Slegiline hydrochloride open-loop impurity as well as preparation method and application thereof

Abstract

The invention discloses a selegiline hydrochloride ring-opening impurity, namely a compound 1, a compound 2 and a compound 3. Besides, the invention further discloses a preparation method and application of the selegiline hydrochloride ring-opening impurity, specifically, the selegiline hydrochloride ring-opening impurity is prepared by taking 3-phenylpropylamine as a raw material through condensation and propargyl, and the impurity prepared by the method is high in purity and can be used as a reference substance for quality research of selegiline hydrochloride; the three compounds are all new compounds, are not reported in literatures, are all new process intermediate impurities of the selegiline hydrochloride, and are of great significance to research of the selegiline hydrochloride.

Description

Technical Field

[0001] The invention relates to the technical field of chemical pharmacy, in particular to a selegiline hydrochloride ring-opening impurity and a preparation method and application thereof. Background Art

[0002] Selegiline hydrochloride, chemically known as (R)-N,α-dimethyl-N-(2-propynyl)phenylethylamine hydrochloride, is an irreversible selective inhibitor of monoamine oxidase type B that effectively inhibits the degradation of dopamine. It was approved for marketing by the US FDA in 1989 and is clinically used to treat Parkinson's disease.

[0003] There are many literature reports on the synthesis of selegiline hydrochloride. The method disclosed in the prior art is to prepare selegiline hydrochloride by first replacing and then splitting the natural product methamphetamine or first splitting and then replacing. The synthesis route is shown in Figure 1 .

[0004] Literature reports and compound patent routes have high yields and stable processes, but the starting material or intermediate uses (-)-R-methamphetamine, which is the enantiomer of methamphetamine (+)-S-methamphetamine. Although (-)-R-methamphetamine is not considered to be addictive and can even be used to treat cardiovascular diseases, it is extremely difficult to source and obtain. In the existing technology, it is mainly synthesized through N-methylation of amphetamine (amphetamine), and the source and acquisition of amphetamine are also extremely difficult. Therefore, it is very difficult for companies to obtain a production license for selegiline hydrochloride.

[0005] The synthesis methods of selegiline reported in recent years at home and abroad mostly involve dangerous reactions such as azidation and Grignard reaction. The reaction routes are too long and flammable and explosive lithium aluminum tetrahydride, sodium hydride, etc. are used. Low temperature conditions are used and there is no cost advantage, so industrial production cannot be achieved.

[0006] The invention with application number 201811569604.2 and titled "Method for preparing selegiline hydrochloride" discloses a new method for synthesizing selegiline hydrochloride. The method uses the cheap and readily available chiral source compound (S)-2-benzyl-N,N-dimethylaziridine-1-sulfonamide (cobicistat intermediate) as a raw material, and obtains selegiline hydrochloride through sodium borohydride ring opening, propargylation, deprotection, and amination reduction. The conversion rate of each step is about 90%, and the post-treatment only requires simple operations such as recrystallization and salt formation, which is very suitable for industrial production. For the synthesis route, see Figure 2 .

[0007] Impurity research is an important part of drug quality research and one of the key factors in drug quality assurance. As a pharmaceutical industry, it is very necessary to strictly control the impurity content in products. Research on material impurities helps optimize the synthesis process and quality control of drugs. In order to improve the safety of clinical drug use, it is necessary to conduct detailed research and control on drug process impurities and degradation impurities during storage.

[0008] The inventors found in the process of studying selegiline hydrochloride that the starting material BDS inevitably produces a ring-opening isomer impurity (Compound 1) during the ring-opening step due to stereoelectronic effects and steric hindrance effects. The chemical structure is It is an important impurity in the intermediate SG-I, accounting for about 1%, and its content hardly changes in the post-ring opening treatment step; in the propargylation step, the ring-opening isomer impurity (compound 1) will be converted into a new impurity (compound 2), the chemical structure of which is It is an important impurity in the intermediate SG-II; compound 2 will further derive a new impurity (compound 3) in the deprotection step, and the chemical structure is It is an important impurity in the intermediate SG-III.

[0009] The synthesis of these three open-ring impurities (Compound 1, Compound 2, Compound 3) provides a reference and basis for the study of the impurity spectrum of selegiline hydrochloride raw materials and intermediates and the establishment of quality standards. However, there is currently no literature report on the preparation method of selegiline hydrochloride open-ring impurities (Compound 1, Compound 2, Compound 3). Summary of the invention

[0010] The purpose of the present invention is to provide a selegiline hydrochloride ring-opening impurity and a preparation method and use thereof, so as to solve the problems raised in the above background technology.

