Preparation method and application of demethylselegiline
Through the opening of the ring, cymbalization and restoring protection steps of the hand -based compound 2, it was successfully controlled to the Akiki Division to come to Jilan, solving the problem that it is difficult to obtain raw materials in the existing technology, and achieved efficient and safe synthesis of synthesis. process.
Patent Information
- Application Number
- CN202411693230.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-25
- Publication Date
- 2025-01-24
AI Technical Summary
In the prior art, the synthetic route of demethylslegiline relies on difficult-to-obtain α-methylphenethylamine, which makes it difficult to produce licensing.
The use of hand -dynamic compounds 2 is used as the starting raw material. Through the opening of the loop, cymbalization and restoring protection steps, it can be used to go to Jilan to Jilan to avoid the difficulty of the original route.
It provides a novel synthetic route. The starting raw materials are cheap, the response conditions are mild, the operation is simple and safe, the income is high, the purity of each step is as high as HPLC purity> 97 %, and the difficulty of the original route is avoided.
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Figure CN119350166A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical pharmacy, in particular to a preparation method and application of demethylselegiline. Background Art
[0002] Desmethylselegiline is one of the metabolites of selegiline hydrochloride and an important related substance in selegiline hydrochloride API and preparations. Impurity D in the European Pharmacopoeia of selegiline hydrochloride (EP 10.0) is desmethylselegiline. Somerset Pharmaceuticals Ltd. reported that desmethylselegiline itself can also be used as a drug to treat trauma, burns or skin damage, and desmethylselegiline or its composition can be used to treat selegiline-responsive diseases and symptoms. In addition, desmethylselegiline also has the function of preventing and treating peripheral neuropathy.
[0003] 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.
[0004] The prior art discloses that demethylselegiline can be synthesized by propargylation of α-methylphenethylamine (amphetamine), but the raw material source is extremely difficult, and it is very difficult for enterprises to obtain production licenses. Summary of the invention
[0005] The object of the present invention is to provide a method for preparing desmethylselegiline to solve the problems raised in the above background technology.
[0006] To achieve the above object, the present invention provides the following technical solutions:
[0007] A method for preparing demethylselegiline, specifically, using a chiral source compound 2 as a starting material, and obtaining compound 1, i.e. demethylselegiline, through ring opening, alkynylation, and reduction deprotection. The synthesis route is as follows:
[0008]
[0009] As a further solution of the present invention: the preparation method comprises the following steps:
[0010] (1) Ring opening: Compound 2 is subjected to ring opening reduction with sodium borohydride to obtain compound 3;
[0011] (2) Propynylation: Under alkaline conditions, the compound 3 prepared in step (1) is reacted with substituted propyne Alkylation reaction occurs to obtain compound 4;
[0012] (3) Reductive deprotection: Under the action of a reducing agent, the compound 4 obtained in step (2) is reduced to remove the sulfonyl group, and then salt is formed to obtain compound 1, i.e., demethylselegiline.
[0013] As a further scheme of the present invention: in the step (2), X in the substituted propyne is one or more of chlorine, bromine, benzenesulfonate or p-toluenesulfonate, and 3-bromopropyne is preferred in the present invention; the reaction temperature is -10°C to 120°C, and 0°C to 50°C is preferred in the present invention; the base used is selected from one or more of triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and ammonia water, and one or more of triethylamine, sodium hydroxide, potassium hydroxide and ammonia water is preferred in the present invention; the molar ratio of the compound 3, the substituted propyne and the base is 1:(1-2):(1-5), and 1:(1-1.5):(1-2) is preferred in the present invention.
[0014] As a further scheme of the present invention: in step (3), the reaction temperature is -10°C to 120°C, and in the present invention, it is preferably 70°C to 90°C; the solvent used is selected from one or more of toluene, tetrahydrofuran, and dioxane, and in the present invention, it is preferably toluene; the reducing agent is selected from one or more of lithium aluminum tetrahydride, sodium dihydrogen bis(2-methoxyethoxy)aluminate, sodium borohydride and potassium borohydride, and in the present invention, it is preferably sodium dihydrogen bis(2-methoxyethoxy)aluminate; the molar ratio between the compound 4 and the reducing agent is 1:(1-10), and in the present invention, it is preferably 1:(3-6).
