Process for the preparation of peptide amine complexes
By improving the preparation method of peptide-amine methylamine, using safe and readily available brominated reagents and cyclization reactions, the problems of unsafe production and serious pollution in the existing technology have been solved, realizing the preparation of peptide-amine methylamine in a high-efficiency and environmentally friendly manner, which is suitable for large-scale industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 上海埃逸科技有限公司
- Filing Date
- 2025-01-07
- Publication Date
- 2026-07-07
AI Technical Summary
Existing methods for synthesizing peptide amines have problems such as unsafe production and serious pollution, which limit their large-scale industrial production.
Using compound II as a raw material, compound III is generated through bromination, and then cyclized with compound IV to generate peptide amine metronidazole. The reagents used, such as liquid bromine, copper bromide, and phenyltrimethylammonium tribromide, are safe and readily available, and the reaction route is short and easy to control.
A safe and environmentally friendly preparation process for peptide amines has been achieved, with high yields at each step, making it suitable for large-scale industrial production.
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Figure CN122344167A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis technology, and specifically relates to a method for preparing peptide aminomido. Background Technology
[0002] Human tyrosinase is fundamental to melanin formation. Once synthesized, it is integrated into the melanosome membrane and responsible for converting tyrosine into melanin. When the melanosome is filled with melanin, it forms melanin granules. These granules are then transported to the ends of melanocyte processes and subsequently to adjacent basal cells or distal keratinocytes. This is the general pattern of melanin formation and transport.
[0003] Thiamidol can inhibit human tyrosinase activity, with an activity 20 times that of 4-butylresorcinol and 120 times that of 377. Beiersdorf also conducted skin model tests, showing that Thiamidol is 15 times more potent than 4-butylresorcinol and 450 times more potent than kojic acid. Comparing 0.2% Thiamidol with 2% hydroquinone, Thiamidol's effect was significantly more pronounced, exhibiting the same performance in both low and high UV environments, showing better results than hydroquinone.
[0004] US20160015615 discloses a synthetic route for peptide aminomido, as shown below:
[0005]
[0006] The first step of this synthetic route, hydroxyl protection, uses the highly toxic compound methyl chloroformate, followed by bromination with bromine. These two steps are prone to environmental pollution and have poor safety in industrial production, thus limiting its large-scale production. Summary of the Invention
[0007] This invention provides a method for preparing peptide aminomethylpyridinium, which solves the problems of unsafe production and serious pollution caused by current synthesis methods.
[0008] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: the preparation method of the peptide aminomidoin involves using a compound of formula II as a raw material, which is then brominated to obtain a compound of formula III. The compound of formula III is then cyclized with a compound of formula IV to obtain a compound of formula I. The reaction route is shown below:
[0009]
[0010] Optionally, the brominating agent of the compound of formula II is liquid bromine, copper bromide, cuprous bromide, or phenyltrimethylammonium tribromide.
[0011] Optionally, the brominating agent of the compound of formula II is copper bromide, cuprous bromide, or phenyltrimethylammonium tribromide.
[0012] Optionally, the preparation process of the peptide aminomido involves adding compounds of formula II and formula IV into a solvent, then adding a brominating agent and a condensing agent and stirring to generate compound I.
[0013] Optionally, the solvent is selected from acetone, ethyl acetate, or water.
[0014] Optionally, the condensing agent may be selected from TEA (triethylamine), sodium carbonate, or potassium carbonate.
[0015] Optionally, the compound of formula IV is obtained by reacting thiourea with isobutyric anhydride, as shown in the following reaction equation:
[0016]
[0017] Optionally, the preparation process of compound IV is as follows: DMAP (4-dimethylaminopyridine) and TEA are added to a dichloromethane solution of thiourea, and isobutyric anhydride is added dropwise in an ice bath with stirring.
[0018] Optionally, the dosage of thiourea, TEA, and isobutyric anhydride by molar meter is as follows:
[0019] Thiourea 1
[0020] TEA 2-2.2
[0021] Isobutyric anhydride 1-1.2.
[0022] The technical solution provided by this invention has a short reaction route, uses safe and readily available reagents, is easy to control as a whole, and has high yields at each step, making it particularly suitable for large-scale industrial production. Detailed Implementation
[0023] For ease of understanding, the preparation method of the peptide aminomido is described below with reference to the embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.
[0024] Example 1:
[0025] Thiourea (5g, 65.7mmol) was added to a single-necked flask, dissolved in 50mL of DCM, followed by DMAP (0.4g, 3.6mmol) and TEA (13.3g, 2eq). After cooling to about 5°C on an ice bath, isobutyric anhydride (10.4g, 68.9mmol) was slowly added dropwise, and the mixture was stirred overnight at room temperature.
[0026] The reaction was quenched by adding water (50 mL), and the mixture was stirred and separated. The aqueous phase was extracted with DCM (20 mL), and the organic phases were combined and washed twice with saturated saline. The crude product was dried and concentrated and washed with ethanol to obtain 7.0 g of crude intermediate compound IV for later use.
[0027] Comparative Example 1
[0028] Add thiourea (5g, 65.7mmol) to a single-necked flask, dissolve it in 50mL of toluene, then add isobutyrate chloride (7.0g, 65.7mmol), and stir overnight at room temperature.
[0029] The reaction was quenched by adding water (50 mL), and the mixture was stirred and separated. The aqueous phase was extracted with toluene (20 mL), and the organic phases were combined and washed twice with saturated saline. The crude product was dried and concentrated and passed through a column to obtain 4.2 g of intermediate compound IV.
