Method for synthesizing (R)-1, 3-dimethyl piperazine-2-ketone

Abstract

The invention provides a method for synthesizing (R)-1, 3-dimethyl piperazine-2-ketone, which is characterized by comprising the following steps: S1, taking 2-methylaminoethanol as a raw material, and protecting amino through amidation reaction to obtain an intermediate 2; s2, the intermediate 2 is subjected to an oxidation reaction, hydroxyl is hydroformylated, and an intermediate 3 is obtained; s3, the intermediate 3 is subjected to an aldehyde amine condensation reaction, and an intermediate 4 with side chain methyl is obtained; and S4, carrying out ring-closure reaction on the intermediate 4 to obtain a target product. By changing the synthetic route, optimizing the reaction conditions and selecting proper catalyst and reagent, the product yield of (R)-1, 3-dimethyl piperazine-2-ketone is obviously improved, and the economic benefit is improved.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular, to a method for synthesizing (R)-1,3-dimethylpiperazin-2-one. Background Art

[0006] Existing Process Route 1

[0007]

[0008] In this synthesis process, benzyl chloroformate and 2,2-dimethoxy-N-methylethylamine are chemically active and not easy to store. Especially, 2,2-dimethoxy-N-methylethylamine is expensive and can cause strong irritation to the eyes. Therefore, strict protection must be taken during operation, and relevant protective equipment should be worn. In the cyclization reaction of the acetal intermediate, under the action of anhydrous strong acid p-toluenesulfonic acid, part of the acetal group is converted into an aldehyde group and then reacts with substituted (2R)-2-(benzyloxycarbonylamino)propanoic acid. Since the amino group in the molecular structure is relatively stable and inactive chemically, in order to make it react, it needs to be heated to 80 °C in toluene solution and maintained for a long time. This process helps to overcome the chemical inertness of the amino group and promote the smooth progress of the reaction. During this process, the α-H of the aldehyde group is prone to aldol condensation side reaction under the reaction conditions, resulting in a low yield of this step, only 71%.

[0009] Existing Process Route 2

[0010]

[0011] In this process, first, D-alanine (1) is used as the starting material, and the amino group is protected with di-tert-butyl dicarbonate in sodium hydroxide solution to obtain N-BOC-D-alanine (2). Then, it is condensed with 2-methylaminoethanol under CDI to obtain compound (3). Then, it undergoes a Mitsunobu reaction to form a ring to obtain compound (4). Then, it is deprotected under acidic conditions, and (3R)-1,3-dimethylpiperazin-2-one (5) is obtained with a total yield of 59.4% through four steps. This synthesis route is simple to operate, has a high yield, and avoids the problem of racemization under alkaline conditions. Although the Mitsunobu reaction in the synthesis route of compound (4) has mild conditions, basically occurring under neutral conditions and with a fast reaction rate, its yield is at an intermediate level, and two warnings of the Mitsunobu reaction need to be solved: difficult purification and poor atom economy. Summary of the Invention

[0012] The present invention aims to overcome the above defects and develop a simple, efficient, and environmentally friendly method for synthesizing (R)-1,3-dimethylpiperazin-2-one.

[0013] The present invention provides a method for synthesizing (R)-1,3-dimethylpiperazin-2-one, which is characterized by comprising the following steps:

[0014] S1. Using 2-methylaminoethanol as a raw material, protecting the amino group through an amidation reaction to obtain intermediate 2;

[0015] S2. Intermediate 2 undergoes an oxidation reaction to aldehydeylate the hydroxyl group to obtain intermediate 3;

[0016] S3. Intermediate 3 undergoes an aldehyde-amine condensation reaction to obtain intermediate 4 with a side-chain methyl group;

[0017] S4. Intermediate 4 undergoes a ring-closure reaction to obtain the target product.

[0018] Furthermore, the method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0019] The above intermediate 2 can be a compound represented by the following structure:

[0020]

[0021] R1 is selected from alkyl, alkoxy, benzyl, phenyl.

