Preparation method and application of 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester. According to the preparation method, cheap (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine is taken as a raw material, a racemic compound 5 is obtained through a two-step reaction under the action of substituted sulfonyl chloride, and racemic 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester is obtained through a hydrazinolysis reaction. The preparation method provided by the invention is simple and convenient to operate, the production safety is remarkably improved, the purity and yield of the obtained target product can be further improved, and industrial production is facilitated. In addition, the invention also provides a method for preparing racemic 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester by using the obtained 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of tert-butyl 3-aminopyrrolidine-1-carboxylate. Background Art

[0002] 3-Aminopyrrolidine-1-carboxylic acid tert-butyl ester and 3-aminopyrrolidine dihydrochloride are important pharmaceutical intermediates. 3-Aminopyrrolidine dihydrochloride can be obtained by removing the tert-butyloxycarbonyl group from tert-aminopyrrolidine-1-carboxylic acid tert-butyl ester. Both tert-butyl 3-aminopyrrolidine-1-carboxylate and 3-aminopyrrolidine dihydrochloride contain two amino groups and possess some of the chemical properties of amines. They can undergo alkylation reactions and acylation reactions with acyl chlorides, anhydrides, and esters to construct compounds with biopharmaceutical activity, such as central nervous system drugs, antibiotics with quinolone backbone structures, and anti-tumor drugs. Therefore, the preparation of tert-butyl 3-aminopyrrolidine-1-carboxylate and 3-aminopyrrolidine dihydrochloride has attracted widespread attention.

[0003] The existing preparation routes of tert-butyl 3-aminopyrrolidine-1-carboxylate mainly include the following:

[0004] Patent WO2005 / 077924 discloses a method using 1-tert-butyloxycarbonyl-3-pyrrolidone and benzylamine as raw materials, undergoing reductive amination with sodium triacetoxyborohydride to obtain an intermediate, followed by high-pressure hydrogenation with 10% Pd / C to produce tert-butyl 3-aminopyrrolidine-1-carboxylate. This method uses the relatively expensive raw material 1-tert-butyloxycarbonyl-3-pyrrolidone and requires high-pressure equipment, making it difficult to scale up.

[0005]

[0006] Patent EP1500643 discloses a method for producing tert-butyl 3-aminopyrrolidine-1-carboxylate using 1-tert-butyloxycarbonyl-3-hydroxypyrrolidine as a raw material, followed by azidation and hydrogenation with 10% Pd / C. This method uses highly toxic and explosive sodium azide, resulting in a low safety factor and significant difficulty in industrial production.

[0007]

[0008] Literature reports a method using 1-tert-butoxycarbonyl-3-carboxylic acid methyl pyrrolidine as the starting material, hydrolyzing it to the acid, then reacting it with diphenylphosphoryl azide, and finally hydrogenating it over 10% Pd / C under high pressure to produce tert-butyl 3-aminopyrrolidine-1-carboxylate. This method is highly hazardous and requires high pressure and harsh reaction conditions, making it difficult to scale up for production.

[0009] Summary of the Invention

[0010] To overcome the deficiencies of the prior art, the present invention discloses a method for preparing tert-butyl 3-aminopyrrolidine-1-carboxylate and the use of the resulting tert-butyl 3-aminopyrrolidine-1-carboxylate for preparing 3-aminopyrrolidine dihydrochloride. The preparation method is simple and convenient to operate, does not involve high-risk reactions, and avoids the investment of large equipment costs. The present invention utilizes inexpensive R-configured raw materials to obtain a racemized product, meeting the requirements of the pharmaceutical industry, and exhibits high purity and yield, enabling industrial production.

