阅读说明：本技术 一种3-氨基吡咯烷盐酸盐的合成方法 (Synthetic method of 3-aminopyrrolidine hydrochloride ) 是由 刘足和 方靖 舒恺 张力 于 2020-11-27 设计创作，主要内容包括：本发明公开了一种3-氨基吡咯烷盐酸盐的合成方法,包括S1：化合物I与化合物II环合反应得化合物III；S2：化合物III在卤化氢气体作用下得化合物IV；S3：用化合物IV与有机磺酰胺在碱存在下反应得化合物V；S4：化合物V与酸反应得到化合物VI。该3-氨基吡咯烷盐酸盐的合成方法引进芳、烷磺酸基对两个氨基进行保护,脱保护时,可以使用单一反应条件,有效减少操作步骤；用苄基保护氨时,脱保护要用到贵金属钯和高压催化加氢,生产成本高,操作风险性高,使用芳、烷磺酸基保护,脱保护只需用酸催化水解,反应条件温和。(The invention discloses a synthesis method of 3-aminopyrrolidine hydrochloride, which comprises the following steps of S1: performing cyclization reaction on the compound I and the compound II to obtain a compound III; s2: the compound III is reacted with hydrogen halide gas to obtain a compound IV; s3: reacting the compound IV with organic sulfamide in the presence of alkali to obtain a compound V; s4: and reacting the compound V with acid to obtain a compound VI. According to the synthesis method of the 3-aminopyrrolidine hydrochloride, the aryl and the alkane sulfonic groups are introduced to protect the two amino groups, and a single reaction condition can be used during deprotection, so that the operation steps are effectively reduced; when benzyl is used for protecting ammonia, noble metal palladium and high-pressure catalytic hydrogenation are used for deprotection, the production cost is high, the operation risk is high, aromatic and alkane sulfonic groups are used for protection, only acid catalytic hydrolysis is used for deprotection, and the reaction condition is mild.)

1. A synthetic method of 3-aminopyrrolidine hydrochloride is characterized by comprising the following steps: the method comprises the following steps in sequence:

s1: performing cyclization reaction on a compound I and a compound II in the presence of a base and a solvent, wherein the molar ratio of the compound I to the compound II is 1: 1-3, the molar ratio of compound I to base is 1: 2-6, the weight ratio of the compound I to the solvent is 1: 3-15, the reaction conditions are 5-120 ℃, the time is 3-10h, the system is cooled and filtered after the reaction is finished, the filter cake is leached by an organic solvent, and the mother liquor is combined to remove the solvent under reduced pressure to obtain a compound III;

s2: dissolving the compound III obtained in the step by using an organic solvent, and introducing hydrogen halide gas to carry out addition reaction under the catalysis of Lewis acid, wherein the weight ratio of the compound III to the organic solvent is 1: 3-10, the weight ratio of compound III to lewis acid is 1: 0.01-0.2, the molar ratio of the compound III to the introduced hydrogen halide gas is 1: 1-5, reacting at 10-100 ℃ for 5-10h, transferring the reaction liquid into ice water added with sodium carbonate to separate the liquid after the reaction is finished, extracting the water phase with an organic solvent, and combining the organic phases to remove the solvent under reduced pressure to obtain a compound IV;

s3: dissolving the compound IV obtained in the step by using a solvent in the presence of alkali, and adding an organic sulfonamide into the system for reaction, wherein the weight ratio of the compound IV to the solvent is 1: 3-10, the molar ratio of compound IV to base is 1: 1-3, the molar ratio of the compound IV to the organic sulfonamide is 1: 0.8-3, the reaction condition is 30-70 ℃, the time is 2-7h, after the reaction is finished, the reaction system is cooled to room temperature, the filtration is carried out, the filter cake is soaked by the solvent, and the solvents are combined to obtain the solution of the compound V;

s4: adding concentrated hydrochloric acid into the solution of the compound V to react, wherein the molar ratio of the compound V to hydrogen chloride in the concentrated hydrochloric acid is 1: 1.8-5, controlling the reaction temperature at 10-70 ℃, the reaction time at 3-10h, after the reaction is finished, carrying out heat preservation and crystallization on the reaction system at-10-30 ℃, wherein the crystallization time is 1-5h, filtering crystals by adopting a solvent leaching mode to obtain a wet product compound VI, and drying the wet product under vacuum to constant weight to obtain a dry product of the compound VI;

wherein the compound I isThe compound II isThe compound III isThe compound IV isThe compound V isThe compound VI isWherein R1 is one of alkyl, aryl and aralkyl, R2 is one of alkyl, aryl and aralkyl, and X is chlorine or bromine.

2. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in steps S1 and S3, the base includes one of organic amine, organic sodium salt, pyridine, and carbonate.

3. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in steps S1 and S3, the solvent includes one or more of alcohols, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, and N, N-dimethylformamide.

4. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in step S2, the organic solvent includes one of aromatic hydrocarbons, ethers, and halogenated hydrocarbons.

5. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in step S2, the lewis acid is one of aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride, and titanium tetrachloride.

6. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in step S2, the hydrogen halide is hydrogen chloride or hydrogen bromide.

7. The method for synthesizing 3-aminopyrrolidine hydrochloride according to claim 1, wherein the method comprises the following steps: in step S3, the organic sulfonamide includes one of an alkylamine and an arylsulfonamide.

Technical Field

The invention belongs to the technical field of organic synthesis of medical intermediates, and particularly relates to a synthesis method of 3-aminopyrrolidine hydrochloride.

Background

3-amino-pyrrolidine is an important chemical organic intermediate, is widely applied to the synthesis of medicines, pesticides and fine chemicals, and can be used for synthesizing a fourth-generation quinolone antibacterial drug clinafloxacin and a broad-spectrum antibacterial drug trovafloxacin through 3-amino-pyrrolidine; optically active 3-aminopyrrolidine derivatives are important intermediates for agrochemicals and pharmaceutically active compounds. At present, the compound mainly comprises the following chemical synthesis methods:

1. in Japanese Kokai publication No. 1978: 28161(CA 1978; 89; 43107V), patents EP1849770, EP1849781, Synthetic Communications,1983, vol.13, #13, p.1117-1124 report: reacting 1, 4-dichlorobutene with benzylamine to obtain N-benzyl-3-hydroxypyrrolidine, oxidizing with hydrogen peroxide in the presence of hydroboration, chlorinating with thionyl chloride, reacting with Gabriel, and hydrogenating with palladium-carbon under pressure to obtain 3-aminopyrrolidine. The reaction route is as follows:

in the second step of the route, borane reagent is easy to explode, and meanwhile, the borane reagent is a highly toxic gas, hydrogen peroxide and explosive products are also used in the second step, so that the requirements on production equipment are high, the reaction route is also long, and the production cost is higher.

2. Nemia MMB, Lee J et al Synthetic Communications,1983, vol.13, #13, p.1117-1124, Kocalka, Petrr et al Tetrahedron,2006, vol.62, #24, p.5763-5774 report: the DL-malic acid is firstly cyclized with benzylamine and is reduced by LiAlH4 or NaBH4 to obtain N-benzyl-3-hydroxypyrrolidine, and then the 3-aminopyrrolidine can be obtained by the method.

By using the route, the reduction reagent LiAlH4 is a sensitive chemical, and when the production operation requirement is higher, and the base price is higher, or the reduction is carried out by NaBH4, the reaction period is longer, and the reduction time is 120h reported in the literature, the method is suitable for higher production cost.

3. Patent EP0218249 reports: 1,2, 4-tribromobutane and benzylamine are subjected to substitution reaction to obtain a cyclic compound, and then 3-aminopyrrolidine is obtained through hydrogenolysis debenzylation, wherein the reaction route is as follows:

by using the route, the 1,2, 4-tribromobutane raw material is less in commercial supply and expensive in price, and simultaneously reacts with benzylamine, a four-membered ring is generated, and a plurality of double molecules are combined with benzylamine, so that a plurality of large and complex compounds are generated in a reaction system, the purification cost of a target compound is increased, more byproducts are generated, and the method is not suitable for industrial production.

4. In patent CN1733720A, 1,2, 4-butanetriol as main starting material is halogenated, aminated and salified to form 3-aminopyrrolidine hydrochloride. The route is as follows:

by using the route, the generated 1,2, 4-trichlorobutane uses an autoclave in the ammonolysis process, and due to a plurality of chlorines, the activity difference is not large, a plurality of impurities can be generated, such as 2, 4-diaminobutylamino, 2-aminomethyl cyclobutylamino forming a four-membered ring, bimolecular combination, trimolecular combination and other byproducts are generated, the reaction system is relatively complicated, the purification of a target product is difficult, and the method is not suitable for industrial production.

