Preparation method of (3R, 6R)-1-dodecyl-3, 6-diisobutyl piperazine-2, 5-diketone
(3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione was successfully prepared by using L-leucine tert-butyl ester hydrochloride and dodecanaldehyde as raw materials, through the steps of reducing amination, condensation and ring-closing reaction, which solved the lack of the preparation method of this compound in the prior art, and achieved an efficient and simple preparation process and high yield.
Patent Information
- Application Number
- CN202411837050.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-03-21
AI Technical Summary
The lack of the synthesis method of (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione in the prior art has resulted in the inability to prepare the compound effectively.
Using L-leucine tert-butyl ester hydrochloride and dodecanaldehyde as starting materials, (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione was successfully prepared through the steps of reducing amination, condensation reaction and ring-closing reaction.
The method is simple to operate, with a yield of up to 72%, and no by-products are produced during the subsequent purification process, which significantly improves the preparation efficiency and purity of the compound.
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Figure CN119661447A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione. Background Art
[0002] Most 2,5-piperazinedione compounds have biological activity. For example, 1,4-bis(2,6-dimethylphenyl)-2,5-piperazinedione is a plant antibacterial agent, which is prepared by bimolecular condensation of 2,6-dimethylchloroacetanilide. Its chemical structure and the anti-Alzheimer's drug Nefiracetam both belong to the diamide class. 2,6-Dimethylchloroacetanilide is also an important intermediate for the synthesis of Nefiracetam.
[0003] Nefiracetam was developed by Daiichi Pharmaceutical Co., Ltd. of Japan for the treatment of cognitive impairment in the elderly. It also has significant therapeutic effects on cognitive impairment caused by various drugs, basal forebrain damage, and local cerebral ischemia. "Racetam" drugs are one of the fastest-growing nootropics. They act directly on the cerebral cortex, activate, protect, and repair nerves, improve brain function, promote the brain's utilization of phospholipids and amino acids, increase protein synthesis in the brain, promote information transmission in the cerebral hemispheres, improve learning and memory, and improve various types of brain damage caused by brain hypoxia or physical and chemical factors. The anti-Alzheimer's drug, Revostigmine, which was launched in Switzerland in 1997, is also an amide drug. It was approved by the FDA for marketing in the United States in April 2000 and has been launched in 70 countries. The use of acyl diphosphate-ribose polymerase (PARP) inhibitors as neuroprotective drugs is a relatively new and active field. Pharmacological experiments have shown that mice with PARP gene eliminated have a protective effect against cerebral ischemia and brain nerve damage. Typical PARP inhibitors contain more lactam structures. Caffeine, as a central nervous system stimulant, is an adenosine receptor antagonist and its structure also belongs to the lactam class.
[0004] Currently, there is no report on (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione compounds, and there is no synthetic preparation method. Summary of the invention
[0005] In view of the deficiencies of the prior art, the present invention provides a method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione. The method has simple operation, high yield and simple post-processing and purification process.
[0006] The technical solution of the present invention is as follows:
[0007] A method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, wherein the preparation method is carried out according to the following process:
[0008]
[0009] The specific steps are:
[0010] (1) Compound 1 and Compound 2 are dissolved in a solvent I, and a reductive amination reaction is carried out under the action of acetic acid and a reducing agent to obtain Compound 3;
[0011] (2) Compound 3 and a condensing agent are dissolved in solvent II, and compound 4 is added dropwise at low temperature to undergo a condensation reaction to obtain compound 5;
[0012] (3) Compound 5 is dissolved in solvent III, and piperidine is added dropwise to undergo a ring-closure reaction to obtain (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione.
[0013] Furthermore, in step (1), the solvent I is selected from at least one of dichloromethane, tetrahydrofuran, methanol, and acetonitrile; and the concentration of the compound 1 in the solvent I is 0.1 to 2 mol / L.
