CN110642721A - Preparation method of selegiline hydrochloride - Google Patents
Preparation method of selegiline hydrochloride Download PDFInfo
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- CN110642721A CN110642721A CN201811569604.2A CN201811569604A CN110642721A CN 110642721 A CN110642721 A CN 110642721A CN 201811569604 A CN201811569604 A CN 201811569604A CN 110642721 A CN110642721 A CN 110642721A
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- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
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- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
The invention relates to the field of chemical pharmacy, in particular to a preparation method of selegiline hydrochloride. The method avoids using control products such as ephedrine, pseudoephedrine, methamphetamine and the like; the invention has the advantages of cheap and easily obtained raw materials, short synthetic route, safe and environment-friendly production and reduced synthetic cost. The preparation method can obtain the target compound with high purity in high yield, and is easy for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of selegiline hydrochloride.
Background
The selegiline (1) belongs to a high-efficiency, high-selectivity and irreversible monoamine oxidase B (MAO-B) inhibitor, can enhance the transfer signal of dopamine, block the decomposition of brain dopamine, and delay or reduce the death of dopamine cells in the substantia nigra of the brain, and is clinically used for treating Parkinson's disease, Alzheimer's disease and depression.
EP0344675A2 discloses a preparation method of selegiline hydrochloride, which takes hydrochloric acid (R) -desoxyephedrine (4) as a raw material, and the hydrochloric acid and bromopropyne are subjected to amine alkylation under the action of alkali to obtain selegiline (1), and the selegiline hydrochloride (2) is obtained after hydrochloride is formed. The raw material (R) -methamphetamine hydrochloride (4) can be deoxidized from the natural product (1S,2R) -ephedrine hydrochloride (3) to obtain (org. process Res. Dev.2014,18, 495-:
US4564706A discloses a preparation method of selegiline hydrochloride, which is characterized in that D-tartaric acid (R) -desoxyephedrine (7) is used as a raw material, amine alkylation is carried out on the raw material and bromopropyne under the action of alkali to obtain selegiline (1), and hydrochloride is formed to obtain selegiline hydrochloride (2). The raw material D-tartaric acid (R) -methamphetamine (7) can be prepared into racemic methamphetamine (6) by enamine and catalytic hydrogenation of propiophenone (5), and then is prepared into (J.chem.Soc.Perkin Trans II 1986,1881-86) by resolution of D-tartaric acid, and the reaction equation is as follows:
5 asymmetric synthetic routes for preparing selegiline hydrochloride disclosed in the literature (Tetrahedron: Asymmetry 2004,15, 3111-.
Among them, methamphetamine (4,6,7) and amphetamine (8), both in their racemic forms and in their optically pure forms, and in their alkali forms and their salt forms, are illicit compounds. It belongs to the control of public security bureau and can not be used and produced at will.
The literature (chem. eur. j.2010,16,12474-12480) discloses a method for preparing selegiline hydrochloride, which does not involve the preparation of intermediates of forbidden compounds, but has severe reaction conditions, such as low temperature of-78 ℃; the starting material (R) -aminopropanol is derived from non-natural alanine and is expensive; reagent 2-pyrimidinesulfonyl chloride (RSO)2Cl, R ═ 2-pyrimidinyl) are also difficult to purchase; sulfur-containing wastewater is also generated in the reaction process. Is not suitable for industrial production. The reaction equation is as follows:
disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel method for preparing selegiline hydrochloride (2), which has the advantages of cheap and easily-obtained raw materials, short synthetic route, safe and environment-friendly production, low cost, high yield and no related prohibited compound.
In one aspect, the present invention provides a novel method for preparing selegiline hydrochloride (2), wherein the reaction equation is as follows:
the method comprises the following steps:
5) propynylation: reacting the compound (12) with a substituted propyne under basic conditionsCarrying out alkylation reaction to obtain a compound (13), wherein X is chlorine, bromine, iodine, mesylate, triflate, benzene sulfonate or p-toluene sulfonate;
6) reduction deprotection: reducing the compound (13) prepared in the step 5) under the action of a reducing agent to remove sulfonyl, so as to prepare a compound (14);
7) methylation: carrying out methylation reaction on the compound (14) prepared in the step 6) and a methylation reagent to prepare selegiline (1);
8) salifying: reacting the selegiline (1) prepared in the step 7) with concentrated hydrochloric acid or hydrogen chloride alcohol solution to prepare selegiline hydrochloride (2);
wherein R is any one of methyl, trifluoromethyl, phenyl, p-tolyl, 2,3 or 4-pyridyl, 2-pyrimidyl, dimethylamino and diisopropylamino, and is preferably p-tolyl or dimethylamino.