[0015] As a further solution of the present invention: the present invention also provides the use of demethylselegiline prepared by the preparation method of the present invention as a reference substance for quality research of selegiline hydrochloride intermediates, raw materials and compound preparations thereof.
[0016] Compared with the prior art, the invention has the following beneficial effects: the invention provides a new idea for the synthesis of demethylselegiline, the starting raw materials are cheap and easily available, the reaction conditions are mild, the operation is simple and safe, the yield is high, and the purity of each step HPLC is greater than 97%, and more importantly, the synthesis route of alpha-methylphenethylamine is avoided.
[0017] The chemical name of the compound of the present invention is:
[0018] Compound 1: (R)-α-methyl-N-(2-propynyl)phenylethylamine hydrochloride;
[0019] Compound 2: (S)-2-Benzyl-N,N-dimethylaziridine-1-sulfonamide;
[0020] Compound 3: (R)-α-methyl-N-(N,N-dimethylsulfonyl)phenethylamine;
[0021] Compound 4: (R)-α-methyl-N,N-(N,N-dimethylsulfonyl, 2-propynyl)phenethylamine. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 The synthetic route of desmethylselegiline described in the embodiment of the present invention is shown in FIG. DETAILED DESCRIPTION
[0023] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. 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.
[0024] See also Figure 1 The present invention discloses a method for preparing demethylselegiline. Specifically, a chiral source compound (S)-2-benzyl-N,N-dimethylaziridinyl-1-sulfonamide is used as a raw material, and (R)-α-methyl-N-(N,N-dimethylsulfonyl)phenethylamine is obtained by ring opening, (R)-α-methyl-N-(N,N-dimethylsulfonyl)phenethylamine and 3-bromopropynyl are propargylated to obtain (R)-α-methyl-N,N-(N,N-dimethylsulfonyl, 2-propynyl)phenethylamine, and (R)-α-methyl-N,N-(N,N-dimethylsulfonyl, 2-propynyl)phenethylamine is deprotected and then salified under the action of a reducing agent to obtain (R)-α-methyl-N-(2-propynyl)phenethylamine hydrochloride, i.e. demethylselegiline. Specific embodiments are as follows:
[0025] Example 1
[0026] (1) Preparation of compound 3:
[0027] Compound 2 (25 g, 104 mmol) and ethanol (100 g) were added to a 250 ml three-necked flask and stirred at 25-30 ° C to clarify. Sodium borohydride aqueous solution was prepared, 4.5 g sodium borohydride was dissolved in 9 g water, and the sodium borohydride aqueous solution was added dropwise to the reaction flask, the temperature was raised to 40-45 ° C, and the temperature was kept and stirred for 14 hours to complete the reaction. The reaction solution was cooled to 0-5 ° C, 6 M hydrochloric acid was added to adjust the pH to 5-6, stirred for 30 minutes, the temperature was controlled to be less than 30 ° C, 15% sodium hydroxide aqueous solution was added to adjust the pH to 7-8, stirred for 30 minutes, and the pH was still in the range of 7-8 after repeated measurement, and filtered, 20 g ethanol was added to the filter cake for leaching, and the ethanol was evaporated under reduced pressure to obtain an oily substance, 66 g toluene and 25 g water were added thereto, and the layers were stirred and separated. The water layer was extracted once with 20 g toluene, the toluene layers were combined, and the toluene was evaporated under reduced pressure at 55 ° C to obtain an oily compound 3 (27.7 g, HPLC: 98.95%).