[0022] Furthermore, the method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0023] The intermediate 3 is a compound represented by the following structure:

[0024]

[0025] R1 is selected from alkyl, alkoxy, benzyl, phenyl.

[0026] Furthermore, the method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0027] The intermediate 4 is a compound represented by the following structure:

[0028]

[0029] R1 and R2 are selected from groups that are easy to leave.

[0030] Furthermore, the method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0031] R1 is selected from alkyl, alkoxy, benzyl, phenyl;

[0032] R2 is selected from alkyl, alkoxy, benzyl, phenyl, and ester groups.

[0033] Furthermore, a method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0034] The intermediate 2 is a compound shown as follows:

[0035]

[0036] Furthermore, a method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0037] The intermediate 3 is a compound shown as follows:

[0038]

[0039] Furthermore, a method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0040] The intermediate 4 is a compound shown as the following structure:

[0041]

[0042] Furthermore, a method for synthesizing (R)-1,3-dimethylpiperazin-2-one provided by the present invention is further characterized in that:

[0043] The intermediate 2 is obtained by slowly dropping a solution of di-tert-butyl dicarbonate into methylaminoethanol at 10 - 30°C, reacting for 1 - 3 hours, and then washing with water, extracting, drying, and rotary evaporation;

[0044] For the intermediate 3, sodium acetate, 2,2,6,6-tetramethylpiperidine 1-oxide, and trichloroisocyanuric acid are added to the intermediate 2. After addition, the mixture is stirred at 0 - 10°C for 10 - 30 minutes. The reaction solution is filtered, washed, dried, and rotary evaporated to obtain the intermediate 3;

[0045] For the intermediate 4, (D)-methyl 2-aminopropionate hydrochloride and triethylamine are mixed, and then the intermediate 3 is added dropwise. At 0 - 10°C, sodium borohydride is added in batches, and the temperature is slowly raised to room temperature and stirred for 4 - 6 hours. The reaction solution is rotary evaporated, extracted, washed, dried, and rotary evaporated to obtain the intermediate 4;

[0046] Target product: A solution of hydrogen chloride in alcohol was slowly added dropwise to Intermediate 4 at 5 - 10°C. After the temperature rose to 40 - 50°C and the reaction was kept at this temperature for 1 - 2 hours, it was added dropwise to a solution of sodium carbonate in alcohol. At 45 - 55°C, the reaction was continued to be kept at this temperature for 1 - 2 hours. After the reaction solution was filtered and rotary evaporated, alcohol was added again, and it was stirred at 40 - 50°C for 1 - 2 hours. After filtration and rotary evaporation, the target product was obtained.

[0047] Functions and effects of the present invention:

[0048] 1. Yield improvement: By changing the synthesis route, optimizing the reaction conditions, and selecting appropriate catalysts and reagents, the product yield of (R)-1,3-dimethylpiperazin-2-one was significantly increased (the total yield was increased to 75.4%, an increase of 16%), improving the economic benefits.

[0049] 2. Environmental pollution reduction: Using green and environmentally friendly reagents and solvents, avoiding the generation of toxic by-products, and reducing the difficulty of waste treatment, meeting the requirements of green chemistry.

[0050] 3. Industrial feasibility improvement: By adjusting the reaction conditions and raw material selection, this method can be efficiently implemented both in the laboratory and in large-scale industrial production, having good industrial application prospects. Description of the Drawings

[0051] Figure 1 , 1H NMR spectrum of the product;

[0052] Figure 2 , 13C NMR spectrum of the product;

[0053] Figure 3 , Mass spectrum of the product;

[0054] Figure 4 , GC results of the product; Detailed Embodiments

[0055] The present invention can be subject to various changes and can have various embodiments. Therefore, specific embodiments are illustrated in the drawings and described herein. However, this is not to limit the present invention to specific embodiments, but should be understood to include all changes, equivalents, and alternatives falling within the spirit and technical scope of the present invention.