Preferably, in the step 5), the reaction temperature is-10 ℃ to 150 ℃, and preferably 0 ℃ to 60 ℃;
preferably, in step 5), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide, N-dimethylacetamide and water, preferably acetonitrile or N, N-dimethylformamide;
preferably, in step 5), the base used is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous ammonia, preferably from one or more of triethylamine, sodium hydroxide, potassium hydroxide and aqueous ammonia;
preferably, in step 5), the substituted propyne is bromopropyne;
preferably, in the step 5), the molar ratio among the compound (12), the substituted propyne and the base is 1: 1-2: 1-5, preferably 1: 1-1.5: 1-2;
preferably, in step 6), the reaction temperature is from-20 ℃ to 150 ℃, preferably from 50 ℃ to 100 ℃, more preferably from 70 ℃ to 90 ℃;
preferably, in step 6), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether, preferably toluene;
preferably, in step 6), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium dihydrobis (2-methoxyethoxy) aluminate;
preferably, in step 6), the molar ratio between the compound (13) and the reducing agent is 1:1 to 10, preferably 1:3 to 6;
preferably, in the step 7), the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 50 ℃;
preferably, in step 7), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water, preferably methanol;
preferably, in step 7), the methylating agent is selected from one or more of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl methanesulfonate, methyl trifluoromethanesulfonate, methyl benzenesulfonate, methyl p-toluenesulfonate, paraformaldehyde-sodium borohydride, paraformaldehyde-potassium borohydride, paraformaldehyde-lithium borohydride, paraformaldehyde-zinc borohydride, paraformaldehyde-sodium cyanoborohydride, paraformaldehyde-sodium triacetoxyborohydride, formaldehyde-sodium borohydride, formaldehyde-potassium borohydride, formaldehyde-lithium borohydride, formaldehyde-zinc borohydride, formaldehyde-sodium cyanoborohydride and formaldehyde-sodium triacetoxyborohydride, preferably from among paraformaldehyde-sodium borohydride, paraformaldehyde-sodium cyanoborohydride;
preferably, in the step 7), the molar ratio between the compound (14) and the methylating agent is 1: 1-5, preferably 1: 1-2;
preferably, in the step 8), the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 50 ℃;
preferably, in step 8), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water;
preferably, in step 8), the hydrogen chloride alcohol solution is selected from one or more of a hydrogen chloride methanol solution, a hydrogen chloride ethanol solution, and a hydrogen chloride isopropanol solution;
preferably, in the step 8), the molar ratio of the selegiline (1) to the concentrated hydrochloric acid or hydrogen chloride alcohol solution is 1: 1-10, preferably 1: 1-2;
preferably, the compound (12) is subjected to a reduction ring-opening reaction by the compound (18) under the action of a reducing agent, and the reaction equation is as follows:
wherein R is as defined above.
Preferably, in the reductive ring-opening reaction for preparing the compound (12), the reaction temperature is-20 ℃ to 150 ℃, preferably 0 ℃ to 80 ℃;
preferably, in the reductive ring-opening reaction for preparing the compound (12), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol and isopropanol, preferably ethanol;
preferably, in the reductive ring-opening reaction for preparing compound (12), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride;
preferably, in the reduction ring-opening reaction for preparing the compound (12), the molar ratio between the compound (18) and the reducing agent is 1: 1-10, preferably 1: 1-1.5.
Preferably, the compound (18) is prepared from the compound (17) and sulfonyl chloride (RSO)2Cl) is prepared by sulfonylation reaction under alkaline conditionThe equation is as follows:
wherein R is as defined above.
Preferably, in the sulfonylation reaction for preparing the compound (18), the reaction temperature is-20 ℃ to 100 ℃, preferably 0 ℃ to 50 ℃;
preferably, in the sulfonylation reaction for producing compound (18), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide and water;
preferably, in the sulfonylation reaction for preparing compound (18), the base used is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably triethylamine or sodium hydroxide;
preferably, in the sulfonylation reaction for preparing compound (18), the sulfonyl chloride is selected from one or more of methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3 or 4-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, dimethylaminosulfonyl chloride and diisopropylaminesulfonyl chloride, preferably p-toluenesulfonyl chloride or dimethylaminosulfonyl chloride;
preferably, in the sulfonylation reaction for preparing the compound (18), the molar ratio of the compound amine (17), the sulfonyl chloride and the base is 1: 1-2: 1-5, preferably 1: 1-1.5: 1-3;
preferably, the compound (17) is prepared by dehydrating and cyclizing the compound (16) with a cyclizing reagent, wherein the reaction equation is as follows:
preferably, in the dehydration cyclization reaction for preparing the compound (17), the reaction temperature is 25-150 ℃, preferably 80-130 ℃;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, dichloromethane and water;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the cyclization agent is selected from one or more of sulfuric acid-sodium hydroxide, sulfuric acid-potassium hydroxide, sulfuric acid-lithium hydroxide, sulfuric acid-calcium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-potassium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-lithium hydroxide and chlorosulfonic acid-triethylamine-calcium hydroxide, preferably sulfuric acid-sodium hydroxide or sulfuric acid-potassium hydroxide;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the molar ratio between the compound (16) and the cyclization reagent is 1: 1-5, preferably 1: 1-2;
preferably, the compound (16) is prepared by the reduction reaction of the compound (15) under the action of a reducing agent and a reduction auxiliary agent, and the reaction equation is as follows:
preferably, in the reduction reaction for preparing the compound (16), the reaction temperature is-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃;
preferably, in the reduction reaction for preparing compound (16), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether, preferably 2-methyltetrahydrofuran or dioxane;
preferably, in the reduction reaction for preparing compound (16), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, borane tetrahydrofuran, borane dimethylsulfide, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride or potassium borohydride;
preferably, in the reduction reaction for preparing the compound (16), the reduction auxiliary is selected from one or more of aluminum trichloride, boron trifluoride diethyl etherate, zinc chloride, titanium tetrachloride, p-toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, iodine and trimethylchlorosilane, and is preferably methanesulfonic acid or sulfuric acid;