[0011] The present invention is achieved through the following technical means:

[0012] In one aspect, the present invention provides a method for preparing tert-butyl 3-aminopyrrolidine-1-carboxylate, and the reaction scheme is as follows:

[0013]

[0014] It includes the following steps:

[0015] In the step of preparing compound 4 from compound 3, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine and substituted sulfonyl chloride react in the presence of reaction solvent 1 and a base to generate compound 4, wherein the substituted sulfonyl chloride is R-SO2Cl, and R is selected from at least one of methyl (-CH3) and p-tolyl (4-CH3-Ph-); in the step of preparing compound 5 from compound 4, compound 4 and phthalimide salt are reacted at high temperature under the action of substituted sulfonyl chloride to purify to obtain racemic compound 5; in the step of preparing compound 1 from compound 5, compound 5 is subjected to hydrazinolysis to obtain racemic tert-butyl 3-aminopyrrolidine-1-carboxylate. Based on the above scheme, an excess of substituted sulfonyl chloride can be added to the step of preparing compound 4 from compound 3, so that the substituted sulfonyl chloride remains and is added to the step of preparing compound 5 from compound 4 together with compound 4; in addition, the reaction of preparing compound 5 from compound 4 can be smoothly carried out by adding substituted sulfonyl chloride in the step of preparing compound 5 from compound 4.

[0016] Preferably, in the step of preparing compound 4 from compound 3, (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, reaction solvent 1, and a base are first added, the internal temperature is controlled, and a substituted sulfonyl chloride is added. After the addition is complete, the reaction temperature is controlled to allow the reaction to proceed. After the reaction is completed, the reaction solution is cooled, and a mixture containing compound 4 and residual substituted sulfonyl chloride is obtained after post-treatment, which can be directly added to the step of preparing compound 5 from compound 4. Based on the above scheme, the post-treatment includes washing with water, concentrating the organic phase, or directly concentrating the organic phase.

[0017] Preferably, in the step of preparing compound 4 from compound 3, the internal temperature is controlled at 5-15°C when adding substituted sulfonyl chloride. After the addition is completed, the reaction temperature is controlled at 20-40°C and the reaction is carried out for 6-16 hours.

[0018] Preferably, the base comprises at least one of triethylamine, N,N-diisopropylethylamine, and 1,8-diazacyclo[5,4,0]undecene-7; and / or in the step of preparing compound 4 from compound 3, the molar ratio of (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, base, and substituted sulfonyl chloride is 1:1.2~1.5:1.1~1.5.

[0019] Preferably, the reaction solvent 1 comprises at least one of dichloromethane, dichloroethane, and 2-methyltetrahydrofuran, preferably dichloromethane; and / or the mass volume ratio of the (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine and the reaction solvent 1 is 1:5-7 g / mL.

[0020] Preferably, the phthalimide salt includes at least one of potassium phthalimide and sodium phthalimide; and / or the amount of the phthalimide salt is calculated based on (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, and the molar ratio of (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine to the phthalimide salt is 1:1 to 2, more preferably 1:1 to 1.5.

[0021] Preferably, in the step of preparing compound 5 from compound 4, the high temperature reaction occurs and a reaction solvent 2 is required to be added; the reaction solvent 2 includes at least one of N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, and dimethyl sulfoxide; and / or the amount of the reaction solvent 2 is calculated as (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine, and the mass volume ratio of (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine and the reaction solvent 2 is 1:7.0~9.5g / mL, and more preferably 1:7.5~9.0g / mL.

[0022] Preferably, in the step of preparing compound 5 from compound 4, the high-temperature reaction needs to control the internal temperature to 80-140°C and react for 2-20 hours; and / or the purification includes: cooling, filtering, concentrating, adding ethyl acetate and water for washing, drying, filtering, concentrating, adding n-heptane for slurrying, filtering, and drying the filter cake to obtain compound 5.

[0023] Preferably, in the step of preparing compound 1 from compound 5, the hydrazinolysis reaction also requires the addition of a reaction solvent 3, and compound 5 is reacted with hydrazine hydrate in the reaction solvent 3 at 55-80° C. for 6-24 hours, cooled, filtered, concentrated, added with toluene, filtered to obtain a filtrate, the solvent is removed, and the fraction is collected by vacuum distillation to obtain racemic tert-butyl 3-aminopyrrolidine-1-carboxylate; wherein the molar ratio of compound 5 to hydrazine hydrate is 1:1-4; and / or the mass volume ratio of compound 5 to reaction solvent 3 is 0.08-0.2 g / mL; and / or the reaction solvent 3 is a 50%-100% ethanol solution; and / or the hydrazine hydrate is a 70%-90% hydrazine hydrate solution.