[0028] The structural characterization data are as follows: 1 HNMR(CDCl3,400MHz),δ:1.19-1.59(q,3H,CH3),2.45-2.67(m,6H,N(CH3)2),2.78-2.79(t,2H ,CH2),3.60-3.67(m,1H,CH),4.00(d,1H,NH),7.18-7.33(m,5H,C6H5); ESI-MS:m / z=243.12[M] + .
[0029] (2) Preparation of compound 4:
[0030] In a 250ml three-necked flask, add the oily compound 3, DMF (100g), and potassium hydroxide (10g, 178.2mmol) from the previous step, control the temperature at 25-30℃, stir for 1.5 hours, then cool to 20-25℃, drop 3-bromopropyne (15g, 126.1mmol), then keep warm and stir for 1 hour, and the reaction is over. Add 43g toluene, stir for several minutes, filter, wash the filter cake with 43g toluene, combine the filtrate, add 50g water, separate the layers, wash the organic phase with 25g water again, combine the water layers, extract with 40g and 20g toluene respectively, combine the toluene, wash with 27g 10% sodium chloride solution, add 3g anhydrous sodium sulfate and 1.5g activated carbon to the organic phase, stir for 1 hour, filter, wash the filter cake with 10ml toluene, evaporate the filtrate to dryness at 55℃, and dry it with 18g isopropanol twice to obtain a yellow-brown oil.
[0031] Add 19.6 g of isopropanol and 34.6 g of n-hexane to the oily substance, raise the temperature to 40-45 ° C, slowly cool to 10-15 ° C for 2 hours after the solution is dissolved, keep warm for 2 hours, then cool to 0-5 ° C, keep warm for 1 hour, filter with suction, wash the filter cake with 13 g of n-hexane, and dry at 45 ° C under normal pressure to obtain light yellow solid particles, which are compound 4 (20.1 g, HPLC: 99.39%).
[0032] The structural characterization data are as follows: 1 HNMR(CDCl3,400MHz),δ:1.26-1.28(q,3H,CH3),2.27-2.28(t,1H,-CCH),2.71(s,6H,N(CH3)2),2.76-2.82(m,1H,pHCH2), 3.03-3.08(q,1H,pHCH2),3.95-3.96(q,2H,NCH2),4.06-4.11(m,1H,NCH),7.19-7.31(m,5H,C6H5); ESI-MS: m / z=281.13[M] +
[0033] (3) Preparation of Compound 1 (Demethylselegiline):
[0034] 113.3g of red aluminum toluene solution was added to a 500ml four-necked bottle, and 52g of toluene was added. The mixture was sealed with N2 and heated to 75-80°C. A mixed solution of compound 4 in 52g toluene was prepared. After the mixture was heated to 75°C, the mixed solution was added dropwise. The temperature did not change. The addition took 2 hours. After the addition was completed, the temperature was controlled at 80-85°C. The mixture was stirred for 2-4 hours and the reaction was completed. The reaction was cooled. 180g of water and 20g of sodium hydroxide were added to another 500ml three-necked bottle. After stirring, the mixture was cooled to 0-5°C. The reaction solution was then added dropwise to the sodium hydroxide aqueous solution. The temperature was controlled within 20°C. After the addition was completed, the mixture was stirred at 25-30°C for 30 minutes. The mixture was separated into layers. The aqueous layer was extracted with 35g toluene. The toluene layers were combined and then washed with 40g of 5% sodium hydroxide and 40g of 10% sodium chloride in turn. The organic phase was dried under reduced pressure at 55°C and dried twice with 16g of isopropanol.
[0035] Add 47 g of isopropanol to the dried product, cool to 10-15 ° C, then add 7.5 g of concentrated hydrochloric acid dropwise, keep stirring at 10-15 ° C for 4 hours, continue to cool to 0-5 ° C, then stir for 1 hour, filter, rinse the filter cake with 10 g of isopropanol, drain and dry under reduced pressure at 50 ° C to obtain an off-white solid, which is compound 1 (demethylselegiline) (10.0 g, HPLC: 99.29%).