preferably, in the reduction reaction for preparing the compound (16), the molar ratio of the compound (15), the reducing agent and the reduction auxiliary agent is 1: 1-10: 0-10, preferably 1: 2-5: 0-5;
preferably, the compound (18) is prepared from the compound (16) and sulfonyl chloride (RSO)2Cl) under basic conditions, wherein R is as defined above, the reaction equation is as follows:
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the reaction temperature is-20 ℃ to 100 ℃, preferably 0 ℃ to 50 ℃;
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl t-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide and water;
preferably, in the sulfonylation-cyclization reaction for producing compound (18), the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably triethylamine or sodium hydroxide;
preferably, in the sulfonylation-cyclization reaction for preparing compound (18), the sulfonyl chloride (RSO)2Cl) is selected from methanesulfonyl chloride, trifluoromethanesulfonylOne or more of chlorine, benzene sulfonyl chloride, p-toluene sulfonyl chloride, 2,3 or 4-pyridine sulfonyl chloride, 2-pyrimidine sulfonyl chloride, dimethylamine sulfonyl chloride and diisopropylamine sulfonyl chloride, preferably p-toluene sulfonyl chloride or dimethylamine sulfonyl chloride;
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the molar ratio of the compound (16), the sulfonyl chloride and the base is 1: 1-5: 1-10, preferably 1: 1-3: 1-5;
in a specific technical scheme, the method for preparing the selegiline hydrochloride (2) comprises the following steps:
the method specifically comprises the following steps:
1) reduction: under the conditions of proper temperature, solvent and reduction auxiliary agent, the compound (15) and proper reducing agent and reduction auxiliary agent are subjected to reduction reaction to prepare a compound (16);
2) dehydration cyclization: under the conditions of proper temperature and solvent, the compound (16) and a proper cyclization reagent undergo dehydration cyclization to prepare a compound (17);
3) sulfonylation: under the conditions of proper temperature, solvent and alkali, the compound (17) is reacted with sulfonyl chloride (RSO)2Cl) to produce a compound (18);
4) reduction and ring opening: under the conditions of proper temperature and solvent, the compound (18) and a proper reducing agent undergo a reduction reaction to prepare a compound (12);
5) propynylation: under the conditions of proper temperature, solvent and alkali, the compound (12) is mixed with substituted propyneAlkylation reaction is carried out to obtain a compound (13), wherein X is selected from one or more of chlorine, bromine, iodine, mesylate, triflate, benzenesulfonate and p-toluenesulfonate, and is preferably bromine;
6) reduction deprotection: under the conditions of proper temperature and solvent, the compound (13) and proper reducing agent are subjected to reduction reaction to remove sulfonyl, and the compound (14) is prepared;
7) methylation: under the conditions of proper temperature and solvent, carrying out methylation reaction on the compound (14) and a proper methylating agent to prepare selegiline (1);
8) salifying: under the conditions of proper temperature and solvent, the selegiline (1) and concentrated hydrochloric acid or hydrochloric alcohol solution form salt to prepare selegiline hydrochloride (2);
wherein R is selected from any one of methyl, trifluoromethyl, phenyl, p-tolyl, 2,3 or 4-pyridyl, 2-pyrimidyl, dimethylamino and diisopropylamino, and is preferably p-tolyl or dimethylamino.
Preferably, in the step 1), the reaction temperature is-20 ℃ to 150 ℃, and preferably 0 ℃ to 100 ℃;
preferably, in step 1), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether, preferably 2-methyltetrahydrofuran or dioxane;
preferably, in step 1), the reducing agent used is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, borane tetrahydrofuran, borane dimethylsulfide, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride or potassium borohydride;
preferably, in step 1), the reduction assistant is selected from one or more of aluminum trichloride, boron trifluoride diethyl etherate, zinc chloride, titanium tetrachloride, p-toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, iodine and trimethylchlorosilane, preferably methanesulfonic acid or sulfuric acid;
preferably, in the step 1), the molar ratio of the compound (15), the reducing agent and the reduction assistant is 1: 1-10: 0-10, preferably 1: 2-5: 0-5;
preferably, in the step 2), the reaction temperature is 25 to 150 ℃, preferably 80 to 130 ℃;
preferably, in step 2), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, dichloromethane and water, preferably toluene;
preferably, in step 2), the cyclization agent is selected from one or more of sulfuric acid-sodium hydroxide, sulfuric acid-potassium hydroxide, sulfuric acid-lithium hydroxide, sulfuric acid-calcium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-potassium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-lithium hydroxide, and chlorosulfonic acid-triethylamine-calcium hydroxide, preferably sulfuric acid-sodium hydroxide or sulfuric acid-potassium hydroxide;
preferably, in the step 2), the molar ratio between the compound (16) and the cyclization agent is 1: 1-5, preferably 1: 1-2;
preferably, in the step 3), the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 50 ℃;
preferably, in step 3), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide and water;
preferably, in step 3), the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably triethylamine or sodium hydroxide;
preferably, in step 3), the sulfonyl chloride (RSO)2Cl) is selected from one or more of acyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3 or 4-pyridine sulfonyl chloride, 2-pyrimidine sulfonyl chloride, dimethylamine sulfonyl chloride and diisopropylamine sulfonyl chloride, and is preferably p-toluenesulfonyl chloride or dimethylaminosulfonyl chloride;
preferably, in the step 3), the molar ratio among the compound (17), the sulfonyl chloride and the base is 1: 1-2: 1-5, preferably 1: 1-1.5: 1-3;
preferably, in the step 4), the reaction temperature is-20 ℃ to 150 ℃, and preferably 0 ℃ to 100 ℃;
preferably, in step 4), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol and isopropanol, preferably ethanol;
preferably, in step 4), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride;
preferably, in the step 4), the molar ratio between the compound (18) and the reducing agent is 1: 1-10, preferably 1: 1-1.5;
preferably, in the step 5), the reaction temperature is-10 ℃ to 150 ℃, and preferably 0 ℃ to 60 ℃;
preferably, in step 5), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide, N-dimethylacetamide and water, preferably acetonitrile or N, N-dimethylformamide;
preferably, in step 5), the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and aqueous ammonia, preferably from one or more of triethylamine, sodium hydroxide, potassium hydroxide and aqueous ammonia;