[0024] On the other hand, the present invention provides a use of tert-butyl 3-aminopyrrolidine-1-carboxylate prepared by the method according to the first aspect, characterized in that the tert-butyl 3-aminopyrrolidine-1-carboxylate is subjected to a reaction of removing the tert-butyloxycarbonyl group under the action of hydrogen chloride to prepare 3-aminopyrrolidine dihydrochloride;

[0025]

[0026] The molar ratio of tert-butyl 3-aminopyrrolidine-1-carboxylate to hydrogen chloride is 1:2-6; the hydrogen chloride is a 25-30% hydrogen chloride isopropanol solution;

[0027] and / or the reaction solvent of the reaction is at least one of dichloromethane, ethyl acetate, and methyl tert-butyl ether, and the mass volume ratio of the tert-butyl 3-aminopyrrolidine-1-carboxylate to the reaction solvent is 0.08 to 0.3 g / mL;

[0028] And / or the reaction temperature is 20-45° C., and the reaction time is 3-12 hours.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The preparation method of tert-butyl 3-aminopyrrolidine-1-carboxylate provided by the present invention uses cheap R-configuration raw materials, and a racemized product can be obtained by reacting with substituted sulfonyl chloride, which meets the requirements of the pharmaceutical industry.

[0031] (2) The present invention is simple and convenient to operate, does not have high-risk reactions, avoids the investment of large equipment costs, and solves the shortcomings of currently known synthesis processes such as complex operation, large equipment investment, and potential safety hazards.

[0032] (3) The present invention further improves the yields of intermediates and target products by controlling reaction parameters and operations. A single-step yield of 96.3% was achieved when the purity of tert-butyl 3-aminopyrrolidine-1-carboxylate reached 99.4% to 99.6%, making it suitable for industrial production. Furthermore, the present invention provides a post-reaction treatment method for recovering the solvent, which is environmentally friendly and reduces production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the GC purity chart of 3-aminopyrrolidine dihydrochloride prepared in Example 1;

[0034] Figure 2 This is the hydrogen spectrum of 3-aminopyrrolidine dihydrochloride prepared in Example 1. DETAILED DESCRIPTION

[0035] The methods of the present invention are described below by way of specific examples to facilitate understanding and grasp of the technical solutions of the present invention, but the present invention is not limited thereto. The following examples are merely optional embodiments of the present invention and are not exhaustive. The experimental methods described in the following examples, unless otherwise specified, are conventional methods; the reagents and materials described, unless otherwise specified, can all be obtained from commercial sources.

[0036] As used herein, the terms "comprises," "including," "having," "containing" or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a listed element is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0037] The term "eq" is used herein as an abbreviation for equivalent.

[0038] Example 1

[0039] R is methyl (-CH3).

[0040] In a dry reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine (84.5 g, 0.451 mol, 1.0 eq), dichloromethane (425 mL), and triethylamine (63.9 g, 0.631 mol, 1.4 eq) were added, and methylsulfonyl chloride (62.0 g, 0.541 mol, 1.2 eq) was added dropwise. Heat was released, and the mixture was cooled with ice water. The internal temperature was controlled at 5-15°C and the reaction was continued at 20°C for 16 hours after the addition was completed. The reaction mixture was cooled to 10°C, 325 g of water was added dropwise to the reaction solution, stirred for 30 minutes, allowed to stand, and separated into layers; the lower organic layer was concentrated by distillation under reduced pressure and the solvent was recovered, N, N-dimethylacetamide (660 mL) and potassium phthalimide (100.2 g, 0.541 mol, 1.2 eq) were added to the concentrate, and the mixture was heated in an oil bath to an internal temperature of 80°C, stirred, and kept warm for 20 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 400 mL of ethyl acetate and 200 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand and the water layer was separated. Anhydrous sodium sulfate was added and stirred to dryness. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 250 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 124.5 g of a yellow solid (Compound 5) with an optical rotation of 0 and a yield of 87.2% (based on Compound 3).