5. Zhu Shengdong was published in Fine and specialty Chemicals at 14 th year 2001, Shenyiend, Pishiqin et al were published in college chemical engineering journal, 8 months 2003, Vol17(4), Master's paper in Chengni of Zhejiang university, Chemistry of Heterocyclic Compounds,2004, vol.40, #3, p.326-333, and Japanese patent laid-open No. 1991: 133954(CA 1991; 115183086t) reports the following route:

the reaction steps of the route are longer, and 4 steps of reaction require rectifying the intermediate, so that the production period is greatly prolonged, and the method is not beneficial to industrial production.

6. In patent CN108440361A, pyrrole is nitrated, hydrogenated and reduced, and then hydrogen chloride is used for salifying to obtain 3-aminopyrrolidine hydrochloride, and the reported route is as follows:

the first step of the route is nitration reaction, which is a dangerous reaction and generates 2-nitro impurities, and the impurities have similar properties with target chemicals and are difficult to separate; the second step reaction requires high pressure hydrogenation, which has high requirements on production conditions.

Disclosure of Invention

The invention aims to provide a synthetic method of 3-aminopyrrolidine hydrochloride, which aims to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme:

a synthetic method of 3-aminopyrrolidine hydrochloride comprises the following synthetic route:

wherein R1 and R2 may be independently an alkyl group, an aryl group or an aralkyl group, or may be the same alkyl group, aryl group or aralkyl group; x can be chlorine or bromine.

A synthetic method of 3-aminopyrrolidine hydrochloride comprises the following steps in sequence:

s1: performing cyclization reaction on a compound I and a compound II in the presence of a base and a solvent, wherein the molar ratio of the compound I to the compound II is 1: 1-3, preferably 1:1.05-1.2, the molar ratio of compound I to base is 1: 2-6, preferably 1:2.05-2.2, the weight ratio of compound I to solvent is 1: 3-15, preferably 1: 4-8, the compound II is alkylamine and arylsulfonamide, preferably methylsulfonamide and p-toluenesulfonamide, and the reaction conditions are that the temperature is 5-120 ℃, the temperature is preferably 45-55 ℃, the reaction time is 3-10h, and the reaction time is preferably as follows: 5-7h, cooling and filtering the system after the reaction is finished, leaching a filter cake by using an organic solvent, combining mother liquor, and removing the solvent under reduced pressure to obtain a compound III;

s2: dissolving the compound III obtained in the step by using an organic solvent, and introducing hydrogen halide gas to carry out addition reaction under the catalysis of Lewis acid, wherein the weight ratio of the compound III to the organic solvent is 1: 3-10, preferably 1: 5-6, the weight ratio of the compound III to the Lewis acid is 1: 0.01 to 0.2, preferably 1: 0.02-0.05, wherein the molar ratio of the compound III to the introduced hydrogen halide gas is 1: 1-5, preferably 1: 1.3-1.5, the reaction conditions are that the temperature is 10-100 ℃, preferably 65-75 ℃, the time is 5-10 hours, preferably 5-7 hours, after the reaction is finished, the reaction liquid is transferred into ice water added with sodium carbonate to separate the liquid, the water phase is extracted by organic solvent, the organic phases are combined, and the solvent is removed under reduced pressure, thus obtaining a compound IV;

s3: dissolving the compound IV obtained in the step by using a solvent in the presence of alkali, and adding an organic sulfonamide into the system for reaction, wherein the weight ratio of the compound IV to the solvent is 1: 3-10, preferably 1:6-8, the molar ratio of compound IV to base is 1: 1-3, preferably 1:1.05-1.2, the molar ratio of compound IV to organic sulfonamide is 1: 0.8-3, the reaction conditions are 30-70 ℃, and the preferable conditions are as follows: cooling the reaction system to room temperature after the reaction is finished at 55-65 ℃ for 2-7h, preferably 3-5h, filtering, soaking a filter cake in a solvent, and combining the solvents to obtain a solution of a compound V;

s4: adding concentrated hydrochloric acid into the solution of the compound V to react, wherein the molar ratio of the compound V to hydrogen chloride in the concentrated hydrochloric acid is 1: 1.8-5, preferably 1:2.2-2.6, controlling the reaction temperature to be 10-70 ℃, preferably 50-55 ℃, the reaction time to be 3-10h, preferably 3-5h, after the reaction is finished, carrying out heat preservation crystallization on the reaction system at-10-30 ℃, preferably: crystallizing at-5-5 deg.C for 1-5 hr, preferably 2-3 hr, leaching with solvent to obtain wet product compound VI, and drying the wet product under vacuum to constant weight to obtain dry product compound VI;

wherein the compound I isThe compound II isThe compound III isThe compound IV isThe compound V isThe compound VI is

Preferably, in steps S1 and S3, the base includes one of organic amine, organic sodium salt, pyridine, and carbonate.