preferably, in the step 5), the molar ratio among the compound (12), the halopropyne and the base is 1: 1-2: 1-5, preferably 1: 1-1.5: 1-2;
preferably, in step 6), the reaction temperature is-20 ℃ to 150 ℃, preferably 50 ℃ to 100 ℃;
preferably, in step 6), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether;
preferably, in step 6), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium dihydrobis (2-methoxyethoxy) aluminate;
preferably, in step 6), the molar ratio between the compound (13) and the reducing agent is 1:1 to 10, preferably 1:3 to 6;
preferably, in the step 7), the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 50 ℃;
preferably, in step 7), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water, preferably methanol;
preferably, in step 7), the methylating agent is selected from one or more of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl methanesulfonate, methyl trifluoromethanesulfonate, methyl benzenesulfonate, methyl p-toluenesulfonate, paraformaldehyde-sodium borohydride, paraformaldehyde-potassium borohydride, paraformaldehyde-lithium borohydride, paraformaldehyde-zinc borohydride, paraformaldehyde-sodium cyanoborohydride, paraformaldehyde-sodium triacetoxyborohydride, formaldehyde-sodium borohydride, formaldehyde-potassium borohydride, formaldehyde-lithium borohydride, formaldehyde-zinc borohydride, formaldehyde-sodium cyanoborohydride and formaldehyde-sodium triacetoxyborohydride;
preferably, in the step 7), the molar ratio between the compound (14) and the methylating agent is 1: 1-5, preferably 1: 1-2;
preferably, in the step 8), the reaction temperature is-20 ℃ to 100 ℃, and preferably 0 ℃ to 50 ℃;
preferably, in step 8), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water;
preferably, in step 8), the hydrogen chloride alcohol solution is selected from one or more of a hydrogen chloride methanol solution, a hydrogen chloride ethanol solution, and a hydrogen chloride isopropanol solution;
preferably, in the step 8), the molar ratio of the selegiline (1) to the concentrated hydrochloric acid or hydrogen chloride alcohol solution is 1: 1-10, preferably 1: 1-2;
the chemical name of the compound is as follows:
compound (1): (R) -N-methyl-N- (1-methyl-2-phenylethyl) prop-2-ynylamine;
compound (2): (R) -N-methyl-N- (1-methyl-2-phenylethyl) prop-2-ynylamine hydrochloride;
compound (3): (1S,2R) -2-methylamino-1-phenylpropan-1-ol hydrochloride;
mixture (4): (R) -N-methyl-1-phenylpropan-2-amine hydrochloride;
compound (5): 1-phenylpropan-2-one;
compound (6): (R/S) -N-methyl-1-phenylpropan-2-amine
Compound (7): (R) -N-methyl-1-phenylpropan-2-amine D-tartrate;
compound (8): (R/S) -1-phenylpropan-2-amine;
compound (9): (R) -2-aminopropan-1-ol;
compound (10): (R) -2-R for sulfonamidoprop-1-ol R for sulfonate;
compound (11): (R) -2-methyl-1-R-sulfonylethylenimine;
compound (12): (R) -N- (1-methyl-2-phenylethyl) R sulfonamide;
compound (13): (R) -N- (1-methyl-2-phenylethyl) -N-prop-2-ynyl R sulfonamide;
compound (14): (R) -N- (1-methyl-2-phenylethyl) prop-2-ynylamine;
compound (15): (S) -2-amino-3-phenylpropionic acid;
compound (16): (S) -2-amino-3-phenylpropan-1-ol;
compound (17): (S) -2-benzylethylenimine;
compound (18): (S) -2-benzyl-1-R-sulfonylethylenimine.
Detailed Description
The high pressure liquid phase (HPLC) parameters used in the present invention are: column, Sunfire C18, 250mx4.6mm,5 μm; column temperature, 45 ℃; diluent, water-methanol (1:1, v/v); flow rate, 0.8 ml/min; detection wavelength, UV260 nm; sample introduction volume, 10 μ l; sample concentration, 0.5 mg/ml; mobile phase a, 1000ml water containing 1ml triethylamine and 1.56g sodium dihydrogen phosphate dihydrate, phosphoric acid adjusted pH 5.5; mobile phase B, acetonitrile;
the invention obtains a hydrogen spectrum (1HNMR) data used was a 400MHz nuclear magnetic resonance instrument (bruker advance II 400MHz) from bruker; taking Tetramethylsilicon (TMS) as an internal standard, and collecting at room temperature; chemical shifts (δ) are parts per million (ppm); the singlet is denoted as s, the doublet as d, the triplet as t, the quartet as q, the multiplet as m, and the broad singlet as brs; the coupling constant is denoted as j in Hz; the deuterated solvent is deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d)6)；
The instrument used for obtaining Mass Spectrum (MS) data is Shimadzu liquid chromatograph-mass spectrometer (Shimadzu LCMS 2010EV), and the forward direction (positive) gives an ion peak (MH +) of molecular weight hydrogenation;
unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the rest is weight/weight percentage;
the present invention will be specifically described with reference to examples; the embodiments of the present invention are only used for illustrating the technical solutions of the present invention, and are not limited by the embodiments, and any changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit, substance, and principle of the present invention should be regarded as equivalent substitutions, and are included in the scope of the present invention.
Example 1Preparation of Compound (S) -2-amino-3-phenylpropan-1-ol (16)
1) Suspending 165 g of L-phenylalanine (15) in 1L of 1, 4-dioxane at room temperature under stirring, adding 95 g of sodium borohydride in 10 batches, and continuing to stir for half an hour after the addition is finished;
2) controlling the temperature to be lower than 20 ℃, slowly dripping 120 g of concentrated sulfuric acid, and continuously stirring for 20 hours at room temperature;
3) slowly dropwise adding 100 ml of methanol under stirring at room temperature, evaporating the solvent at 60 ℃ under reduced pressure, adding 1L of 5N sodium hydroxide solution, and stirring and refluxing for 3 hours;
4) cooling to room temperature, adding 1L of toluene, stirring for 30 minutes at room temperature, and then standing for layering;
5) the separated organic phase, i.e. the toluene solution of the desired amino alcohol (16), is used directly in the next reaction.
1H-NMR(CDCl3,400MHz)δ2.43(ddt,J＝12.0,8.0,4.0Hz,1H),2.93 (ddt,J＝12.0,8.0,4.0Hz,1H),),3.18(brs,1H),3.32(ddd,J＝14.0,4.0,2.8 Hz,1H),3.37-3.48(m,1H),3.67(brs,2H),3.82(ddd,J＝14.0,4.0,2.8Hz, 1H),7.15-7.18(m,3H),7.20-7.30(m,2H)；m/z 152(M+H)；99.95ee％。
Example 2Preparation of compound (S) -2-benzylethylenimine (17)
1) To the toluene solution of aminoalcohol (16) obtained in example 1, 200 ml of 50% sulfuric acid was added at room temperature, and the mixture was stirred for 30 minutes to form a salt;
2) after refluxing and water distribution, 600 ml of 25% sodium hydroxide solution is added at 80 ℃;
3) continuously stirring and refluxing for 20 hours, cooling to room temperature, standing and layering;
4) the organic layer was washed with a mixed solution of 200 ml of saturated brine and 200 ml of 10% sodium hydroxide;
5) the separated organic phase, i.e. the toluene solution of the desired aziridine (17), was used directly in the next reaction.
