Preparation method of (2R, 5R)-1, 2, 5-trimethylpiperazine

Abstract

The invention relates to a preparation method of (2R, 5R)-1, 2, 5-trimethylpiperazine. The preparation method comprises the following steps: sequentially adding Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOBT and DMF (Dimethyl Formamide) into a reaction flask, stirring for dissolving, activating carboxylic acid, and dropwise adding N-methylmorpholine; after the reaction is finished, adding ethyl acetate to dilute a reaction system, adding 1M hydrochloric acid for washing, layering and reserving an organic phase, and adding a saturated sodium bicarbonate solution for washing, layering and reserving an organic phase; adding saturated salt water for washing, layering, leaving an organic phase, and concentrating the organic phase; adding formic acid; adding sec-butyl alcohol and methylbenzene to neutralize the alkalinity in the crude product; dissolving with methylbenzene, dropwise adding a red aluminum solution, neutralizing, washing, layering, concentrating an organic phase to obtain a crude product, and purifying the crude product to obtain a finished product. The preparation method has the advantages that BOC-N-methyl-D-alanine and D-alanine methyl ester hydrochloride are taken as initial raw materials, the (2R, 5R)-1, 2, 5-trimethylpiperazine is obtained through the steps of condensation, cyclization and reduction, and the chiral purity of the (2R, 5R)-1, 2, 5-trimethylpiperazine is improved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing (2R, 5R)-1,2,5-trimethylpiperazine. Background Art

[0002] (2R,5R)-1,2,5-trimethylpiperazine is an important pharmaceutical intermediate used for the synthesis of anti-tumor drugs. The difficulty in synthesizing (2R,5R)-1,2,5-trimethylpiperazine at present lies in the low chiral purity and the large number of isomers. The present invention provides a method for preparing (2R,5R)-1,2,5-trimethylpiperazine, which uses BOC-N-methyl-D-alanine and D-alanine methyl ester hydrochloride as starting materials, and obtains (2R,5R)-1,2,5-trimethylpiperazine through condensation, cyclization and reduction steps. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide a method for preparing (2R,5R)-1,2,5-trimethylpiperazine, which can solve the problems of low chiral purity and multiple isomers when preparing (2R,5R)-1,2,5-trimethylpiperazine in the prior art.

[0004] In order to solve the above technical problems, the technical solution of the present invention is: comprising the following steps: S1. Prepare a dry reaction bottle and introduce inert gas for replacement; S2, the raw materials Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOBT and DMF are added to the reaction bottle in sequence, stirred to dissolve, and the mixed solution is stirred and dissolved until clear, and then stirred at room temperature for 30 minutes to 60 minutes to activate the carboxylic acid, and N-methylmorpholine is added dropwise, and the temperature is controlled at 20 to 30°C. After the addition of N-methylmorpholine is completed, the temperature is kept at 20 to 30°C for 12 to 16 hours, and the sampling is controlled; S3, after the reaction is completed, ethyl acetate is added to dilute the reaction system, 1M hydrochloric acid is added to wash, the layers are separated, and the organic phase is retained. This step is repeated 2 times, saturated sodium bicarbonate solution is added to wash, the layers are separated, and the organic phase is retained. This step is repeated 2 times; S4, add saturated brine to wash, separate layers, retain the organic phase, concentrate the organic phase, and obtain ; S5. Add formic acid to the material in the previous step, stir overnight at room temperature of 20-30°C for 16 hours, control the reaction, and then desolvate the formic acid; S6, the material of the previous step is placed in a reaction bottle, sec-butyl alcohol and toluene are added, stirred and dissolved, the temperature is raised to reflux, and the temperature is kept for 12 to 16 hours, the temperature is lowered, the toluene and sec-butyl alcohol are desolvated, the remaining formic acid is removed with toluene, and the alkalinity in the crude product is neutralized with a small amount of triethylamine to make the pH close to 7 to 8, and the mixture is set aside; S7, dissolve in toluene , inert gas replacement system, add red aluminum solution, some hydrogen is released during the reaction, after the central control is qualified, use liquid alkali for neutralization and washing, layer separation, and organic phase concentration to obtain a crude product, and the crude product is purified to obtain a finished product.

[0005] Furthermore, in the step S2, sampling is performed during control to control Boc-N-methyl-D-alanine ≤ 5.0%a, HPLC.

[0006] Furthermore, in step S5, the intermediate control reaction, Gas phase area percentage ≤1.0%.

[0007] Furthermore, in step S7, the water content in toluene is controlled to be ≤0.1%; the qualified index of the central control is Gas phase area percentage ≤1.0%.