[0014] Furthermore, in step (1), the reducing agent is selected from at least one of sodium acetic borohydride and sodium cyanoborohydride; the molar ratio of compound 1 to the reducing agent is 1:2.5-10; the molar ratio of compound 1 to acetic acid is 1:0.1-1; the molar ratio of compound 1 to compound 2 is 1:1-1.2.
[0015] Furthermore, in step (1), the temperature of the reductive amination reaction is 20-40° C. and the time is 12-48 hours.
[0016] Furthermore, in step (2), the solvent II is selected from at least one of dichloromethane, tetrahydrofuran, dioxane, and tert-butyl methyl ether; and the concentration of the compound 3 in the solvent II is 0.1 to 2 mol / L.
[0017] Furthermore, in step (2), the condensing agent includes at least one of diisopropylethylamine, triethylamine, trimethylamine, dimethylaminopyridine, and pyridine; the molar ratio of compound 3 to the condensing agent is 1:1.2-20; and the molar ratio of compound 3 to compound 4 is 1:1-3.
[0018] Furthermore, in step (2), the condensation reaction temperature is 0-10°C and the time is 1-4h.
[0019] Furthermore, in step (3), the solvent III is selected from at least one of tetrahydrofuran, acetonitrile, dichloromethane, and N,N-dimethylformamide; and the concentration of the compound 5 in the solvent III is 0.02-0.2 mol / L.
[0020] Furthermore, in step (3), the molar ratio of compound 5 to piperidine is 1:20-100.
[0021] Furthermore, in step (3), the temperature of the ring-closure reaction is 40-60° C., and the time is 8-24 h.
[0022] The beneficial technical effects of the present invention are:
[0023] The invention uses L-leucine tert-butyl ester hydrochloride and dodecanal as reaction starting materials, undergoes reductive amination and condensation reactions, and finally removes Fmoc to undergo a self-cyclization reaction to obtain a target product. The entire preparation process does not generate other byproducts, the operation is simple, and the three-step yield is as high as 72%. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is the H NMR spectrum of (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0025] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.
[0026] Example 1
[0027] A method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, the method comprising the following steps:
[0028] Compound 1 L-leucine tert-butyl ester (1.44g, 0.0077mol) and compound 2 dodecanal (1.4g, 0.0077mol) were dissolved in dichloromethane (30mL), acetic acid (46mg, 0.77mmol) was added first, and then sodium acetate borohydride (3.0g, 0.019mol) was slowly added in batches, and the reaction mixture was stirred at 40°C for 12h. The reaction was detected to be complete by TLC control, and the mixture was poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. After obtaining the crude product, it was purified by flash column chromatography (PE / EA=60 / 1~20 / 1) to obtain a colorless oil, i.e., compound 3 dodecyl-L-leucine tert-butyl ester 2.2g, with a yield of 80% and a purity of 95%.
[0029] Compound 3 dodecyl-L-leucine tert-butyl ester (2.74 g, 0.0077 mol) and diisopropylethylamine (0.94 g, 0.0093 mol) were dissolved in dichloromethane (20 mL), cooled to 10°C, and compound 4 (9H-fluoren-9-yl)methyl-(S)-(1-chloro-4-methyl-1-oxopentan-2-yl)carbamate (3.2 g, 0.0085 mol) was slowly added dropwise, and stirring was continued at 10°C for 1 h. The reaction was complete after TLC control. The mixture was poured into 0.5N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product. The product was purified by flash column chromatography (PE / EA=10 / 1-4 / 1) to obtain a yellow oil, i.e., the compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (4.85 g), with a yield of 92% and a purity of 95%.
[0030] The compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (0.8 g, 1.16 mmol) was dissolved in tetrahydrofuran (10 mL), and then piperidine (4 mL, 0.04 mol) was slowly added dropwise, and then heated to 60°C and stirred for 8 hours. The reaction was detected to be complete by TLC control, and the reaction solution was concentrated by vacuum distillation to obtain a crude product, which was dissolved in EA, washed with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in sequence, and then dried with sodium sulfate. It was concentrated by vacuum distillation to obtain a light yellow oil, i.e., 0.45 g of the (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, with a yield of 98% and a purity of 96%.