1H-NMR(CDCl3,400MHz)δ1.6(brs,1H),2.25-2.32(m,1H),2.34-2.42 (m,2H),2.57-2.66(m,1H),2.88(ddt,J＝12.0,8.0,4.0Hz,1H),7.14-7.18(m, 3H),7.21-7.31(m,2H)；m/z 134(M+H)；99.95ee％。
Example 3Preparation of compound (S) -2-benzyl-1-dimethylaminosulfonylethylenimine (18)
1) 150 g of triethylamine was added to the solution of aziridine (17) in toluene obtained in example 2 at room temperature with stirring;
2) slowly dropwise adding 140 g of dimethylamino sulfonyl chloride, and continuously stirring for 6 hours at room temperature after dropwise adding;
3) performing suction filtration to remove salt, washing the filtrate with 1N hydrochloric acid (until the pH of a water layer is 4-6), washing with saturated sodium bicarbonate (until the pH of the water layer is 7-8), drying with anhydrous sodium sulfate, performing suction filtration to remove sodium sulfate, and performing reduced pressure concentration on the filtrate to remove the solvent to obtain an oily substance;
4) mixing the oily matter with 100 ml of isopropanol and 250 ml of n-hexane, stirring for 30 minutes at 40 ℃,1 hour at 10-15 ℃, and 2 hours at 0-5 ℃;
5) suction filtration, leaching the filter cake with n-hexane, and vacuum drying at 50 ℃ to obtain 200 g of compound (18) as a white solid.
1H-NMR(CDCl3,400MHz)δ1.58(d,J＝4.4Hz,1H),2.13(d,J＝4.4Hz, 1H),2.66(s,6H),2.69(dd,J＝14.0,6.8Hz,1H),2.80-2.90(m,1H),2.95(dd, J＝14.0,7.2Hz,1H),7.20-7.28(m,3H),7.30-7.42(m,2H)；m/z 241(M+H)； 99.95ee％。
Example 4Preparation of compound (S) -2-benzyl-1-dimethylaminosulfonylethylenimine (18)
1) To the toluene solution of aminoalcohol (16) obtained in example 1, 300 g of triethylamine was added under stirring at room temperature;
2) slowly dropwise adding 280 g of dimethylamino sulfonyl chloride, and continuously stirring for 8 hours at room temperature after dropwise adding;
3) carrying out suction filtration to remove salt, mixing the filtrate with 150 g of potassium carbonate, and stirring at room temperature for 6 hours;
4) performing suction filtration and desalting again, washing the filtrate with 1N hydrochloric acid (until the pH of a water layer is 4-6), washing with saturated sodium bicarbonate (until the pH of the water layer is 7-8), drying with anhydrous sodium sulfate, performing suction filtration and desalting, and concentrating the filtrate under reduced pressure to remove the solvent completely to obtain an oily substance;
5) mixing the oily matter with 100 ml of isopropanol and 250 ml of n-hexane, stirring for 30 minutes at 40 ℃,1 hour at 10-15 ℃, and 2 hours at 0-5 ℃;
6) suction filtration, leaching the filter cake with n-hexane, and vacuum drying at 50 ℃ to obtain 230 g of compound (18) as a white solid.
1H-NMR(CDCl3,400MHz)δ1.58(d,J＝4.4Hz,1H),2.13(d,J＝4.4Hz, 1H),2.66(s,6H),2.69(dd,J＝14.0,6.8Hz,1H),2.80-2.90(m,1H),2.95(dd, J＝14.0,7.2Hz,1H),7.20-7.28(m,3H),7.30-7.42(m,2H)；m/z 241(M+H)； 99.95ee％。
Example 5Preparation of compound (R) -N- (1-methyl-2-phenylethyl) dimethylamino sulfonamide (12)
1) Dissolving 170 g of the compound (18) in 800 ml of ethanol, controlling the temperature to be 25-30 ℃, stirring, dropwise adding an aqueous solution of sodium borohydride (30 g of sodium borohydride and 60 ml of water), and then continuously stirring for 16 hours at 40-45 ℃;
2) controlling the temperature to be 10-20 ℃ and stirring, firstly adjusting the pH of the reaction mixture to be 5-6 by using 6N hydrochloric acid, and then adjusting the pH to be 7-8 by using 15% sodium hydroxide;
3) filtering to remove salt, evaporating the filtrate at 50 ℃ under reduced pressure to remove the solvent, and adding 800 ml of toluene and 300 ml of water;
4) stirring for 30 minutes at room temperature, standing for layering, and separating out a toluene phase;
5) the toluene was distilled off under reduced pressure to obtain the desired compound (12), which was used directly in the next reaction.
1H-NMR(CDCl3,400MHz)δ1.16(d,J＝7.0Hz,3H),2.71(ddt,J＝12.0, 8.0,4.0Hz,1H),2.79(s,6H),2.79(ddt,J＝12.0,8.0,4.0Hz,1H),3.17-3.29 (m,1H),4.88(brs,1H),7.10-7.15(m,3H),7.20-7.32(m,2H)；m/z 243(M+H)； 99.95ee％。
Examples 6 to 17Preparation of compound (R) -N- (1-methyl-2-phenylethyl) dimethylamino sulfonamide (12)
Compound (12) is prepared by reductive ring opening of compound (18) according to the procedure of example 5 under other experimental conditions, and the experimental results are summarized in the following table.
The above conditions are found in experiments: 1) examples 5-11, at the preferred temperatures, the reactions have high conversion and high yield, and ethanol is preferred over isopropanol and dioxane; 2) examples 12-17, the reaction showed a higher conversion at the preferred temperature, but the yield was not satisfactory; 3) example 12 lithium aluminum hydride at-78 ℃ shows relatively good conversion rate and yield, but because of its harsh reaction conditions, the post-treatment is very troublesome and dangerous, and is not easy to be industrially produced in large scale; 4) lithium trimethoxy aluminum hydride is relatively safe, but its reductive ring opening performance is far less good than that of sodium borohydride.