It is preferable in any of the above schemes that in steps S1 and S3, the solvent comprises one or more of alcohols, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, N-dimethylformamide, preferably methanol, ethanol or acetone.

In any of the above embodiments, preferably, in step S2, the organic solvent includes one of aromatic hydrocarbons, ethers, and halocarbons, preferably 1, 2-dichloroethane or toluene.

In any of the above schemes, preferably, in step S2, the lewis acid is one of aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride and titanium tetrachloride, and is preferably aluminum trichloride or zinc chloride.

In any of the above embodiments, preferably, in step S2, the hydrogen halide is hydrogen chloride or hydrogen bromide, preferably hydrogen chloride.

It is preferred in any of the above embodiments that, in step S3, the organic sulfonamide includes one of alkylamine and arylsulfonamide, preferably methylsulfonamide or p-toluenesulfonamide.

The invention has the technical effects and advantages that:

1. according to the synthesis method of the 3-aminopyrrolidine hydrochloride, the aryl and the alkane sulfonic groups are introduced to protect the two amino groups, and a single reaction condition can be used during deprotection, so that the operation steps are effectively reduced;

2. when benzyl is used for protecting ammonia, precious metal palladium and high-pressure catalytic hydrogenation are used for deprotection, the production cost is high, the operation risk is high, aromatic hydrocarbon and alkyl sulfonic acid are used for protection, only acid is used for catalytic hydrolysis for deprotection, and the reaction condition is mild;

3. the synthesis method of the 3-aminopyrrolidine hydrochloride adopts three structural formulas of III, IV and V protected by aryl and alkane sulfonic groups, is a solid compound, can be used for carrying out recrystallization purification on the solid compound, has more convenient and better purification effect than the rectification in the traditional process, and has higher purification yield and shorter relative period of large-scale production.

Detailed Description

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention provides a synthetic method of 3-aminopyrrolidine hydrochloride, which has the following synthetic route:

wherein R1 and R2 may be independently an alkyl group, an aryl group or an aralkyl group, or may be the same alkyl group, aryl group or aralkyl group; x can be chlorine or bromine.

Example 1:

a synthetic method of 3-aminopyrrolidine hydrochloride comprises the following steps in sequence:

s1: performing cyclization reaction on a compound I and a compound II in the presence of a base and a solvent, wherein the molar ratio of the compound I to the compound II is 1:1, the molar ratio of compound I to base is 1:2, the weight ratio of the compound I to the solvent is 1: 3, the reaction conditions are 5-120 ℃ and 3-10h, after the reaction is finished, the system is cooled and filtered, the filter cake is leached by an organic solvent, and the mother liquor is combined and the solvent is removed under reduced pressure to obtain a compound III;

s2: dissolving the compound III obtained in the step by using an organic solvent, and introducing hydrogen halide gas to carry out addition reaction under the catalysis of Lewis acid, wherein the weight ratio of the compound III to the organic solvent is 1: 3, the weight ratio of the compound III to the Lewis acid is 1: 0.01, wherein the molar ratio of the compound III to the introduced hydrogen halide gas is 1:1, the reaction conditions are that the temperature is 10-100 ℃, the time is 5-10 hours, after the reaction is finished, the reaction liquid is transferred into ice water added with sodium carbonate for separating liquid, the water phase is extracted by organic solvent, and the organic phase is combined to remove the solvent under reduced pressure, so that a compound IV is obtained;

s3: dissolving the compound IV obtained in the step by using a solvent in the presence of alkali, and adding an organic sulfonamide into the system for reaction, wherein the weight ratio of the compound IV to the solvent is 1: 3, the molar ratio of the compound IV to the base is 1:1, the molar ratio of the compound IV to the organic sulfonamide is 1: 0.8, the reaction condition is that the temperature is 30-70 ℃, the time is 2-7h, after the reaction is finished, the reaction system is cooled to the room temperature, the filtration is carried out, the filter cake is soaked by the solvent, and the solvents are combined to obtain the solution of the compound V;

s4: adding concentrated hydrochloric acid into the solution of the compound V to react, wherein the molar ratio of the compound V to hydrogen chloride in the concentrated hydrochloric acid is 1: 1.8, controlling the reaction temperature to be 10-70 ℃, controlling the reaction time to be 3-10h, after the reaction is finished, carrying out heat preservation and crystallization on a reaction system at the temperature of-10-30 ℃, wherein the crystallization time is 1h, filtering crystals by adopting a solvent leaching mode to obtain a wet product compound VI, and drying the wet product under vacuum to constant weight to obtain a dry product of the compound VI;

wherein the compound I isThe compound II isThe compound III isThe compound IV isThe compound V isThe compound VI isWherein R1 is one of alkyl, aryl and aralkyl, R2 is one of alkyl, aryl and aralkyl, and X is chlorine or bromine.