[0031] The NMR spectrum of the product is shown in Figure 1 As shown, 1 H NMR (400MHz, CDCl3): δ6.64 (d, J=4.0Hz, 1H), 4.02–3.86 (m, 2H), 3.82 (dd, J=9.2, 4.0Hz, 1H), 2.77–2.65 (m, 1H), 1.93(m,1H),1.85–1.76(m,2H),1.72(m,1H),1.63–1.52(m,4H),1.32–1.20(m,18H),0.98(m,12H),0.88(m,3H).
[0032] Example 2
[0033] A method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, the method comprising the following steps:
[0034] Compound 1 L-leucine tert-butyl ester (1.44g, 0.0077mol) and compound 2 dodecanal (1.54g, 0.0085mol) were dissolved in methanol (8mL), acetic acid (230mg, 3.85mmol) was added first, and sodium cyanoborohydride (2.38g, 0.038mol) was slowly added in batches, and the reaction mixture was stirred at 30°C for 24h. The reaction was detected to be complete by TLC control, and the mixture was poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. After obtaining the crude product, it was purified by flash column chromatography (PE / EA=60 / 1~20 / 1) to obtain a colorless oil, i.e., compound 3 dodecyl-L-leucine tert-butyl ester 2.15g, with a yield of 78% and a purity of 95%.
[0035] Compound 3 dodecyl-L-leucine tert-butyl ester (2.74 g, 0.0077 mol) and triethylamine (7.8 g, 0.077 mol) were dissolved in tetrahydrofuran (20 mL), cooled to 5°C, and compound 4 (9H-fluoren-9-yl)methyl-(S)-(1-chloro-4-methyl-1-oxopentan-2-yl)carbamate (4.36 g, 0.0115 mol) was slowly added dropwise, and stirring was continued at 5°C for 2 h. The reaction was complete as detected by TLC. The mixture was poured into 0.5N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product, which was purified by flash column chromatography (PE / EA=10 / 1-4 / 1) to obtain a yellow oil, i.e., the compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (4.8 g), with a yield of 91% and a purity of 95%.
[0036] The compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (0.8 g, 1.16 mmol) was dissolved in acetonitrile (20 mL), and then piperidine (6 mL, 0.06 mol) was slowly added dropwise, and then heated to 50°C and stirred for 16 h. The reaction was detected to be complete by TLC control, and the reaction solution was concentrated by vacuum distillation to obtain a crude product, which was dissolved in EA, washed with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in sequence, and then dried with sodium sulfate. It was concentrated by vacuum distillation to obtain a light yellow oil, i.e., 0.45 g of the (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, with a yield of 98% and a purity of 96%.
[0037] Example 3
[0038] A method for preparing 1-(3-bromo-4-methoxyphenyl)-3-(trifluoromethyl)-1,2,4-triazole, the method comprising the following steps:
[0039] Compound 1 L-leucine tert-butyl ester (1.44g, 0.0077mol) and compound 2 dodecanal (1.68g, 0.0092mol) were dissolved in dichloromethane (5mL), acetic acid (460mg, 7.7mmol) was added first, and then sodium acetate borohydride (12.0g, 0.076mol) was slowly added in batches, and the reaction mixture was stirred at 20°C for 48h. The reaction was detected to be complete by TLC control, and the mixture was poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. After obtaining the crude product, it was purified by flash column chromatography (PE / EA=60 / 1~20 / 1) to obtain a colorless oil, i.e., compound 3 dodecyl-L-leucine tert-butyl ester 2.25g, with a yield of 81% and a purity of 95%.
