation of tert-butyl 4-carbamate-Boc-piperazine (II)

[0096] In a 250 mL round-bottom flask, add 150 mL of dichloromethane, and then add 15 g of N-Boc-O-toluenesulfonylhydroxylamine, 6.34 g of triethylamine and 10.21 g of Boc-piperazine, and react at room temperature (25°C) for 8 h.

[0097] Post-treatment: add 80 mL of clean water to wash twice, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 12.95 g of 4-tert-butyl carbamate-Boc-piperazine with a yield of 82.3%.

[0098] Regarding the preparation of the target product 1-tert-butyl carbamate piperazine (III), refer to Example 1. Example 4

[0099] (I) Preparation of N-Boc-O-p-toluenesulfonylhydroxylamine (I)

[0100] In a 500 mL round-bottom flask, add 100 mL of dichloromethane, 15 g of Boc-hydroxylamine, and 13.68 g of triethylamine, cool to 0-5°C, add dropwise 150 mL of dichloromethane solution containing 22.55 g of p-toluenesulfonyl chloride, and keep warm for 3 h.

[0101] Post-treatment: add 100 mL of clean water to wash twice, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 29.81 g of N-Boc-O-toluenesulfonylhydroxylamine with a yield of 92.1%.

[0102] (II) Preparation of tert-butyl 4-carbamate-Boc-piperazine (II)

[0103] In a 250 mL round-bottom flask, add 150 mL of dichloromethane, and then add 15 g of N-Boc-O-toluenesulfonylhydroxylamine, 6.34 g of triethylamine and 11.67 g of Boc-piperazine. Heat to 40 °C and react for 8 h.

[0104] Post-treatment: add 80 mL of clean water to wash twice, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain 12.37 g of 4-tert-butyl carbamate-Boc-piperazine with a yield of 78.6%.

[0105] Regarding the preparation of the target product 1-tert-butyl carbamate piperazine (III), refer to Example 1.

[0106] In summary, the method for preparing 1-tert-butyl carbamate piperazine of the present invention has the advantages of mild reaction conditions, simple operation and high safety.

[0107] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 1-tert-butyl carbamate piperazine, characterized in that: The steps include: Step S1, reacting N-Boc-O-toluenesulfonylhydroxylamine with Boc-piperazine to obtain 4-tert-butyl carbamate-Boc-piperazine, wherein step S1 is carried out in dichloromethane under the action of triethylamine or N-methylmorpholine; Step S2, removing a Boc protecting group from the 4-tert-butyl carbamate-Boc-piperazine in dichloromethane or acetonitrile under the action of a deprotecting agent to obtain 1-tert-butyl carbamate-piperazine, wherein the deprotecting agent is zinc bromide.

2. The preparation method according to claim 1, characterized in that: The following steps are also included: Step S01, reacting Boc-hydroxylamine and p-toluenesulfonyl chloride to obtain the N-Boc-O-p-toluenesulfonylhydroxylamine.

3. The preparation method according to claim 2, characterized in that: The reaction in step S01 is carried out in a first solvent under the action of a first base. Wherein, the first solvent is selected from any one or more of dichloromethane, methyl tert-butyl ether, tetrahydrofuran, and acetonitrile, The first base is selected from any one or more of triethylamine, pyridine, N-methylmorpholine, and DIEA.

4. The preparation method according to claim 3, characterized in that In the step S01, the molar ratio of Boc-hydroxylamine: p-toluenesulfonyl chloride: first base is 1:(1.0-1.5):(1.0-1.5); the reaction temperature is -5-40°C; and the reaction time is 2-8 h.

5. The preparation method according to claim 1, characterized in that In the step S1, the molar ratio of N-Boc-O-toluenesulfonylhydroxylamine: Boc-piperazine: triethylamine or N-methylmorpholine is 1: (1.0-1.5): (1.0-1.5), the reaction temperature is -5-40°C, and the reaction time is 3-12 h.

6. The preparation method according to claim 1, characterized in that The molar ratio of 4-tert-butyl carbamate-Boc-piperazine: deprotection reagent is 1:(0.1-10.0), the reaction temperature in step S2 is -10-40°C, and the reaction time is 1-12 h.

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