Specifically, in steps S1 and S3, the base includes one of organic amine, organic sodium salt, pyridine, and carbonate.

Specifically, in steps S1 and S3, the solvent includes one or more of alcohols, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, and N, N-dimethylformamide.

Specifically, in step S2, the organic solvent includes one of aromatic hydrocarbons, ethers, and halogenated hydrocarbons.

Specifically, in step S2, the lewis acid is one of aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride, and titanium tetrachloride.

Specifically, in step S2, the hydrogen halide is hydrogen chloride or hydrogen bromide.

Specifically, in step S3, the organic sulfonamide includes one of alkylamine and arylsulfonamide.

Example 2:

a synthetic method of 3-aminopyrrolidine hydrochloride is characterized by comprising the following steps: the method comprises the following steps in sequence:

s1: performing cyclization reaction on a compound I and a compound II in the presence of a base and a solvent, wherein the molar ratio of the compound I to the compound II is 1:2, the molar ratio of compound I to base is 1: 4, the weight ratio of the compound I to the solvent is 1: 10, the reaction conditions are 5-120 ℃, the time is 3-10 hours, the system is cooled and filtered after the reaction is finished, the filter cake is leached by an organic solvent, and the mother liquor is combined to remove the solvent under reduced pressure to obtain a compound III;

s2: dissolving the compound III obtained in the step by using an organic solvent, and introducing hydrogen halide gas to carry out addition reaction under the catalysis of Lewis acid, wherein the weight ratio of the compound III to the organic solvent is 1:6, the weight ratio of the compound III to the Lewis acid is 1: 0.1, the molar ratio of the compound III to the introduced hydrogen halide gas is 1: 3, the reaction conditions are that the temperature is 10-100 ℃, the time is 5-10 hours, after the reaction is finished, the reaction liquid is transferred into ice water added with sodium carbonate for separating liquid, the water phase is extracted by organic solvent, and the organic phase is combined to remove the solvent under reduced pressure, so that a compound IV is obtained;

s3: dissolving the compound IV obtained in the step by using a solvent in the presence of alkali, and adding an organic sulfonamide into the system for reaction, wherein the weight ratio of the compound IV to the solvent is 1:6, the molar ratio of compound IV to base is 1: and 2, the molar ratio of the compound IV to the organic sulfonamide is 1:2, the reaction condition is that the temperature is 30-70 ℃, the time is 2-7h, after the reaction is finished, the reaction system is cooled to the room temperature, the filtration is carried out, after a filter cake is soaked by the solvent, the solvents are combined, and the solution of the compound V is obtained;

s4: adding concentrated hydrochloric acid into the solution of the compound V to react, wherein the molar ratio of the compound V to hydrogen chloride in the concentrated hydrochloric acid is 1: 3, controlling the reaction temperature to be 10-70 ℃, controlling the reaction time to be 3-10h, after the reaction is finished, carrying out heat preservation and crystallization on the reaction system at-10-30 ℃, wherein the crystallization time is 1-5h, filtering the crystals by adopting a solvent leaching mode to obtain a wet product compound VI, and drying the wet product under vacuum to constant weight to obtain a dry product of the compound VI;

wherein the compound I isThe compound II isThe compound III isThe compound IV isThe compound V isThe compound VI isWherein R1 is one of alkyl, aryl and aralkyl, R2 is one of alkyl, aryl and aralkyl, and X is chlorine or bromine.

Specifically, in steps S1 and S3, the base includes one of organic amine, organic sodium salt, pyridine, and carbonate.

Specifically, in steps S1 and S3, the solvent includes one or more of alcohols, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, and N, N-dimethylformamide.

Specifically, in step S2, the organic solvent includes one of aromatic hydrocarbons, ethers, and halogenated hydrocarbons.

Specifically, in step S2, the lewis acid is one of aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride, and titanium tetrachloride.

Specifically, in step S2, the hydrogen halide is hydrogen chloride or hydrogen bromide.

Specifically, in step S3, the organic sulfonamide includes one of alkylamine and arylsulfonamide.