[0041]

[0042] In a reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 5 (110.7 g, 0.35 mol, 1.0 eq) and ethanol (1350 mL) were added, stirred, heated to an internal temperature of 65°C, and 80% hydrazine hydrate (87.6 g, 1.40 mol, 4.0 eq) was added dropwise. After the addition was complete, the mixture was stirred at 65°C for 10 hours. The mixture was cooled to 10°C, the reaction solution was filtered, the filtrate was concentrated by vacuum rotary evaporation and the solvent was recovered. 300 mL of toluene was added to the concentrate, stirred and beaten for 2 hours, filtered, and the filtrate was desolvated. After vacuum distillation (1 mmHg), 61.7 g of the top temperature 85°C fraction (compound 1) was collected. The GC purity was 99.6%, the optical rotation was 0, and the yield was 94.7% (based on compound 5).

[0043]

[0044] In a dry reaction kettle equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 1 (59.6 g, 0.32 mol, 1.0 eq) and dichloromethane (300 mL) were added, stirred, cooled with ice water, and 25% hydrogen chloride isopropanol solution (186.9 g, 1.28 mol, 4.0 eq) was added dropwise. After the addition, the mixture was stirred at 25°C for 3 hours. The mixture was cooled to 5°C, filtered, and the filter cake was vacuum dried at 50°C to constant weight to obtain 49.4 g of a white solid with a GC purity of 99.8% (as Figure 1 The optical rotation is 0 and the yield is 97.1% (based on compound 1). 1 H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 5H), 3.91-3.85 (m, 1H), 3.49-3.40 (m, 2H), 3.29-3.18 (m, 2H), 2.29-2.24 (m, 1H), 2.07-2.02 (m, 1H), hydrogen spectrum as Figure 2 shown.

[0045] Example 2

[0046] R is methyl (-CH3).

[0047] In a dry reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine (84.5 g, 0.451 mol, 1.0 eq), dichloromethane (425 mL), and triethylamine (54.8 g, 0.541 mol, 1.2 eq) were added, and methylsulfonyl chloride (56.8 g, 0.50 mol, 1.1 eq) was added dropwise. Heat was released, and the mixture was cooled with ice water. The internal temperature was controlled at 5-15°C and the reaction was continued at 40°C for 6 hours after the addition was completed. The reaction mixture was cooled to 10°C, 325 g of water was added dropwise to the reaction solution, stirred for 30 minutes, allowed to stand, and separated into layers; the lower organic layer was concentrated by distillation under reduced pressure and the solvent was recovered, N, N-dimethylacetamide (660 mL) and potassium phthalimide (87.7 g, 0.474 mol, 1.05 eq) were added to the concentrate, and the mixture was heated in an oil bath to an internal temperature of 100°C, stirred, and kept warm for 12 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 400 mL of ethyl acetate and 200 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand and the water layer was separated. Anhydrous sodium sulfate was added and stirred to dryness. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 250 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 123.3 g of a yellow solid (Compound 5) with an optical rotation of 0 and a yield of 86.4% (based on Compound 3).

[0048]

[0049] In a reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 5 (110.7 g, 0.35 mol, 1.0 eq) and ethanol (1350 mL) were added, stirred, heated to an internal temperature of 75°C, and 80% hydrazine hydrate (43.8 g, 0.70 mol, 2.0 eq) was added dropwise. After the addition was complete, the mixture was stirred at 75°C for 8 hours. The mixture was cooled to 10°C, the reaction solution was filtered, the filtrate was concentrated by vacuum rotary evaporation and the solvent was recovered, 300 mL of toluene was added to the concentrate, stirred and beaten for 2 hours, filtered, and the filtrate was desolvated. After vacuum distillation (1 mmHg), 62.8 g of the top temperature fraction (compound 1) at 85°C was collected. The GC purity was 99.4%, the optical rotation was 0, and the yield was 96.3% (based on compound 5).