[0008] Furthermore, in step S2, the molar ratio of the raw materials Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOB, and N-methylmorpholine is 1:1:1.15:1.245:0.640.

[0009] Furthermore, in step S3, the added ethyl acetate, 1M hydrochloric acid and saturated sodium bicarbonate solution are 20 times, 10 times and 10 times the weight of the raw material Boc-N-methyl-D-alanine respectively.

[0010] Furthermore, in step S4, the saturated brine added is 10 times the weight of the raw material Boc-N-methyl-D-alanine.

[0011] Furthermore, in step S5, The molar ratio with formic acid is 1:30.

[0012] Furthermore, in step S6, the sec-butyl alcohol and toluene added are respectively 6 times, 3 times the weight.

[0013] Furthermore, in step S7, The molar ratio of the red aluminum solution is 1:2, and the amount of toluene is The weight is twice that of red aluminum solution, and the concentration of red aluminum solution is 70%.

[0014] The invention has the advantages that: the invention uses BOC-N-methyl-D-alanine and D-alanine methyl ester hydrochloride as starting materials, and obtains (2R, 5R)-1,2,5-trimethylpiperazine through condensation, cyclization and reduction steps; the synthesis method is simple, other isomer impurities are not easily generated, and the chiral purity of (2R, 5R)-1,2,5-trimethylpiperazine is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The hydrogen nuclear magnetic resonance spectrum of (2R,5R)-1,2,5-trimethylpiperazine of the present invention is shown in FIG. DETAILED DESCRIPTION

[0016] In order to make the purpose, technical solution and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods. The following embodiments can enable technicians in this field to understand the present invention more comprehensively, but the present invention is not limited to the scope of the embodiments.

[0017] Synthesis reaction equation: ; The specific steps include: S1. Prepare a dry reaction bottle with a thermometer, mechanical stirring, and introduce inert gas replacement; S2, the raw materials Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOBT and DMF are added to the reaction bottle in sequence, stirred to dissolve, and the mixed solution is stirred and dissolved until clear, and then stirred at room temperature for 30 minutes to 60 minutes. This step is to activate the carboxylic acid, drop N-methylmorpholine, and control the temperature at 20-30°C. After the addition of N-methylmorpholine is completed, continue to keep warm at 20-30°C for 12-16 hours, take samples and control the Boc-N-methyl-D-alanine ≤5.0%a, HPLC, the reaction process is ; S3. After the reaction is completed, ethyl acetate is added to dilute the reaction system, 1M hydrochloric acid is added to wash, the layers are separated, and the organic phase is retained. This step is repeated twice; saturated sodium bicarbonate solution is added to wash, the layers are separated, and the organic phase is retained. This step is repeated twice; S4, add saturated brine to wash, separate the layers, retain the organic phase, concentrate the organic phase to obtain PIP-01 , with a yield of about 70%.

[0018] In the above steps S1-S4, the amount of each substance used is shown in Table 1.

[0019] Table 1 Amount of each substance used in steps S1-S4 Material Name Weight g Molecular weight Molar amount Molar Ratio Boc-N-methyl-D-alanine 10.00 203.200 0.049 1.000 D-Alanine methyl ester hydrochloride 6.87 139.600 0.049 1.000 EDC.HCl 10.85 191.700 0.057 1.150 HOBT 8.28 135.130 0.061 1.245 DMF 50.00 73.095 / / NMM (N-methylmorpholine) 3.19 101.150 0.0315 0.640 Ethyl acetate 200.00 / / / 1M hydrochloric acid 100.00 / / / Saturated sodium bicarbonate solution 100.00 / / / Saturated salt water 100.00 / / / S5. Add formic acid to the material in the previous step, stir overnight at room temperature 20-30°C for 16 hours, control the reaction, control the gas phase area percentage of PIP-01 to ≤0.5%, then desolventize the formic acid and remove it as cleanly as possible. The reaction process is: ; S6, the material of the previous step is placed in a reaction bottle, sec-butyl alcohol and toluene are added, stirred and dissolved, the temperature is raised to reflux, and the temperature is kept for 12 to 16 hours, the temperature is lowered, and toluene and sec-butyl alcohol are desolvated to remove most of the solvent, and the remaining formic acid is removed as much as possible, which can be removed with toluene, and the alkalinity in the crude product is neutralized with a small amount of triethylamine to make the pH close to 7 to 8, and standby; In the above steps S5 and S6, the amount of each substance used is shown in Table 2.