Example 3:

a synthetic method of 3-aminopyrrolidine hydrochloride is characterized by comprising the following steps: the method comprises the following steps in sequence:

s1: performing cyclization reaction on a compound I and a compound II in the presence of a base and a solvent, wherein the molar ratio of the compound I to the compound II is 1: 3, the molar ratio of compound I to base is 1:6, the weight ratio of the compound I to the solvent is 1: 15, the reaction conditions are 5-120 ℃ and 3-10h, after the reaction is finished, the system is cooled and filtered, the filter cake is leached by an organic solvent, and the mother liquor is combined and the solvent is removed under reduced pressure to obtain a compound III;

s2: dissolving the compound III obtained in the step by using an organic solvent, and introducing hydrogen halide gas to carry out addition reaction under the catalysis of Lewis acid, wherein the weight ratio of the compound III to the organic solvent is 1: 10, the weight ratio of compound III to lewis acid is 1: 0.2, the molar ratio of the compound III to the introduced hydrogen halide gas is 1: 5, the reaction conditions are that the temperature is 10-100 ℃, the time is 5-10 hours, after the reaction is finished, the reaction liquid is transferred into ice water added with sodium carbonate for separating liquid, the water phase is extracted by organic solvent, and the organic phase is combined to remove the solvent under reduced pressure, so that a compound IV is obtained;

s3: dissolving the compound IV obtained in the step by using a solvent in the presence of alkali, and adding an organic sulfonamide into the system for reaction, wherein the weight ratio of the compound IV to the solvent is 1: 10, the molar ratio of compound IV to base is 1: and 3, the molar ratio of the compound IV to the organic sulfonamide is 1: 3, the reaction condition is that the temperature is 30-70 ℃, the time is 2-7h, after the reaction is finished, the reaction system is cooled to the room temperature, the filtration is carried out, after a filter cake is soaked by the solvent, the solvents are combined, and the solution of the compound V is obtained;

s4: adding concentrated hydrochloric acid into the solution of the compound V to react, wherein the molar ratio of the compound V to hydrogen chloride in the concentrated hydrochloric acid is 1: 5, controlling the reaction temperature to be 10-70 ℃, controlling the reaction time to be 3-10h, after the reaction is finished, carrying out heat preservation and crystallization on the reaction system at-10-30 ℃, wherein the crystallization time is 1-5h, filtering crystals by adopting a solvent leaching mode to obtain a wet product compound VI, and drying the wet product under vacuum to constant weight to obtain a dry product of the compound VI;

wherein the compound I isThe compound II isThe compound III isThe compound IV isSaid compoundsV isThe compound VI isWherein R1 is one of alkyl, aryl and aralkyl, R2 is one of alkyl, aryl and aralkyl, and X is chlorine or bromine.

Specifically, in steps S1 and S3, the base includes one of organic amine, organic sodium salt, pyridine, and carbonate.

Specifically, in steps S1 and S3, the solvent includes one or more of alcohols, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, and N, N-dimethylformamide.

Specifically, in step S2, the organic solvent includes one of aromatic hydrocarbons, ethers, and halogenated hydrocarbons.

Specifically, in step S2, the lewis acid is one of aluminum trichloride, ferric trichloride, stannic chloride, zinc chloride, and titanium tetrachloride.

Specifically, in step S2, the hydrogen halide is hydrogen chloride or hydrogen bromide.

Specifically, in step S3, the organic sulfonamide includes one of alkylamine and arylsulfonamide.

Example 4:

the synthetic route of the 3-aminopyrrolidine hydrochloride provided in the present example is as follows:

1) and (3) cyclization reaction: under mechanical stirring, sequentially adding 350g of absolute ethyl alcohol, 106g of (1.05moL) triethylamine, 62.5g of (0.5moL)1, 4-dichloro-2-butene and 52.3g of (0.55moL) methylsulfonamide into a 1000mL four-mouth bottle at room temperature, heating the system to 50 ℃ by using a water bath, carrying out heat preservation reaction at the temperature for 6 hours, cooling the reaction system to 10-15 ℃, carrying out heat preservation stirring at the temperature for 2 hours, filtering, soaking a filter cake by using 62.5 absolute ethyl alcohol to obtain mother liquor, merging mother liquor, and removing a solvent on a rotary evaporator under reduced pressure to obtain 64.7g of viscous liquid of a compound III, wherein the purity is 94% and the yield is 88%;