[0030] Example 2:
[0031] Add the starting compound II (5 g, 32.9 mmol) to a single-necked flask, add DCM (50 mL) to dissolve it, cool to about 5 °C and slowly add bromine (5.26 g, 32.9 mmol), react for 2 h and then slowly raise to room temperature to continue the reaction.
[0032] After the reaction was completed, 50 mL of saturated sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with DCM (20 mL). The organic phases were combined, washed with saturated brine, dried and concentrated to obtain 6.4 g of intermediate compound III.
[0033] Example 3:
[0034] The commercially available compound of formula II (5 g, 32.9 mmol) was added to a single-necked flask, dissolved in ethyl acetate (50 mL), and copper bromide (7.3 g, 32.9 mmol) was added at room temperature. After the addition was complete, the temperature was raised to 40 degrees Celsius to react.
[0035] After the reaction was completed, 50 mL of saturated sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with 20 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried and concentrated to give 6.1 g of intermediate compound III.
[0036] Example 4:
[0037] Compound III (2.3 g, 10 mmol) prepared in Example 3, compound IV (1.46 g, 10 mmol) prepared in Example 1, sodium carbonate (1.06 g, 10 mmol) were added to a single-necked flask, isopropanol (20 mL) was added, and the mixture was heated to 80 °C and refluxed for 8 h.
[0038] After the reaction was completed, the solvent was removed by concentration, and ethyl acetate (30 mL) and water (30 mL) were added for extraction. The organic phase was washed with saturated brine, dried and concentrated to obtain crude product, which was then subjected to column chromatography to obtain 1.7 g of product compound I.
[0039] 1H NMR(500MHz,DMSO-d6)δ12.18(s,1H),10.88(s,1H),9.50(s,1H),7.66(d,J=8.4Hz ,1H),7.41(s,1H),6.34-6.27(m,2H),2.75(p,J=7.0Hz,1H),1.13(d,J=6.8Hz,6H).
[0040] Example 5:
[0041] The commercially available compound II (1.5 g, 10 mmol) and the compound IV prepared in Example 1 (1.46 g, 10 mmol) were mixed and added to acetone (10 mL) solvent. TEA (1.2 g, 12 mmol) was added and stirred. Liquid bromine (1.6 g, 10 mmol) was added dropwise at low temperature. After reacting for 1 hour, the temperature was raised to 80 °C and refluxed for 6 hours.
[0042] After the reaction was completed, ethyl acetate (30 mL) and water (30 mL) were added for extraction. The organic phase was washed with saturated brine, dried and concentrated to give 1.56 g of product compound I.
[0043] Example 6:
[0044] The commercially available compound II (1.5 g, 10 mmol) and the compound IV prepared in Example 1 (1.46 g, 10 mmol) were mixed and added to ethyl acetate (10 mL) solvent. TEA (1.2 g, 12 mmol) was added and stirred. Copper bromide (2.3 g, 10 mmol) was added at 40 °C and the mixture was stirred for 1 hour. The temperature was then raised to 60 °C and refluxed for 10 hours.
[0045] After the reaction was completed, ethyl acetate (30 mL) and water (30 mL) were added for extraction. The organic phase was washed with saturated brine, dried and concentrated to give 1.63 g of product compound I.
[0046] Example 7:
[0047] The commercially available compound II (1.5 g, 10 mmol) and the compound IV prepared in Example 1 (1.46 g, 10 mmol) were mixed and added to water (10 mL). Sodium carbonate (1.1 g, 11 mmol) was added and stirred. Liquid bromine (1.6 g, 10 mmol) was added dropwise at 10 °C. After reacting for 1 hour, the temperature was raised to 60 °C and refluxed for 10 hours.
[0048] After the reaction was completed, ethyl acetate (30 mL) and water (30 mL) were added for extraction. The organic phase was washed with saturated brine, dried and concentrated to give 1.51 g of product compound I.
[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein, and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A process for the preparation of a peptide amine complex, characterized in that, The compound of formula II is brominated to obtain the compound of formula III. The compound of formula III is then cyclized with the compound of formula IV to obtain the compound of formula I. The reaction route is shown below:
2. The method for preparing peptide-aminomido according to claim 1, characterized in that, The brominating reagent of the compound of formula II is liquid bromine, copper bromide, cuprous bromide, or phenyltrimethylammonium tribromide.
3. The method for preparing peptide-aminomethylpyridinium according to claim 2, characterized in that, The brominating reagent of the compound of formula II is copper bromide, cuprous bromide, or phenyltrimethylammonium tribromide.
4. The method for preparing peptide-aminomido according to claim 1, characterized in that, The preparation process of the peptide aminomido involves adding compounds of formula II and formula IV into a solvent, then adding a brominating agent and a condensing agent and stirring to generate compound I.
5. The method for preparing peptide-aminomido according to claim 4, characterized in that, The solvent is selected from acetone, ethyl acetate or water.
6. The method for preparing peptide-aminomido according to claim 4, characterized in that, The condensing agent is selected from TEA (triethylamine), sodium carbonate, or potassium carbonate.
7. The method for preparing peptide-aminomido according to claim 1, characterized in that, The compound of formula IV is obtained by reacting thiourea with isobutyric anhydride, and the reaction equation is as follows:
8. The method for preparing peptide-aminomido according to claim 7, characterized in that, The preparation process of compound IV is as follows: DMAP and TEA are added to a dichloromethane solution of thiourea, and isobutyric anhydride is added dropwise in an ice bath with stirring.
9. The method for preparing peptide-amine methylamine according to claim 8, characterized in that, The dosage of thiourea, TEA, and isobutyric anhydride by molar meter is as follows: Thiourea 1 TEA 2-2.2 Isobutyric anhydride 1-1.2.