[0011] To achieve the above object, the present invention provides the following technical solutions:

[0012] A selegiline hydrochloride ring-opening impurity, including compound 1, compound 2, and compound 3, and its structure is as follows:

[0013]

[0014] As a further scheme of the present invention: the present invention also provides a method for preparing the selegiline hydrochloride ring-opening impurity, specifically, using 3-phenylpropylamine as a raw material, and dimethylaminosulfonyl chloride through condensation to obtain the ring-opening product N,-(N,N-dimethylaminosulfonyl) amphetamine (compound 1), the obtained compound 1 and 3-bromopropyne are propargylated to obtain N,-(N,N-dimethylaminosulfonyl)-N-(2-propynyl) amphetamine (compound 2), 3-phenylpropylamine and 3-bromopropyne are propargylated and then salified to obtain N-(2-propynyl) amphetamine hydrochloride (compound 3). Its synthetic route is as follows:

[0015]

[0016] As a further solution of the present invention: the preparation method of selegiline hydrochloride ring-opening impurity comprises the following steps:

[0017] (1) Condensation: 3-phenylpropylamine and dimethylaminosulfonyl chloride are condensed in toluene as solvent and triethylamine as acid-binding agent to obtain compound 1;

[0018] (2) Propargylation: Compound 1 obtained in step (1) and 3-bromopropyne are subjected to propargylation in acetonitrile as solvent and potassium hydroxide as acid-binding agent to obtain compound 2;

[0019] (3) Propargylation: 3-Phenylpropylamine and 3-bromopropyne were reacted in acetonitrile as solvent and potassium hydroxide as acid-binding agent to form a salt to obtain compound 3.

[0020] As a further scheme of the present invention: the reaction temperature of step (1) is -10°C to 100°C, preferably 40°C to 45°C; the solvent can also be any one of methanol, ethanol, isopropanol, dichloromethane, and tetrahydrofuran; the acid binding agent can also be any one of sodium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide; specifically, under the conditions of toluene as solvent and triethylamine as acid binding agent, 3-phenylpropylamine and dimethylaminosulfonyl chloride are reacted at 40°C to 45°C; after the reaction, the obtained material is filtered, acidified, alkali adjusted, extracted, and subjected to column chromatography to obtain the target compound 1.

[0021] As a further scheme of the present invention: the reaction temperature of step (2) is -10°C to 100°C, preferably 40°C to 45°C; the solvent can also be any one of methanol, ethanol, isopropanol, tetrahydrofuran, and N,N-dimethylformamide; the acid-binding agent can also be any one of sodium carbonate, sodium bicarbonate, triethylamine, and sodium hydroxide; specifically, under the conditions of acetonitrile as solvent and potassium hydroxide as acid-binding agent, compound 1 and 3-bromopropyne are reacted at 40°C to 45°C; after the reaction, the obtained material is evaporated to dryness, extracted, decolorized, and subjected to column chromatography to obtain the target compound 2.

[0022] As a further scheme of the present invention: the reaction temperature of step (3) is -10°C to 100°C, preferably 25°C to 30°C; the solvent can also be any one of methanol, ethanol, isopropanol, tetrahydrofuran, and N,N-dimethylformamide; the acid binding agent can also be any one of sodium carbonate, sodium bicarbonate, triethylamine, and sodium hydroxide; specifically, under the conditions of acetonitrile as solvent and potassium hydroxide as acid binding agent, 3-phenylpropylamine and 3-bromopropyne are reacted at 25°C to 30°C; after the reaction, the obtained material is evaporated to dryness, extracted, and subjected to column chromatography to obtain the target compound 3.

[0023] As a further solution of the present invention: the present invention also provides the use of the selegiline hydrochloride ring-opening impurity as a reference substance for quality research of selegiline hydrochloride intermediates, raw materials and compound preparations thereof.

[0024] Compared with the prior art, the invention has the following beneficial effects: for the first time, a method for preparing selegiline hydrochloride ring-opening impurities: compound 1, compound 2, and compound 3 is provided; new substances: compound 1, compound 2, and compound 3 are synthesized for the first time, and all of them are intermediate impurities of selegiline hydrochloride in a new process; the purity of compound 1 prepared by the method is 99%, the purity of compound 2 is 99%, and the purity of compound 3 is 97%, and they can be used as reference substances for quality research of selegiline hydrochloride, which is of great significance to the research of selegiline hydrochloride.