Example 18Preparation of compound (R) -N- (1-methyl-2-phenylethyl) -N-prop-2-ynyldimethylaminosulfonamide (13)
1) Dissolving the compound (12) obtained in the example 5 in 300 ml of dimethylformamide, controlling the temperature to be 25-30 ℃, stirring, adding 60 g of potassium hydroxide, dropwise adding 100 g of propynyl bromide after 30 minutes, and continuing to keep the temperature and stir for 3 hours;
2) adding 1L toluene and 500 ml saturated common salt water, stirring at room temperature for 30 minutes, standing for layering, washing an organic phase with 300 ml 5% common salt water, drying with anhydrous sodium sulfate, and filtering to remove salt;
3) after the filtrate was distilled off toluene at 50 ℃ under reduced pressure, 150 ml of isopropyl alcohol and 300 ml of n-hexane were added;
4) stirring for 30 minutes at 40-45 ℃,2 hours at 10-15 ℃ and 1 hour at 0-5 ℃;
5) suction filtration, leaching the filter cake with n-hexane, and vacuum drying at 50 ℃ to obtain 180 g of compound (13) as a white solid.
1H-NMR(CDCl3,400MHz)δ1.26(d,J＝6.8Hz,3H),2.20-2.30(m,1H), 2.71(s,6H),2.81(dd,J＝14.0,6.8Hz,1H),3.07(dd,J＝14.0,7.2Hz,1H), 3.90-4.00(m,2H),4.05-4.20(m,1H),7.15-7.35(m,5H)；m/z 281(M+H)； 99.97ee％。
Example 19Preparation of compound (R) -N- (1-methyl-2-phenylethyl) prop-2-ynylamine (14)
1) Dissolving 680 g of reduced aluminum (Red-Al) in 350 ml of toluene, slowly dropwise adding 120 g of a toluene (350 ml) solution of a compound (13) while stirring at the temperature of 80-85 ℃, continuously keeping the temperature and stirring for 5 hours, and then cooling to room temperature for later use;
2) slowly dripping 1200 g of 10% sodium hydroxide solution into the reaction liquid cooled to room temperature under stirring at the temperature of 25-30 ℃, keeping the temperature and stirring for 1 hour after the dripping is finished, and standing for layering;
3) the organic layer was washed with 500 ml of 5% sodium bicarbonate and 500 ml of 5% brine in this order;
4) drying the anhydrous sodium sulfate, removing the sodium sulfate by suction filtration, concentrating the filtrate under reduced pressure, completely removing the solvent, and adding 500 ml of methanol;
5) about 200 ml of methanol was distilled off under reduced pressure, and the remaining methanol solution of compound (14) was used for the next reaction.
1H-NMR(CDCl3,400MHz)δ1.16(d,J＝6.8Hz,3H),2.34(t,J＝3.8Hz, 1H),2.41-2.46(m,1H),2.80(ddt,J＝12.0,8.0,4.0Hz,1H),3.08(ddt,J＝ 12.0,8.0,4.0Hz,1H),3.33(ddd,J＝8.0,3.8,2.2Hz,1H),3.39(ddd,J＝8.0, 3.8,2.2Hz,1H),3.53(hept,J＝3.8Hz,1H),7.15-7.35(m,5H)；m/z 174(M+H)；99.97ee％。
Examples 20 to 30Preparation of compound (R) -N- (1-methyl-2-phenylethyl) prop-2-ynylamine (14)
Compound (14) is obtained by reduction of compound (13) according to the procedure of example 19 under other experimental conditions, the results of which are summarized in the following table.
| Examples of the invention | Reducing agent | Solvent(s) | Temperature of | Conversion rate% | Yield% |
| 19 | Reducing aluminium (Red-Al) | Toluene | 85 | 100 | 97 |
| 20 | Reducing aluminium (Red-Al) | Toluene | 25 | 68 | 55 |
| 21 | Reducing aluminium (Red-Al) | Toluene | 100 | 100 | 75 |
| 22 | Lithium aluminum hydride | Tetrahydrofuran (THF) | 0 | 65 | 60 |
| 23 | Lithium aluminum hydride | Tetrahydrofuran (THF) | 25 | 95 | 85 |
| 24 | Lithium aluminum hydride | Tetrahydrofuran (THF) | 65 | 100 | 72 |
| 25 | Trimethoxy lithium aluminum hydride | Dioxane (dioxane) | 25 | 56 | 48 |
| 26 | Trimethoxy lithium aluminum hydride | Dioxane (dioxane) | 80 | 61 | 75 |
| 27 | Trimethoxy lithium aluminum hydride | Dioxane (dioxane) | 100 | 100 | 68 |
| 28 | Lithium aluminum tri-tert-butoxyhydride | Toluene | 25 | 60 | 51 |
| 29 | Lithium aluminum tri-tert-butoxyhydride | Toluene | 80 | 100 | 83 |
| 30 | Lithium aluminum tri-tert-butoxyhydride | Toluene | 100 | 100 | 65 |
The above conditions are found in experiments: 1) examples 19-21, at the preferred temperatures, the reactions had high conversion and high yield; 2) examples 22-30, the reaction showed a higher conversion at the preferred temperature, but the yield was not satisfactory; 3) in the reducing agent used at 25 ℃, lithium aluminum hydride shows relatively good conversion rate and yield, but the treatment after the reaction is very troublesome and dangerous, so that the industrial mass production is not easy to realize; 4) Lithium trimethoxy aluminum hydride and lithium tri-tert-butoxyaluminum hydride are relatively mild, but their reductive deprotection performance is far less good than that of reduced aluminum (Red-Al).