[0040] Compound 3 dodecyl-L-leucine tert-butyl ester (2.74 g, 0.0077 mol) and diisopropylethylamine (9.4 g, 0.093 mol) were dissolved in dioxane (20 mL), cooled to below 0°C, and compound 4 (9H-fluoren-9-yl)methyl-(S)-(1-chloro-4-methyl-1-oxopentan-2-yl)carbamate (7.93 g, 0.021 mol) was slowly added dropwise, and stirring was continued for 4 h. The reaction was complete as detected by TLC. The mixture was poured into 0.5N hydrochloric acid and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain a crude product. The product was purified by flash column chromatography (PE / EA=10 / 1-4 / 1) to obtain a yellow oil, i.e., the compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (4.75 g), with a yield of 91% and a purity of 95%.
[0041] The compound 5N-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-N-dodecyl-L-leucine tert-butyl ester (0.8 g, 1.16 mmol) was dissolved in dichloromethane (40 mL), and then piperidine (8 mL, 0.08 mol) was slowly added dropwise, and then heated to 40°C and stirred for 24 hours. The reaction was detected to be complete by TLC control, and the reaction solution was concentrated by vacuum distillation to obtain a crude product, which was dissolved in EA, washed with 2N dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in sequence, and then dried with sodium sulfate. It was concentrated by vacuum distillation to obtain a light yellow oil, i.e., 0.45 g of the (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, with a yield of 98% and a purity of 96%.
[0042] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing (3R, 6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione, characterized in that: The preparation method is carried out according to the following process: The specific steps are: (1) Compound 1 and Compound 2 are dissolved in a solvent I, and a reductive amination reaction is carried out under the action of acetic acid and a reducing agent to obtain Compound 3; (2) Compound 3 and a condensing agent are dissolved in solvent II, and compound 4 is added dropwise at low temperature to undergo a condensation reaction to obtain compound 5; (3) Compound 5 is dissolved in solvent III, and piperidine is added dropwise to undergo a ring-closure reaction to obtain (3R,6R)-1-dodecyl-3,6-diisobutylpiperazine-2,5-dione.
2. The preparation method according to claim 1, characterized in that: In step (1), the solvent I is selected from at least one of dichloromethane, tetrahydrofuran, methanol, and acetonitrile; and the concentration of the compound 1 in the solvent I is 0.1 to 2 mol / L.
3. The preparation method according to claim 1, characterized in that: In step (1), the reducing agent is selected from at least one of sodium acetic borohydride and sodium cyanoborohydride; the molar ratio of compound 1 to the reducing agent is 1:2.5-10; the molar ratio of compound 1 to acetic acid is 1:0.1-1; the molar ratio of compound 1 to compound 2 is 1:1-1.
2.
4. The preparation method according to claim 1, characterized in that: In step (1), the temperature of the reductive amination reaction is 20-40° C. and the time is 12-48 hours.
5. The preparation method according to claim 1, characterized in that: In step (2), the solvent II is selected from at least one of dichloromethane, tetrahydrofuran, dioxane, and tert-butyl methyl ether; and the concentration of the compound 3 in the solvent II is 0.1 to 2 mol / L.
6. The preparation method according to claim 1, characterized in that: In step (2), the condensing agent includes at least one of diisopropylethylamine, triethylamine, trimethylamine, dimethylaminopyridine and pyridine; the molar ratio of compound 3 to the condensing agent is 1:1.2-20; the molar ratio of compound 3 to compound 4 is 1:1-3.
7. The preparation method according to claim 1, characterized in that: In step (2), the condensation reaction temperature is 0-10°C and the time is 1-4h.
8. The preparation method according to claim 1, characterized in that: In step (3), the solvent III is selected from at least one of tetrahydrofuran, acetonitrile, dichloromethane, and N,N-dimethylformamide; and the concentration of the compound 5 in the solvent III is 0.02-0.2 mol / L.
9. The preparation method according to claim 1, characterized in that: In step (3), the molar ratio of compound 5 to piperidine is 1:20-100.
10. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the ring-closure reaction is 40-60° C. and the time is 8-24 h.