[0025] The chemical name of the compound of the present invention is:

[0026] Compound 1: N,-(N,N-dimethylsulfamoyl)amphetamine;

[0027] Compound 2: N,-(N,N-dimethylsulfamoyl)-N-(2-propynyl)amphetamine;

[0028] Compound 3: N-(2-propynyl)amphetamine hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The synthetic route of selegiline hydrochloride in the prior art;

[0030] Figure 2 A new synthetic route of selegiline hydrochloride in the prior art;

[0031] Figure 3 A synthetic route of a selegiline hydrochloride ring-opening impurity described in an embodiment of the present invention. DETAILED DESCRIPTION

[0032] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] See also Figure 3 The present invention provides a method for preparing selegiline hydrochloride ring-opening impurities. Specifically, 3-phenylpropylamine is used as a raw material, and dimethylaminosulfonyl chloride is condensed to obtain the ring-opening product N,-(N,N-dimethylaminosulfonyl) amphetamine (compound 1). The obtained compound 1 and 3-bromopropyne are propargylated to obtain N,-(N,N-dimethylaminosulfonyl)-N-(2-propynyl) amphetamine (compound 2). 3-phenylpropylamine and 3-bromopropyne are propargylated and then salified to obtain N-(2-propynyl) amphetamine hydrochloride (compound 3). Specific embodiments are as follows:

[0034] Example 1

[0035] Synthesis of compound 1:

[0036]

[0037] In a 500ml three-necked flask, add 3-phenylpropylamine (40.8g, 301.8mmol), toluene (120ml), triethylamine (45.8g, 452.8mmol), and add dimethylaminosulfonyl chloride (47.6g, 332mmol) dropwise at 20℃-25℃. After the addition, raise the temperature to 40℃-45℃ and react for 2h. Cool down, filter with suction, add 1M HCl to the filtrate to adjust the pH to 4-5, and then add 30% NaOH solution to adjust the pH to 11-12. Layer. Add toluene (40ml) to extract the water layer, combine the toluene layers, and wash with 5% NaHCO3 solution (100ml). The toluene layer is dried under reduced pressure to obtain 75.6g of a light yellow oil. The light yellow oil is separated by column chromatography to obtain a colorless oil, namely compound 1 (45g, yield: 61.5%, purity 99%).

[0038] Its structural characterization data are as follows: 1 H NMR (CDCl3, 600MHz), δ: 1.85-1.90 (m, 2H, CH2), 2.66-2.69 (t, 2H, CH2), 2.76 (s, 6H, CH3), 3.06-3.09 (t, 2H, CH2), 7.17-7.30 (m, 5H, C6H5); 13C NMR (CDCl3), δ: 141.09, 128.60, 126.21, 77.35, 43.18, 38.22, 32.98, 31.5; ESI-MS: m / z=243.12[M] + .

[0039] Example 2

[0040] Synthesis of compound 2:

[0041]

[0042] Compound 1 (21.0 g, 86.67 mmol) and acetonitrile (100 ml) were added to a 250 ml three-necked flask, stirred to dissolve, and KOH aqueous solution (prepared from KOH (11.4 g, 173.3 mol) and water (50 ml)) was quickly added dropwise at 25°C-30°C. The temperature was raised to 40°C-45°C, and 3-bromopropyne (31.2 g, 260 mmol) was quickly added dropwise. After the addition, the temperature was kept at 40°C-45°C for 1 h. The temperature was lowered to 20°C-25°C, and the layers were separated. The upper layer was dried under reduced pressure. Toluene (80 ml) and water (50 ml) were added for extraction, and the toluene layer was retained. The toluene layer was washed with 5% NaHCO3 solution (50 ml) and dried with anhydrous sodium sulfate. Filtered by suction, activated carbon (5 g) was added to the filtrate, and the temperature was raised to 60°C-65°C for decolorization for 1 h. Hot filtration was performed, and the filtrate was dried under reduced pressure to obtain 21.2 g of a pale yellow oil. The pale yellow oil was separated by column chromatography to obtain a colorless oil (Compound 2) (14.7 g, yield: 60.5%, purity 99%).

[0043] Its structural characterization data are as follows: 1 HNMR(CDCl3,600MHz),δ:1.94-2.00(q,2H,CH2),2.33(s,1H,-CCH),2.66-2.70(t,2H,CH2),2.83(s, 6H,CH3),3.38-3.42(t,2H,CH2),4.05(s,2H,CH2),7.20-7.33(m,5H,C6H5); ESI-MS:m / z=281.13[M] + .

[0044] Example 3

[0045] Synthesis of compound 3:

[0046]

[0047] In a 500ml three-necked flask, add 3-phenylpropylamine (27.4g, 200mmol) and acetonitrile (140ml), and quickly add KOH aqueous solution (prepared from KOH (26.4g, 400mol) and water (110ml)) dropwise at 25℃-30℃. After the addition, keep the temperature at 25℃-30℃, and then add 3-bromopropyne (24.0g, 200mmol). After the addition, keep the temperature at 25℃-30℃ and stir for 1h. Separate the layers, and decompress and spin-dry the upper layer. Add toluene (100ml) and water (100ml) for extraction, and keep the toluene layer. Decompress and spin-dry the toluene layer to obtain a reddish brown oil. The reddish brown oil is separated by column chromatography to obtain a light yellow oil (10.1g).