2) addition reaction: under mechanical stirring, 350g of 1, 2-dichloroethane, 2g of aluminum trichloride and 64.7g (0.44moL) of the viscous liquid of the compound III obtained in the previous step are sequentially added into a 1000mL four-mouth bottle at room temperature, the temperature of the system is raised to 70 ℃ by using a water bath, 20.9g (0.573moL) of dry hydrogen chloride gas is slowly introduced into the system, the system is kept at the temperature for reaction for 6 hours, the reaction system is cooled to 0-10 ℃, poured into 100g of 10% sodium carbonate aqueous solution, after the addition, the system is stirred at 0-10 ℃ for 10 minutes, then kept stand for 10 minutes for liquid separation, an upper aqueous phase is extracted once by using 64.7g of 1, 2-dichloroethane, an organic phase is combined, and the solvent is removed under reduced pressure on a rotary evaporator to obtain 79.8g of the viscous liquid of the compound IV, wherein the purity is as follows: 94%, yield is: 98.7 percent.

3) And (3) substitution reaction: under mechanical stirring, sequentially adding 450g of absolute ethyl alcohol, 48.2g (0.477moL) of triethylamine, 43.37g (0.456moL) of methylsulfonamide and 79.8g (0.434moL) of compound IV viscous liquid obtained in the previous step into a 1000mL four-mouth bottle at room temperature, heating the system to 55 ℃ by using a water bath, and preserving the temperature at the temperature for reacting for 3 hours; cooling the reaction system to 20-25 ℃, preserving heat at the temperature, stirring for 2 hours, filtering, and soaking a filter cake in 79.8g of absolute ethyl alcohol to obtain mother liquor containing a compound V;

4) deprotection to form a hydrochloride: under mechanical stirring, sequentially adding the compound V mother liquor in the last step and 95.5g (0.955moL) of concentrated hydrochloric acid into a 1000mL four-mouth bottle at room temperature, heating the system to 50 ℃ by using a water bath, and carrying out heat preservation reaction at the temperature for 3 hours; cooling the reaction system to 0-5 ℃, keeping the temperature and stirring for 2h, filtering, soaking a filter cake in 79.8g of absolute ethyl alcohol to obtain a wet product of the 3-aminopyrrolidine hydrochloride, and drying the wet product to constant weight in vacuum at 50 ℃ to obtain 57.3g of a dry product of the 3-aminopyrrolidine hydrochloride, wherein the purity is 98.7 percent, and the yield of the 3-4 steps is 83 percent.

Example 5:

the synthetic route of the 3-aminopyrrolidine hydrochloride provided in the present example is as follows:

1) and (3) cyclization reaction: under mechanical stirring, 450g of absolute ethyl alcohol, 106g (1.05moL) of triethylamine, 62.5g (0.5moL) of 1, 4-dichloro-2-butene and 94.2g (0.55moL) of p-toluenesulfonamide are sequentially added into a 1000mL four-mouth bottle at room temperature, the system is heated to 50 ℃ by water bath, the temperature is kept for reaction for 5 hours, the reaction system is cooled to 10-15 ℃, the temperature is kept for stirring for 2 hours, the filtration is carried out, a filter cake is soaked by 62.5 absolute ethyl alcohol, mother liquor is obtained and combined, and the solvent is removed on a rotary evaporator under reduced pressure to obtain 97.7g of viscous liquid of a compound III, wherein the purity is 95.2%, and the yield is 87.5%.

2) Addition reaction: under mechanical stirring, 580g of toluene, 4g of aluminum trichloride and 97.7g (0.437moL) of the viscous liquid of the compound III obtained in the previous step are sequentially added into a 1000mL four-mouth bottle at room temperature, the temperature of the system is raised to 75 ℃ by using a water bath, 23.7g (0.65moL) of dry hydrogen chloride gas is slowly introduced into the system, the temperature is kept for 6 hours, the reaction system is cooled to 0-10 ℃, the reaction system is poured into 100g of 10% sodium carbonate aqueous solution, after the addition is completed, the system is stirred for 10 minutes at 0-10 ℃, the reaction is kept still for 10 minutes, liquid separation is carried out, the lower-layer aqueous phase is extracted once by 97.7g of toluene, organic phases are combined, and the solvent is removed under reduced pressure on a rotary evaporator to obtain 109.2g of the viscous liquid of the compound IV, the purity is 93.7%, and the yield is 96..