[0036] The structural characterization data are as follows: 1HNMR(DMSO,400MHz),δ:0.97-1.30(m,3H,CH3),2.66-2.69(t,1H,-NCH),3.27-3.35(m,1H,pHCH2),3.39-3.71(m,1H,pH CH2),3.72(s,1H,-CCH),3.93-4.02(t,2H,NCH2),7.23-7.37(m,5H,C6H5),9.84(s,2H,NH.HCl); ESI-MS: m / z=174.13[M] + .
[0037] Example 2
[0038] (1) Preparation of compound 3:
[0039] Compound 2 (25 g, 104 mmol) and ethanol (100 g) were added to a 250 ml three-necked flask, and stirred at 25-30°C to clarify. Sodium borohydride aqueous solution was prepared by dissolving 5.1 g of sodium borohydride in 10.2 g of water, and the sodium borohydride aqueous solution was added dropwise to the reaction flask, and the temperature was raised to 40-45°C, and the temperature was kept and stirred for 14 hours to complete the reaction. The reaction solution was cooled to 0-5°C, 6M hydrochloric acid was added to adjust the pH to 5-6, stirred for 30 minutes, the temperature was controlled below 30°C, 15% aqueous sodium hydroxide solution was added to adjust the pH to 7-8, stirred for 30 minutes, the pH was re-measured and still in the range of 7-8, filtered, 20g ethanol was added to the filter cake for rinsing, the ethanol was evaporated under reduced pressure to obtain an oily substance, 66g toluene and 25g water were added thereto, the layers were stirred and separated, the aqueous layer was extracted once with 20g toluene, the toluene layers were combined, and the toluene was evaporated under reduced pressure at 55°C to obtain an oily compound 3 (27.5g, HPLC: 97.95%).
[0040] (2) Preparation of compound 4:
[0041] In a 250ml three-necked flask, add the oily compound 3, DMF (100g), and potassium hydroxide (8.7g, 156.3mmol) from the previous step, control the temperature at 25-30℃, stir for 1.5 hours, then cool to 20-25℃, drop 3-bromopropyne (13.6g, 114.6mmol), then keep warm and stir for 1 hour, and the reaction is over. Add 43g toluene, stir for several minutes, filter, wash the filter cake with 43g toluene, combine the filtrate, add 50g water, separate the layers, wash the organic phase with 25g water again, combine the water layers, extract with 40g and 20g toluene respectively, combine the toluene, wash with 27g 10% sodium chloride solution, add 3g anhydrous sodium sulfate and 1.5g activated carbon to the organic phase, stir for 1 hour, filter, wash the filter cake with 10ml toluene, evaporate the filtrate at 55℃, and dry it with 18g isopropanol twice to obtain a yellow-brown oil.
[0042] Add 19.6 g of isopropanol and 34.6 g of n-hexane to the oily substance, raise the temperature to 40-45 ° C, slowly cool to 10-15 ° C for 2 hours after the solution is dissolved, keep warm for 2 hours, then cool to 0-5 ° C, keep warm for 1 hour, filter with suction, wash the filter cake with 13 g of n-hexane, and dry at 45 ° C under normal pressure to obtain light yellow solid particles, which are compound 4 (13.8 g, HPLC: 98.82%).
[0043] (3) Preparation of Compound 1 (Demethylselegiline):
[0044] Add 36g of red aluminum toluene solution to a 500ml four-necked bottle, add 52g of toluene, seal with N2, and heat to 75-80°C. Prepare a mixed solution of compound 4 in 52g toluene. After heating to 75°C, add the mixed solution dropwise. The temperature does not change. The addition takes 2 hours. After the addition is completed, the temperature is controlled at 80-85°C. Stir for 2-4 hours, and the reaction is completed. Cool down, add 180g of water and 20g of sodium hydroxide to another 500ml three-necked bottle, stir and dissolve, and then cool to 0-5°C. Then add the reaction solution dropwise to the sodium hydroxide aqueous solution, control the temperature within 20°C, complete the addition, stir at 25-30°C for 30 minutes, separate, extract the water layer with 35g toluene, combine the toluene layers, and then wash with 40g of 5% sodium hydroxide and 40g of 10% sodium chloride in turn. The organic phase is decompressed and dried at 55°C, and dried twice with 16g of isopropanol.