[0050]

[0051] Compound 1 (59.6 g, 0.32 mol, 1.0 eq) and dichloromethane (300 mL) were added to a dry reaction kettle equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel. Stirring was started, ice-cooled, and 25% hydrogen chloride isopropanol solution (280.4 g, 1.92 mol, 6.0 eq) was added dropwise. After completion of the addition, the mixture was stirred at 40°C for 1 hour. The mixture was cooled to 5°C, filtered, and the filter cake was vacuum-dried at 50°C to constant weight to obtain 47.7 g of a white solid with a GC purity of 99.8%, an optical rotation of 0, and a yield of 93.7% (based on compound 1).

[0052] Example 3

[0053] R is methyl (-CH3).

[0054] In a dry reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine (84.5 g, 0.451 mol, 1.0 eq), dichloromethane (500 mL), and N,N-diisopropylethylamine (87.4 g, 0.677 mol, 1.5 eq) were added, and methylsulfonyl chloride (67.2 g, 0.586 mol, 1.3 eq) was added dropwise. Heat was released and ice-cooled. The internal temperature was controlled at 5-15°C and the reaction was continued dropwise at 30°C for 10 hours after the addition was completed. The reaction mixture was cooled to 10°C, 325 g of water was added dropwise to the reaction solution, stirred for 30 minutes, allowed to stand, and separated into layers; the lower organic layer was concentrated by distillation under reduced pressure and the solvent was recovered, N,N-dimethylformamide (750 mL) and potassium phthalimide (116.9 g, 0.631 mol, 1.4 eq) were added to the concentrate, and the temperature was raised to 120°C in an oil bath, stirred, and kept warm for 4 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 400 mL of ethyl acetate and 200 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand and the water layer was separated. Anhydrous sodium sulfate was added and stirred to dryness. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 250 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 122.3 g of a yellow solid (Compound 5) with an optical rotation of 0 and a yield of 85.7% (based on Compound 3).

[0055]

[0056] In a reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 5 (110.7 g, 0.35 mol, 1.0 eq) and ethanol (1350 mL) were added, stirred, heated to an internal temperature of 55 ° C, and 80% hydrazine hydrate (65.7 g, 1.05 mol, 3.0 eq) was added dropwise. After the addition was completed, the mixture was stirred at 55 ° C for 24 hours. After cooling to 10 ° C, the reaction solution was filtered, the filtrate was concentrated by vacuum rotary evaporation and the solvent was recovered. 300 mL of toluene was added to the concentrate, stirred and beaten for 2 hours, filtered, and the filtrate was desolvated. After vacuum distillation (1 mmHg), 62.1 g of the top temperature 85 ° C fraction (compound 1) was collected. The GC purity was 99.6%, the optical rotation was 0, and the yield was 95.3% (based on compound 5).

[0057]

[0058] Compound 1 (59.6 g, 0.32 mol, 1.0 eq) and ethyl acetate (250 mL) were added to a dry reaction kettle equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel. Stirring was started, ice-cooled, and 25% hydrogen chloride isopropanol solution (140.2 g, 0.96 mol, 3.0 eq) was added dropwise. After completion of the addition, the mixture was stirred at 25°C for 6 hours. The mixture was cooled to 5°C, filtered, and the filter cake was vacuum-dried at 50°C to constant weight to obtain 48.5 g of a white solid with a GC purity of 99.7%, an optical rotation of 0, and a yield of 95.3% (based on compound 1).

[0059] Example 4

[0060] R is p-tolyl (4-CH3-Ph-).