[0048] Ethyl acetate (100 ml) was added to the light yellow oil (10.1 g), stirred to dissolve, concentrated hydrochloric acid (6.5 g, content 36.5%) was added, the temperature was raised to 40°C-45°C, stirred for 1 h, and dried under reduced pressure to obtain white solid compound 3 (10.9 g, yield: 26%, purity 97%).

[0049] Its structural characterization data are as follows: 1 HNMR(DMSO-d,600MHz),δ:1.93-1.99(m,2H,CH2),2.65-2.68(t,2H,CH2),2.91-2.94(t,2H ,CH2),3.67-3.68(t,1H,CCH),3.86(s,2H,CH2),7.19-7.32(m,5H,C6H5),9.73(s,1H,HCl); 13 C NMR (CDCl3), δ: 141.19, 128.95, 128.81, 126.60, 79.84, 75.61, 45.85, 40.49, 35.80, 32.46, 27.42; ESI-MS: m / z=174.13[M] + .

[0050] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations within the meaning and scope of the equivalent elements of the claims be included in the invention. Any marking in a claim should not be considered as limiting the claim to which it relates.

[0051] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A selegiline hydrochloride ring-opening impurity, characterized in that: Including compound 1, compound 2, and compound 3, whose structures are as follows:

2. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 1, characterized in that: Using 3-phenylpropylamine as raw material, selegiline hydrochloride ring-opening impurity was obtained through condensation and propargylation. The synthetic route is as follows:

3. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 2, characterized in that: The preparation method comprises the following steps: (1) Condensation: 3-phenylpropylamine and dimethylaminosulfonyl chloride are condensed in toluene as solvent and triethylamine as acid-binding agent to obtain compound 1; (2) Propargylation: Compound 1 obtained in step (1) and 3-bromopropyne are subjected to propargylation in acetonitrile as solvent and potassium hydroxide as acid-binding agent to obtain compound 2; (3) Propargylation: 3-Phenylpropylamine and 3-bromopropyne were reacted in acetonitrile as solvent and potassium hydroxide as acid-binding agent to form a salt to obtain compound 3.

4. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 3, characterized in that: The reaction temperature of step (1) is -10°C to 100°C; the solvent can also be any one of methanol, ethanol, isopropanol, dichloromethane, and tetrahydrofuran; the acid binding agent can also be any one of sodium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

5. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 4, characterized in that: In the step (1), 3-phenylpropylamine and dimethylaminosulfonyl chloride are reacted at 40°C to 45°C under the conditions of toluene as solvent and triethylamine as acid-binding agent; after the reaction, the obtained material is filtered, acidified, alkali adjusted, extracted, and subjected to column chromatography to obtain the target compound 1.

6. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 3, characterized in that: The reaction temperature of step (2) is -10°C to 100°C; the solvent can also be any one of methanol, ethanol, isopropanol, tetrahydrofuran, and N,N-dimethylformamide; the acid binding agent can also be any one of sodium carbonate, sodium bicarbonate, triethylamine, and sodium hydroxide.

7. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 6, characterized in that: In the step (2), compound 1 and 3-bromopropyne are reacted at 40°C to 45°C under the conditions of acetonitrile as solvent and potassium hydroxide as acid binding agent; after the reaction, the obtained material is evaporated to dryness, extracted, decolorized, and subjected to column chromatography to obtain the target compound 2.

8. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 3, characterized in that: The reaction temperature of step (3) is -10°C to 100°C; the solvent can also be any one of methanol, ethanol, isopropanol, tetrahydrofuran, and N,N-dimethylformamide; the acid binding agent can also be any one of sodium carbonate, sodium bicarbonate, triethylamine, and sodium hydroxide.

9. The method for preparing a selegiline hydrochloride ring-opening impurity according to claim 8, characterized in that: In the step (3), 3-phenylpropylamine and 3-bromopropyne are reacted at 25° C. to 30° C. under the conditions of acetonitrile as solvent and potassium hydroxide as acid-binding agent; after the reaction, the obtained material is evaporated to dryness, extracted, and subjected to column chromatography to obtain the target compound 3.

10. Use of the selegiline hydrochloride ring-opening impurity as claimed in claim 1 as a reference substance for quality research of selegiline hydrochloride intermediates, raw materials and compound preparations thereof.

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