[0056] This embodiment provides a method for synthesizing (R)-1,3-dimethylpiperazin-2-one, comprising the following steps: S1. Using 2-(methylamino)ethanol as a raw material, protecting the amino group through an amidation reaction to obtain Intermediate 2; S2. Intermediate 2 undergoes an oxidation reaction to aldehydeylate the hydroxyl group to obtain Intermediate 3; S3. Intermediate 3 undergoes an aldol condensation reaction to obtain Intermediate 4 with a side-chain methyl group; S4. Intermediate 4 undergoes a ring-closure reaction to obtain the target product. Among them, Intermediate 2 is a compound with the following structure:

[0057] R1 is selected from alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl, etc.), alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, etc.), benzyl, and phenyl.

[0058] Intermediate 3 is a compound with the following structure:

[0059] R1 is selected from alkyl groups (such as methyl, ethyl, isopropyl ((CH3)2CH-), tert-butyl ((CH3)3C-), etc.), alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy ((CH3)2CH-O-), tert-butoxy ((CH3)3C-O-), phenoxy (Ph-O-), benzyloxy (PhCH2-O-), etc.), benzyl (PhCH2-), and phenyl (Ph-).

[0060] Intermediate 4 is a compound with the following structure:

[0061] R1 is selected from alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl, etc.), alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, etc.), benzyl, and phenyl. R2 is selected from alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl, etc.), alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, etc.), benzyl, phenyl, ester groups (such as ethyl formate -C(O)-O-C2H5, methyl formate -C(O)-O-Me, ethyl acetate -CH2-C(O)-O-C2H5, methyl propionate -C2H5-C(O)-O-C2H5, methyl isopropionate -CH(CH3)-C(O)-O-C2H5, etc.).

[0062] Its synthesis process can refer to the method of the following preferred route, and only the raw materials need to be adjusted.

[0063] The preferred route is as follows:

[0064]

[0065] S1. Methylethanolamine, after slowly dropping a solution of di-tert-butyl dicarbonate at 10 - 30 °C, react for 1 - 3 hours, and then obtain Intermediate 2 through washing with water, extraction, drying, and rotary evaporation; the mass ratio of 2-methylethanolamine to di-tert-butyl dicarbonate is 1:3 - 4;

[0066] S2. Add sodium acetate, 2,2,6,6 - tetramethylpiperidine 1 - oxide and trichloroisocyanuric acid to Intermediate 2. After the addition, stir at 0 - 10 °C for 10 - 30 minutes. The reaction solution is filtered, washed, dried, and concentrated by rotary evaporation to obtain Intermediate 3. The mass ratio of Intermediate 2 to sodium acetate, 2,2,6,6 - tetramethylpiperidine 1 - oxide and trichloroisocyanuric acid is 1:0.3 - 0.6:0.0001 - 0.01:0.2 - 0.6;

[0067] S3. Mix (D) - methyl 2 - aminopropionate hydrochloride with triethylamine, then dropwise add Intermediate 3. At 0 - 10 °C, add sodium borohydride in batches. Slowly raise the temperature to room temperature and stir for 4 - 6 hours. The reaction solution is concentrated by rotary evaporation, extracted, washed, dried, and concentrated by rotary evaporation again to obtain Intermediate 4. The mass ratio of Intermediate 3 to (D) - methyl 2 - aminopropionate hydrochloride and triethylamine is 1:0.6 - 1:0.6 - 1;

[0068] S4. Slowly dropwise add an alcoholic solution of hydrogen chloride to Intermediate 4 at 5 - 10 °C. Raise the temperature to 40 - 50 °C and keep the temperature for 1 - 2 hours. Then drop it into an alcoholic solution of sodium carbonate and continue to keep the temperature at 45 - 55 °C for 1 - 2 hours. The reaction solution is filtered and concentrated by rotary evaporation, then add alcohol and stir at 40 - 50 °C for 1 - 2 hours, and then filter and concentrate by rotary evaporation to obtain the target product. The molar ratio of Intermediate 4 to hydrogen chloride and sodium carbonate is 1:0.1 - 0.5:1 - 5.