[0061] In a dry reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine (84.5 g, 0.451 mol, 1.0 eq), dichloromethane (425 mL), and 1,8-diazacyclo[5,4,0]undecene-7 (96.1 g, 0.631 mol, 1.4 eq) were added, and p-toluenesulfonyl chloride (103.1 g, 0.541 mol, 1.2 eq) dissolved in 125 mL of dichloromethane was added dropwise. Heat was released, and the mixture was cooled with ice water. The internal temperature was controlled at 5-15°C and the reaction was continued dropwise. After the addition was completed, the reaction was continued at 40°C for 16 hours. The reaction mixture was cooled to 10°C, 325 g of water was added dropwise to the reaction solution, stirred for 30 minutes, allowed to stand, and separated into layers; the lower organic layer was concentrated by distillation under reduced pressure and the solvent was recovered, N, N-dimethylacetamide (660 mL) and potassium phthalimide (100.2 g, 0.541 mol, 1.2 eq) were added to the concentrate, and the temperature was raised to 140°C in an oil bath, and the mixture was stirred and kept warm for 2 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 400 mL of ethyl acetate and 200 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand and the water layer was separated. Anhydrous sodium sulfate was added and stirred to dryness. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 250 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 122.8 g of a yellow solid (Compound 5) with an optical rotation of 0 and a yield of 86.0% (based on Compound 3).

[0062]

[0063] In a reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 5 (110.7 g, 0.35 mol, 1.0 eq) and 50% ethanol (1100 mL) were added, stirred, heated to an internal temperature of 75°C, and 80% hydrazine hydrate (21.9 g, 0.35 mol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was stirred at 80°C for 6 hours. After cooling to 10°C, the reaction solution was filtered, the filtrate was concentrated by vacuum rotary evaporation and the solvent was recovered. 300 mL of toluene was added to the concentrate, stirred and beaten for 2 hours, filtered, and the filtrate was desolvated. After vacuum distillation (1 mmHg), 61.9 g of the top temperature fraction (compound 1) at 85°C was collected. The GC purity was 99.6%, the optical rotation was 0, and the yield was 95.0% (based on compound 5).

[0064]

[0065] Compound 1 (59.6 g, 0.32 mol, 1.0 eq) and methyl tert-butyl ether (500 mL) were added to a dry reaction kettle equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel. Stirring was started, ice-cooled, and 25% hydrogen chloride isopropanol solution (93.5 g, 0.64 mol, 2.0 eq) was added dropwise. After completion of the addition, the mixture was stirred at 25°C for 12 hours. The mixture was cooled to 5°C, filtered, and the filter cake was vacuum-dried at 50°C to constant weight to obtain 48.7 g of a white solid with a GC purity of 99.8%, an optical rotation of 0, and a yield of 95.7% (based on compound 1).

[0066] Example 5

[0067] R is methyl (-CH3).

[0068] In a dry reactor equipped with a thermometer, stirring, and a constant pressure dropping funnel, (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine (84.5 g, 0.451 mol, 1.0 eq), dichloromethane (425 mL), and triethylamine (63.9 g, 0.631 mol, 1.4 eq) were added, and methylsulfonyl chloride (62.0 g, 0.541 mol, 1.2 eq) was added dropwise. Heat was released, and the mixture was cooled with ice water. The internal temperature was controlled at 5-15°C and the reaction was continued at 20°C for 16 hours after the addition was completed. The reaction mixture was cooled to 10°C, 325 g of water was added dropwise to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was allowed to stand and separate into layers. The lower organic layer was washed twice with a saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then recrystallized by adding petroleum ether at low temperature (-15°C) to obtain 108.6 g of a white solid (i.e., compound 4) with a GC purity of 99.4%, an optical rotation of -25.3° (c = 0.01 mg / mL, methanol), and a yield of 90.7%.

[0069] R is methyl (-CH3).

[0070] In a reaction kettle equipped with a thermometer, stirring, and condenser, compound 4 (53.1 g, 0.2 mol, 1.0 eq), N,N-dimethylacetamide (330 mL), and potassium phthalimide (44.5 g, 0.24 mol, 1.2 eq) were added, stirring was started, and methylsulfonyl chloride (0.5 g, 0.004 mol, 0.02 eq) was added. The mixture was heated in an oil bath to an internal temperature of 120°C, stirred, and kept warm for 4 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 200 mL of ethyl acetate and 100 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand, the water layer was separated, anhydrous sodium sulfate was added, and the mixture was stirred and dried. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 125 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 51.8 g of a yellow solid (Compound 5) with an optical rotation of 0 and a yield of 81.9% (based on Compound 4). The two-step yield based on Compound 3 was 74.3%.