[0020] Table 2 Amounts of each substance used in steps S5-S6 Material Name Weight g Molecular weight Molar amount Molar Ratio PIP-01 5.00 288.34 0.02 1 Formic acid 23.95 46.03 0.52 30 Sec-Butanol 30 / / / Toluene 15 / / / S7, dissolve with toluene (control the water content in toluene ≤ 0.1%) , inert gas replacement system, add red aluminum solution dropwise, some hydrogen is released during the reaction, the reaction process is: , After the central control is qualified, The gas phase area percentage is ≤1.0%. The product is neutralized and washed with liquid alkali, separated and concentrated to obtain a crude product. The crude product is purified to obtain the finished product (2R, 5R)-1,2,5-trimethylpiperazine.

[0021] In the above step S7, the amount of each substance used is as shown in Table 3.

[0022] Table 3 Amounts of each substance used in step S7 Material Name Weight g Molecular weight Molar amount Molar Ratio PIP-02 5.000 156.190 0.032 1.000 Toluene 10.000 / / / Red aluminum solution (70%) 18.490 202.160 0.064 2.000 Example 1 obtained The chiral purity is 98.8%. The H NMR spectrum of (2R,5R)-1,2,5-trimethylpiperazine is as follows: Figure 1 As shown; the conventional method obtains The chiral purity of is 98.0%. The chiral purity is higher than that obtained in the prior art chiral purity.

[0023] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing (2R, 5R)-1,2,5-trimethylpiperazine, characterized in that: The following steps are involved: S1. Prepare a dry reaction bottle and introduce inert gas for replacement; S2, the raw materials Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOBT and DMF are added to the reaction bottle in sequence, stirred to dissolve, and the mixed solution is stirred and dissolved until clear, and then stirred at room temperature for 30 minutes to 60 minutes to activate the carboxylic acid, and N-methylmorpholine is added dropwise, and the temperature is controlled at 20 to 30°C. After the addition of N-methylmorpholine is completed, the temperature is kept at 20 to 30°C for 12 to 16 hours, and the sampling is controlled; S3, after the reaction is completed, ethyl acetate is added to dilute the reaction system, 1M hydrochloric acid is added to wash, the layers are separated, and the organic phase is retained. This step is repeated 2 times, saturated sodium bicarbonate solution is added to wash, the layers are separated, and the organic phase is retained. This step is repeated 2 times; S4, add saturated brine to wash, separate layers, retain the organic phase, concentrate the organic phase, and obtain ; S5, in the previous step material Add formic acid, stir overnight at room temperature 20-30°C for 16 hours, control the reaction, and then remove the formic acid; S6, the material of the previous step is placed in a reaction bottle, sec-butyl alcohol and toluene are added, stirred and dissolved, the temperature is raised to reflux, and the temperature is kept for 12 to 16 hours, the temperature is lowered, the toluene and sec-butyl alcohol are desolvated, the remaining formic acid is removed with toluene, and the alkalinity in the crude product is neutralized with a small amount of triethylamine to make the pH close to 7 to 8, and the mixture is set aside; S7, dissolve in toluene , inert gas replacement system, add red aluminum solution, some hydrogen is released during the reaction, after the central control is qualified, use liquid alkali for neutralization and washing, layer separation, and organic phase concentration to obtain a crude product, and the crude product is purified to obtain a finished product.

2. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In the step S2, sampling is performed to control Boc-N-methyl-D-alanine ≤ 5.0%a, HPLC.

3. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S5, the intermediate control reaction is Gas phase area percentage ≤1.0%.

4. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S7, the water content in toluene is controlled to be ≤0.1%; the qualified index of the central control Gas phase area percentage ≤1.0%.

5. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In the step S2, the molar ratio of the raw materials Boc-N-methyl-D-alanine, D-alanine methyl ester hydrochloride, EDC.HCl, HOB, and N-methylmorpholine is 1:1:1.15:1.245:0.

640.

6. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S3, the added ethyl acetate, 1M hydrochloric acid, and saturated sodium bicarbonate solution are 20 times, 10 times, and 10 times the weight of the raw material Boc-N-methyl-D-alanine, respectively.

7. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S4, the saturated brine added is 10 times the weight of the raw material Boc-N-methyl-D-alanine.

8. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In the step S5, The molar ratio with formic acid is 1:

30.

9. The method for preparing (2R, 5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S6, the sec-butyl alcohol and toluene added are respectively 6 times, 3 times the weight.

10. The method for preparing (2R,5R)-1,2,5-trimethylpiperazine according to claim 1, characterized in that: In step S7, The molar ratio of the red aluminum solution is 1:2, and the amount of toluene is The weight is twice that of red aluminum solution, and the concentration of red aluminum solution is 70%.

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