[0069] The best test examples are as follows:

[0070] S1. Dissolve 20 g of 2 - (methylamino)ethanol in 100 ml of dichloromethane, and slowly dropwise add 64.1 g of di - tert - butyl dicarbonate solution at 20 °C. After the addition, slowly raise the temperature of the reaction solution to room temperature and stir at room temperature for 3 hours. Then wash with 10 ml of water, separate the phases, wash the organic phase with 10 ml of saturated brine, separate the phases, dry with anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain 45.8 g (98.3%) of a colorless transparent liquid, Intermediate 2 (N - tert - butoxycarbonyl - methylaminoethanol).

[0071] S2. Dissolve 45.8 g of Intermediate 2 in 90 ml of dichloromethane, then successively add 19.2 g of sodium acetate and 0.14 g of 2,2,6,6 - tetramethylpiperidine 1 - oxide. Add 18.2 g of trichloroisocyanuric acid in batches at 10 °C. After the addition, stir at 10 °C for 30 minutes. Filter the reaction solution, wash the filtrate with 20 ml of saturated brine, dry with anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain 43.4 g (95.7%) of a colorless transparent liquid, Intermediate 3 (N - tert - butoxycarbonyl - methylaminoacetaldehyde).

[0072] S3. Dissolve 35 g of (D)-methyl 2-aminopropionate hydrochloride in 350 ml of methanol, then slowly add dropwise 35.4 g of triethylamine solution. After adding dropwise, then add dropwise 43.4 g of Intermediate 3. Then, at 10 °C, add 14.2 g of sodium borohydride in batches, slowly raise the temperature to room temperature and stir for 6 hours. Rotavaporize the reaction solution, add 35 ml of water and 35 ml of ethyl acetate, stir, separate the phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and then rotavaporize to obtain 56.6 g (86.8%) of Intermediate 4.

[0073] S4. Dissolve 56.6 g of Intermediate 4 in 120 ml of methanol, and slowly add dropwise 90 ml of hydrogen chloride methanol solution (3 M) at 5 - 10 °C. Raise the temperature to 50 °C and hold the reaction for 2 hours. Take another reaction flask, add 120 g of sodium carbonate and 240 ml of methanol, add dropwise the above reaction solution, then raise the temperature to 55 °C and hold the reaction for 2 hours. Filter the reaction solution, rotavaporize, then add 50 ml of ethanol, stir at 50 °C for 1 hour, filter, and rotavaporize to obtain 25.7 g (92.3%) of the final product, Intermediate 5.

[0074] In the oxidative aldolization reaction of S2 in the present invention, according to the results of comparative experiments, when using sodium hypochlorite for oxidation, 8 times water + 8 times dichloromethane need to be added. Once the solvent amount is reduced, the reaction effect will be affected. Moreover, if sodium hypochlorite is slightly in excess, the aldehyde will be further oxidized to form acid, which leads to uncontrollable problems in the industrial scale-up production process.

[0075] In addition, in the oxidative aldolization reaction of S2 in the present invention, the aldolization reactions under heating conditions and in the presence of copper or silver as catalysts were also compared. The results showed that a large number of side reactions occurred, resulting in a significant decrease in the yield, only 1 / 5 - 1 / 4 of the optimal scheme.

[0076] Therefore, through comparison, trichloroisocyanuric acid is used for the oxidation reaction, which greatly reduces the solvent usage amount. Moreover, the isocyanuric acid generated by the reaction can be recycled, reducing waste generation, having environmental friendliness, conforming to green chemistry, and being more suitable for industrial production.

[0077] In the reductive amination reaction of S3 in the present invention, according to the results of comparative experiments, when using sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride, the imine can be reduced to amine. However, due to toxicity problems, the handling and waste management of sodium cyanoborohydride are relatively complex. And sodium triacetoxyborohydride has a low atom economy due to the presence of acetyl groups. Therefore, although these two reducing agents also have high selectivity in such reactions, they are not suitable for large-scale industrial production. Thus, in the present invention, sodium borohydride is preferably used as the reducing agent for imine reduction.