Example 31Preparation of compound selegiline (1)
1) Slowly dropwise adding 32 g of formaldehyde aqueous solution into the methanol solution of the compound (14) obtained in example 19 at 0-10 ℃ under stirring for 1 hour, and continuously stirring for 2 hours;
2) dropwise adding 15 g of sodium borohydride aqueous solution and 30 ml of water at 0-10 ℃ under the stirring condition, finishing dropwise adding within 1 hour, and continuing stirring for 2 hours;
3) adjusting the pH value of the reaction mixture to 4-6 by using 1N hydrochloric acid at 0-10 ℃ under the stirring condition, and then adjusting the pH value to 7-8 by using 1N sodium hydroxide solution;
4) evaporating the solvent at 50 ℃ under reduced pressure, adding 300 ml of toluene and 200 ml of water, stirring for 30 minutes at room temperature, and standing for layering;
5) washing the organic phase with a mixed solution of 100 ml of water and 100 ml of strong ammonia water, evaporating the solvent at 50 ℃ under reduced pressure to obtain oily selegiline (1), and carrying out salt formation purification on the oily selegiline (1);
1H-NMR(CDCl3,400MHz)δ1.01(d,J＝6.8Hz,3H),2.32(s,3H),2.46 (ddt,J＝12.0,8.0,3.8Hz,1H),2.61(t,J＝3.8Hz,1H),2.65(ddt,J＝12.0,8.0, 3.8Hz,1H),2.88-2.98(m,1H),3.57(dd,J＝11.6,3.8Hz,1H),3.72(dd,J＝ 11.6,3.8Hz,1H),7.10-7.32(m,5H)；m/z 188(M+H)；99.97ee％。
example 32Preparation of compound selegiline hydrochloride (2)
1) 300 ml of isopropanol is added into the oily selegiline (1) obtained in the example 31, 35 ml of concentrated hydrochloric acid is slowly dripped into the oily selegiline (1) under the stirring at room temperature, and the stirring is continued for 2 hours after the dripping is finished;
2) evaporating at 50 ℃ under reduced pressure until the mixture is dry, adding 300 ml of isopropanol and 2 g of activated carbon, and stirring at 50-55 ℃ for 1 hour;
3) carrying out vacuum filtration, stirring the filtrate for 2 hours at 10-15 ℃, and stirring for 1 hour at 0-5 ℃;
4) carrying out vacuum filtration, washing a filter cake by using cold isopropanol, and carrying out suction drying;
5) and drying the filter cake at 40-45 ℃ under reduced pressure to obtain a selegiline hydrochloride (2) product, 72 g of which is a white solid.
1H-NMR(DMSO-d6,400MHz)δ1.10(d,J＝6.8Hz,3H),2.65(ddt,J＝ 12.0,8.0,4.0Hz,1H),2.79(s,3H),3.37(ddt,J＝12.0,8.0,4.0Hz,1H), 3.62-3.78(m,1H),3.86(dd,J＝11.6,3.8Hz,1H),4.22(dd,J＝11.6,3.8Hz, 1H),7.20-7.30(m,3H),7.30-7.40(m,2H),11.77(brs,1H)；m/z 188(M+H)； 99.98ee％。
Claims (10)
1. A process for the preparation of selegiline hydrochloride (2), which comprises the steps of:
5) propynylation: reacting the compound (12) with a substituted propyne under basic conditions
Carrying out alkylation reaction to obtain a compound (13), wherein X is chlorine, bromine, iodine, mesylate, triflate, benzene sulfonate or p-toluene sulfonate;
6) reduction deprotection: reducing the compound (13) prepared in the step 5) under the action of a reducing agent to remove sulfonyl, so as to prepare a compound (14);
7) methylation: carrying out methylation reaction on the compound (14) prepared in the step 6) and a methylation reagent to prepare selegiline (1);
8) salifying: reacting the selegiline (1) prepared in the step 7) with concentrated hydrochloric acid or hydrogen chloride alcohol solution to prepare selegiline hydrochloride (2);
wherein R is any one of methyl, trifluoromethyl, phenyl, p-tolyl, 2,3 or 4-pyridyl, 2-pyrimidyl, dimethylamino and diisopropylamino, and is preferably p-tolyl or dimethylamino.
2. The method of claim 1, wherein in step 5), the reaction temperature is-10 ℃ to 150 ℃, preferably 0 ℃ to 60 ℃;
preferably, in step 5), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide, N-dimethylacetamide and water, preferably acetonitrile or N, N-dimethylformamide;
preferably, in step 5), the base used is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous ammonia, preferably from one or more of triethylamine, sodium hydroxide, potassium hydroxide and aqueous ammonia;
preferably, in step 5), the substituted propyne is bromopropyne;
preferably, in the step 5), the molar ratio among the compound (12), the substituted propyne and the base is 1:1 to 2:1 to 5, preferably 1:1 to 1.5:1 to 2.
3. The method of claim 1 or 2, wherein in step 6), the reaction temperature is-20 ℃ to 150 ℃, preferably 50 ℃ to 100 ℃, more preferably 70 ℃ to 90 ℃;
preferably, in step 6), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether, preferably toluene;
preferably, in step 6), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium dihydrobis (2-methoxyethoxy) aluminate;
preferably, in step 6), the molar ratio between the compound (13) and the reducing agent is 1:1 to 10, preferably 1:3 to 6.
4. The method of any one of claims 1 to 3, wherein in step 7), the reaction temperature is from-20 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃;
preferably, in step 7), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water, preferably methanol;
preferably, in step 7), the methylating agent is selected from one or more of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl methanesulfonate, methyl trifluoromethanesulfonate, methyl benzenesulfonate, methyl p-toluenesulfonate, paraformaldehyde-sodium borohydride, paraformaldehyde-potassium borohydride, paraformaldehyde-lithium borohydride, paraformaldehyde-zinc borohydride, paraformaldehyde-sodium cyanoborohydride, paraformaldehyde-sodium triacetoxyborohydride, formaldehyde-sodium borohydride, formaldehyde-potassium borohydride, formaldehyde-lithium borohydride, formaldehyde-zinc borohydride, formaldehyde-sodium cyanoborohydride and formaldehyde-sodium triacetoxyborohydride, preferably from among paraformaldehyde-sodium borohydride, paraformaldehyde-sodium cyanoborohydride;
preferably, in the step 7), the molar ratio between the compound (14) and the methylating agent is 1: 1-5, preferably 1: 1-2.