3) And (3) substitution reaction: under mechanical stirring, 700g of absolute ethyl alcohol, 46.5g (0.46moL) of triethylamine, 43.7g (0.46moL) of methylsulfonamide and 109.2g (0.42moL) of the viscous liquid of the compound IV obtained in the previous step are sequentially added into a 2000mL four-mouth bottle at room temperature, the temperature of the system is raised to 55 ℃ by using a water bath, and the temperature is kept for reaction for 3 hours; cooling the reaction system to 20-25 ℃, preserving heat at the temperature, stirring for 2 hours, filtering, and soaking a filter cake in 100g of absolute ethyl alcohol to obtain mother liquor containing a compound V;

4) deprotection to form a hydrochloride: under mechanical stirring, sequentially adding the compound V mother liquor in the last step and 100g (1.0moL) of concentrated hydrochloric acid into a 2000mL four-mouth bottle at room temperature, heating the system to 50 ℃ by using a water bath, and carrying out heat preservation reaction at the temperature for 3 hours; cooling the reaction system to 0-5 ℃, keeping the temperature and stirring for 2h at the temperature, filtering, soaking a filter cake in 80g of absolute ethyl alcohol to obtain a wet product of the 3-aminopyrrolidine hydrochloride, drying the wet product at 50 ℃ in vacuum to constant weight to obtain 54.5g of a dry product of the 3-aminopyrrolidine hydrochloride, wherein the purity is 99.1 percent, and the yield of the two steps of 3 and 4 is 81.7 percent.

Example 6:

the synthetic route of the 3-aminopyrrolidine hydrochloride provided in the present example is as follows:

1) and (3) cyclization reaction: under mechanical stirring, sequentially adding 450g of acetone, 106g (1.05moL) of triethylamine, 62.5g (0.5moL) of 1, 4-dichloro-2-butene and 94.2g (0.55moL) of p-toluenesulfonamide into a 1000mL four-mouth bottle at room temperature, heating the system to 50 ℃ in water bath, and carrying out heat preservation reaction at the temperature for 5 hours; cooling the reaction system to 10-15 ℃, preserving heat and stirring for 2h at the temperature, filtering, soaking filter cakes in 62.5 acetone to obtain mother liquor, merging the mother liquor, and removing the solvent on a rotary evaporator under reduced pressure to obtain 95.9g of viscous liquid of a compound III, wherein the purity is 96.1 percent, and the yield is 85.9 percent.

2) Addition reaction: under mechanical stirring, 580g of chloroform, 4g of aluminum trichloride and 95.9g (0.43moL) of the viscous liquid of the compound III-2 obtained in the previous step are sequentially added into a 1000mL four-mouth bottle at room temperature, the temperature of the system is raised to 75 ℃ by using a water bath, 23.7g (0.65moL) of dry hydrogen chloride gas is slowly introduced into the system, and the temperature is kept for reaction for 6 hours; cooling the reaction system to 0-10 ℃, pouring the reaction system into 100g of 10% sodium carbonate aqueous solution, stirring the system for 10 minutes at 0-10 ℃ after the addition is finished, standing for 10 minutes, separating liquid, extracting the lower-layer water phase once with 97.7g of chloroform, combining organic phases, and removing the solvent on a rotary evaporator under reduced pressure to obtain 99.4g of viscous liquid of a compound IV, wherein the purity is 94.6%, and the yield is 89%.

3) And (3) substitution reaction: under mechanical stirring, 700g of acetone, 46.5g (0.46moL) of triethylamine, 71.9g (0.42moL) of p-toluenesulfonamide and 99.4g (0.383moL) of the viscous liquid of the compound IV obtained in the previous step are sequentially added into a 2000mL four-mouth bottle at room temperature, the temperature of the system is raised to 60 ℃ by using a water bath, and the temperature is kept for reaction for 3 hours; cooling the reaction system to 20-25 ℃, preserving heat and stirring for 2h at the temperature, filtering, and soaking a filter cake in 100g of acetone to obtain a mother liquor containing a compound V;

4) deprotection to form a hydrochloride: under mechanical stirring, sequentially adding the compound V mother liquor in the last step and 100g (1.0moL) of concentrated hydrochloric acid into a 2000mL four-mouth bottle at room temperature, heating the system to 50 ℃ by using a water bath, and carrying out heat preservation reaction at the temperature for 3 hours; cooling the reaction system to 0-5 ℃, keeping the temperature and stirring for 2h, filtering, soaking a filter cake in 80g of acetone to obtain a wet product of the 3-aminopyrrolidine hydrochloride, and drying the wet product at 50 ℃ in vacuum to constant weight to obtain 51.2g of a dry product of the 3-aminopyrrolidine hydrochloride, wherein the purity is 98.4 percent, and the yield of the two steps of 3 and 4 is 84 percent.

Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.