[0045] Add 47 g of isopropanol to the dried product, cool to 10-15 ° C, then add 7.5 g of concentrated hydrochloric acid dropwise, keep stirring at 10-15 ° C for 4 hours, continue to cool to 0-5 ° C, then stir for 1 hour, filter, rinse the filter cake with 10 g of isopropanol, drain and dry under reduced pressure at 50 ° C to obtain an off-white solid, which is compound 1 (demethylselegiline) (5.1 g, HPLC: 97.36%).
[0046] Example 3
[0047] (1) Preparation of compound 3:
[0048] Compound 2 (25 g, 104 mmol) and ethanol (100 g) were added to a 250 ml three-necked flask and stirred at 40-45 ° C to clarify. Sodium borohydride aqueous solution was prepared, 4.5 g sodium borohydride was dissolved in 9 g water, and the sodium borohydride aqueous solution was added dropwise to the reaction flask, the temperature was raised to 40-45 ° C, and the temperature was kept and stirred for 14 hours to complete the reaction. The reaction solution was cooled to 0-5 ° C, 6 M hydrochloric acid was added to adjust the pH to 5-6, stirred for 30 minutes, the temperature was controlled to be less than 30 ° C, 15% sodium hydroxide aqueous solution was added to adjust the pH to 7-8, stirred for 30 minutes, and the pH was still in the range of 7-8 after repeated measurement, and suction filtered, 20 g ethanol was added to the filter cake for leaching, and the ethanol was evaporated under reduced pressure to obtain an oily substance, 66 g toluene and 25 g water were added thereto, and the layers were stirred and separated, and the water layer was extracted once with 20 g toluene, the toluene layers were combined, and the toluene was evaporated under reduced pressure at 55 ° C to obtain an oily compound 3 (26.7 g, HPLC: 98.1%).
[0049] (2) Preparation of compound 4:
[0050] In a 250ml three-necked flask, add the oily compound 3 from the previous step, DMF (100g), and potassium hydroxide (10g, 178.2mmol), control the temperature at 40-45℃, stir for 1.5 hours, drop 3-bromopropyne (15g, 126.1mmol), then keep warm and stir for 1 hour at 40-45℃, and the reaction is over. Add 43g toluene, stir for several minutes, filter with suction, wash the filter cake with 43g toluene, combine the filtrate, add 50g water, separate the layers, wash the organic phase with 25g water again, combine the water layers, extract with 40g and 20g toluene respectively, combine the toluene, wash with 27g 10% sodium chloride solution, add 3g anhydrous sodium sulfate and 1.5g activated carbon to the organic phase, stir for 1 hour, filter with suction, wash the filter cake with 10ml toluene, evaporate the filtrate to dryness at 55℃, and dry it with 18g isopropanol twice to obtain a yellow-brown oil.
[0051] Add 19.6 g of isopropanol and 34.6 g of n-hexane to the oily substance, raise the temperature to 40-45 ° C, slowly cool to 10-15 ° C for 2 hours after the solution is dissolved, keep warm for 2 hours, then cool to 0-5 ° C, keep warm for 1 hour, filter with suction, rinse the filter cake with 13 g of n-hexane, and dry at 45 ° C under normal pressure to obtain light yellow solid particles, which are compound 4 (18.3 g, HPLC: 98.45%).