5. The method according to any one of claims 1 to 4, wherein, in step 8), the reaction temperature is from-20 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃;
preferably, in step 8), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol and water;
preferably, in step 8), the hydrogen chloride alcohol solution is selected from one or more of a hydrogen chloride methanol solution, a hydrogen chloride ethanol solution, and a hydrogen chloride isopropanol solution;
preferably, in the step 8), the molar ratio of the selegiline (1) to the concentrated hydrochloric acid or hydrogen chloride alcohol solution is 1: 1-10, preferably 1: 1-2.
6. The production method according to any one of claims 1 to 5, characterized in that the compound (12) is subjected to a reduction ring-opening reaction from the compound (18) under the action of a reducing agent,
wherein R is as defined in any one of claims 1 to 5;
preferably, in the reductive ring-opening reaction for preparing the compound (12), the reaction temperature is-20 ℃ to 150 ℃, preferably 0 ℃ to 80 ℃;
preferably, in the reductive ring-opening reaction for preparing the compound (12), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol and isopropanol, preferably ethanol;
preferably, in the reductive ring-opening reaction for preparing compound (12), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride;
preferably, in the reduction ring-opening reaction for preparing the compound (12), the molar ratio between the compound (18) and the reducing agent is 1: 1-10, preferably 1: 1-1.5.
7. The process according to any one of claims 1 to 6, wherein compound (18) is prepared from compound (17) and sulfonyl chloride (RSO)2Cl) is subjected to sulfonylation reaction under alkaline condition,
wherein R is as defined in any one of claims 1 to 6;
preferably, in the sulfonylation reaction for preparing the compound (18), the reaction temperature is-20 ℃ to 100 ℃, preferably 0 ℃ to 50 ℃;
preferably, in the sulfonylation reaction for producing compound (18), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide and water;
preferably, in the sulfonylation reaction for preparing compound (18), the base used is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably triethylamine or sodium hydroxide;
preferably, in the sulfonylation reaction for preparing compound (18), the sulfonyl chloride is selected from one or more of methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3 or 4-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, dimethylaminosulfonyl chloride and diisopropylaminesulfonyl chloride, preferably p-toluenesulfonyl chloride or dimethylaminosulfonyl chloride;
preferably, in the sulfonylation reaction for preparing the compound (18), the molar ratio of the compound amine (17), the sulfonyl chloride and the base is 1: 1-2: 1-5, preferably 1: 1-1.5: 1-3.
8. The production method according to any one of claims 1 to 7, wherein the compound (17) is produced by subjecting the compound (16) to a dehydration cyclization reaction with a cyclization agent,
preferably, in the dehydration cyclization reaction for preparing the compound (17), the reaction temperature is 25-150 ℃, preferably 80-130 ℃;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetonitrile, dichloromethane and water;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the cyclization agent is selected from one or more of sulfuric acid-sodium hydroxide, sulfuric acid-potassium hydroxide, sulfuric acid-lithium hydroxide, sulfuric acid-calcium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-potassium hydroxide, chlorosulfonic acid-triethylamine-sodium hydroxide, chlorosulfonic acid-triethylamine-lithium hydroxide and chlorosulfonic acid-triethylamine-calcium hydroxide, preferably sulfuric acid-sodium hydroxide or sulfuric acid-potassium hydroxide;
preferably, in the dehydration cyclization reaction for preparing the compound (17), the molar ratio between the compound (16) and the cyclization reagent is 1: 1-5, preferably 1: 1-2.
9. The production method according to any one of claims 1 to 8, wherein the compound (16) is produced by a reduction reaction of the compound (15) with a reducing agent and a reducing assistant,
preferably, in the reduction reaction for preparing the compound (16), the reaction temperature is-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃;
preferably, in the reduction reaction for preparing compound (16), the solvent used is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene glycol dimethyl ether, preferably 2-methyltetrahydrofuran or dioxane;
preferably, in the reduction reaction for preparing compound (16), the reducing agent is selected from one or more of lithium aluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate, lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tri-tert-butoxyaluminum hydride, borane tetrahydrofuran, borane dimethylsulfide, lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride, preferably sodium borohydride or potassium borohydride;
preferably, in the reduction reaction for preparing the compound (16), the reduction auxiliary is selected from one or more of aluminum trichloride, boron trifluoride diethyl etherate, zinc chloride, titanium tetrachloride, p-toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, iodine and trimethylchlorosilane, and is preferably methanesulfonic acid or sulfuric acid;
preferably, in the reduction reaction for preparing the compound (16), the molar ratio of the compound (15), the reducing agent and the reduction auxiliary agent is 1: 1-10: 0-10, and preferably 1: 2-5: 0-5.
10. The process according to any one of claims 1 to 9, wherein compound (18) is prepared from compound (16) and sulfonyl chloride (RSO)2Cl) under basic conditions, wherein R is as defined above, the reaction equation is as follows:
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the reaction temperature is-20 ℃ to 100 ℃, preferably 0 ℃ to 50 ℃;
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the solvent is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, isopropyl ether, methyl t-butyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dimethylformamide and water;
preferably, in the sulfonylation-cyclization reaction for producing compound (18), the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably triethylamine or sodium hydroxide;
preferably, in the sulfonylation-cyclization reaction for preparing compound (18), the sulfonyl chloride (RSO)2Cl) is selected from one or more of methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3 or 4-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, dimethylamine sulfonyl chloride and diisopropylamine sulfonyl chloride, and is preferably p-toluenesulfonyl chloride or dimethylaminosulfonyl chloride;
preferably, in the sulfonylation-cyclization reaction for preparing the compound (18), the molar ratio of the compound (16), the sulfonyl chloride and the base is 1: 1-5: 1-10, preferably 1: 1-3: 1-5.
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