[0078] In the closed-loop reaction of S4 in the present invention, a deprotection process is also involved. According to the results of comparative experiments, when trifluoroacetic acid (TFA) is used as the deprotection reagent, although the protection can be removed well, it has an impact on some sensitive chemical groups, resulting in more impurities in the obtained compound, affecting the product yield (the yield is only 1 / 2 - 1 / 3 of the optimal scheme) and subsequent reactions (due to excessive impurities, the subsequent reactions are chaotic and by-products are numerous). Hydrochloric acid has mild reaction conditions, simple operation, low cost and good selectivity, so hydrochloric acid is selected as the deprotection reagent in the present invention.

[0079] Although the above has been described centered around the embodiments, this is only an illustration and does not limit the present invention. Those of ordinary skill in the art understand that various deformations and applications not illustrated above can be carried out without departing from the essential characteristics of this embodiment. For example, each component specifically shown in the embodiment can be implemented after being deformed. Moreover, various differences related to such deformations and applications should be interpreted as being included in the scope of the present invention defined in the appended claims.

Claims

1. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one, characterized in that: The following steps are included: S1. Using 2-methylaminoethanol as a raw material, the amino group is protected by amidation reaction to obtain intermediate 2; S2. Intermediate 2 is subjected to an oxidation reaction to hydroformylate the hydroxyl group to obtain intermediate 3; S3. Intermediate 3 is subjected to an aldehyde-amine condensation reaction to obtain intermediate 4 with a side chain methyl group; S4. Intermediate 4, the target product is obtained through ring closure reaction.

2. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 2 is a compound shown in the following structure: R1 is selected from alkyl, alkoxy, benzyl, and phenyl.

3. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 3 is a compound shown in the following structure: R1 is selected from alkyl, alkoxy, benzyl, and phenyl.

4. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 4 is a compound shown in the following structure: R1 and R2 are selected from groups that are easy to leave.

5. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 4, characterized in that: R1 is selected from alkyl, alkoxy, benzyl, phenyl; R2 is selected from alkyl, alkoxy, benzyl, phenyl, and ester groups.

6. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 2 is the compound shown in the following results:

7. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 3 is the compound shown in the following results:

8. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in claim 1, characterized in that: The intermediate 4 is a compound shown in the following structure:

9. A method for synthesizing (R)-1,3-dimethylpiperazine-2-one as claimed in any one of claims 6 to 8, characterized in that: The intermediate 2 is prepared by slowly dropping a di-tert-butyl dicarbonate solution into 2-methylaminoethanol at 10-30° C., reacting for 1-3 hours, and then washing, extracting, drying, and spin drying to obtain the intermediate 2; The intermediate 3 is prepared by adding sodium acetate, 2,2,6,6-tetramethylpiperidinoxide and trichloroisocyanuric acid to the intermediate 2. After the addition, the mixture is stirred at 0-10° C. for 10-30 minutes. The reaction solution is filtered, washed, dried and spin-dried to obtain the intermediate 3. The intermediate 4 is prepared by mixing (D)-2-aminopropionic acid methyl ester hydrochloride with triethylamine, adding intermediate 3 dropwise, adding sodium borohydride in batches at 0-10° C., slowly heating to room temperature and stirring for 4-6 hours, and the reaction solution is spin-dried, extracted, washed, dried, and spin-dried to obtain intermediate 4; To obtain the target product, slowly add an alcohol solution of hydrogen chloride to the intermediate 4 at 5-10°C, raise the temperature to 40-50°C, and keep the reaction for 1-2 hours. Then, add it dropwise to an alcohol solution of sodium carbonate, keep the reaction at 45-55°C for 1-2 hours. After filtering and drying the reaction solution, add alcohol, stir at 40-50°C for 1-2 hours, filter, and dry to obtain the target product.

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