[0052] (3) Preparation of Compound 1 (Demethylselegiline):
[0053] 113.3g of red aluminum toluene solution was added to a 500ml four-necked bottle, and 52g of toluene was added. The mixture was sealed with N2 and heated to 40-45°C. A mixed solution of compound 4 in 52g toluene was prepared and the mixed solution was added dropwise. The temperature did not change. The addition took 2 hours. After the addition was completed, the temperature was controlled at 40-45°C and stirred for 28 hours. The reaction was completed. Cooling was performed. 180g of water and 20g of sodium hydroxide were added to another 500ml three-necked bottle. After stirring and dissolving, the temperature was cooled to 0-5°C. The reaction solution was then added dropwise to the sodium hydroxide aqueous solution. The temperature was controlled within 20°C. After the addition was completed, the mixture was stirred at 25-30°C for 30 minutes. The layers were separated. The aqueous layer was extracted with 35g toluene. The toluene layers were combined and then washed with 40g of 5% sodium hydroxide and 40g of 10% sodium chloride in turn. The organic phase was dried under reduced pressure at 55°C and dried twice with 16g of isopropanol.
[0054] Add 47 g of isopropanol to the dried product, cool to 10-15 ° C, then add 7.5 g of concentrated hydrochloric acid dropwise, keep stirring at 10-15 ° C for 4 hours, continue to cool to 0-5 ° C, then stir for 1 hour, filter, rinse the filter cake with 10 g of isopropanol, drain and dry under reduced pressure at 50 ° C to obtain an off-white solid, which is compound 1 (desmethylselegiline) (7.5 g, HPLC: 97.83%).
[0055] 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 exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.
[0056] 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 method for preparing desmethylselegiline, characterized in that: Using chiral source compound 2 as the starting material, compound 1, i.e. demethylselegiline, is obtained through ring opening, alkynylation, and reductive deprotection. The synthetic route is as follows:
2. The method for preparing desmethylselegiline according to claim 1, wherein: The preparation method comprises the following steps: (1) Ring opening: Compound 2 is subjected to ring opening reduction with sodium borohydride to obtain compound 3; (2) Propynylation: Under alkaline conditions, the compound 3 prepared in step (1) is reacted with substituted propyne Alkylation reaction occurs to obtain compound 4; (3) Reductive deprotection: Under the action of a reducing agent, the compound 4 obtained in step (2) is reduced to remove the sulfonyl group, and then salt is formed to obtain compound 1, i.e., demethylselegiline.
3. A method for preparing desmethylselegiline according to claim 2, characterized in that, In step (2), X in the substituted propyne is one or more of chlorine, bromine, benzenesulfonate or p-toluenesulfonate; the reaction temperature is -10°C to 120°C; the base used is selected from one or more of triethylamine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and ammonia water; the molar ratio of the compound 3, the substituted propyne and the base is 1:(1-2):(1-5).
4. The method for preparing desmethylselegiline according to claim 3, wherein: The substituted propyne in step (2) is 3-bromopropyne; the reaction temperature is 0°C to 50°C; the base used is selected from one or more of triethylamine, sodium hydroxide, potassium hydroxide and ammonia water; the molar ratio of the compound 3, the substituted propyne and the base is 1:(1-1.5):(1-2).
5. A method for preparing desmethylselegiline according to claim 2, characterized in that, In step (3), the reaction temperature is -10°C to 120°C; the solvent used is selected from one or more of toluene, tetrahydrofuran, and dioxane; the reducing agent is selected from one or more of lithium aluminum tetrahydride, sodium dihydrogen bis(2-methoxyethoxy)aluminate, sodium borohydride, and potassium borohydride; and the molar ratio between the compound 4 and the reducing agent is 1:(1 to 10).
6. The method for preparing desmethylselegiline according to claim 5, characterized in that: The reaction temperature in step (3) is 70° C. to 90° C.; the solvent used is toluene; the reducing agent is selected from sodium dihydrogen bis(2-methoxyethoxy)aluminate; and the molar ratio between the compound 4 and the reducing agent is 1:(3 to 6).
7. Use of desmethylselegiline prepared by the preparation method according to any one of claims 1 to 6 as a reference substance for quality research of selegiline hydrochloride intermediates, raw materials and compound preparations thereof.