[0071]

[0072] In a reactor equipped with a thermometer, stirring, condenser, and constant pressure dropping funnel, compound 5 (47.5 g, 0.15 mol, 1.0 eq) and ethanol (580 mL) were added, stirred, heated to an internal temperature of 65 ° C, and 80% hydrazine hydrate (37.5 g, 0.6 mol, 4.0 eq) was added dropwise. After the addition was completed, the mixture was stirred at 65 ° C for 10 hours. After cooling to 10 ° C, the reaction solution was filtered, the filtrate was concentrated by vacuum rotary evaporation and the solvent was recovered. 130 mL of toluene was added to the concentrate, stirred and beaten for 2 hours, filtered, and the filtrate was desolvated. After vacuum distillation (1 mmHg), 26.1 g of the top temperature fraction (compound 1) at 85 ° C was collected. The GC purity was 99.6%, the optical rotation was 0, and the yield was 93.4% (based on compound 5).

[0073] Comparative Example 1

[0074] R is methyl (-CH3).

[0075] In a reaction kettle equipped with a thermometer, stirring, and condenser, compound 4 (53.1 g, 0.2 mol, 1.0 eq, purity 99.4%), N,N-dimethylacetamide (330 mL) and potassium phthalimide (44.5 g, 0.24 mol, 1.2 eq) were added. Stirring was started and the oil bath was heated to an internal temperature of 120°C and stirred for 4 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 200 mL of ethyl acetate and 100 mL of water were added to the concentrate, and the mixture was stirred until the solid was completely dissolved. The mixture was allowed to stand, the water layer was separated, anhydrous sodium sulfate was added, and the mixture was stirred and dried. The mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure and the solvent was recovered. 125 mL of n-heptane was added to the concentrate, and the mixture was beaten at 60°C for 30 minutes. The mixture was then cooled to 0°C and filtered. The filter cake was dried at 80°C for 2 hours to give 49.5 g of a yellow solid (compound (S)-5) with an optical rotation of -13.1° (c = 0.01 mg / mL, methanol) and a yield of 78.2% (based on compound 4).

[0076]

[0077] Compound (S)-5 (47.5 g, 0.15 mol, 1.0 eq) and ethanol (580 mL) were added to a reaction kettle equipped with a thermometer, stirring, a condenser, and a constant pressure dropping funnel. Stirring was initiated and the mixture was heated to an internal temperature of 65°C. 80% hydrazine hydrate (37.5 g, 0.6 mol, 4.0 eq) was added dropwise, and stirring was continued at 65°C for 10 hours. The mixture was cooled to 10°C, the reaction solution was filtered, and the filtrate was concentrated by vacuum rotary evaporation to recover the solvent. 130 mL of toluene was then added to the concentrate, stirred and slurried for 2 hours, and filtered. After desolvation, the filtrate was evaporated under reduced pressure (1 mmHg) to collect 25.7 g of the top temperature fraction (compound (S)-1) at 85°C. The fraction had a GC purity of 99.5%, an optical rotation of -3.7° (c = 0.01 mg / mL, methanol), and a yield of 92.0% (based on compound (S)-5).

Claims

1. A method for preparing tert-butyl 3-aminopyrrolidine-1-carboxylate, characterized in that: The reaction route is as follows: It includes the following steps: In the step of preparing compound 4 from compound 3, (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine and a substituted sulfonyl chloride react in the presence of a reaction solvent 1 and a base to generate compound 4; the substituted sulfonyl chloride is R-SO2Cl, and R is selected from at least one of methyl and p-tolyl. In the step of preparing compound 5 from compound 4, compound 4 and a phthalimide salt are reacted at high temperature under the action of a substituted sulfonyl chloride, and purified to obtain a racemic compound 5. In the step of preparing compound 1 from compound 5, compound 5 is subjected to a hydrazinolysis reaction to obtain a racemic tert-butyl 3-aminopyrrolidine-1-carboxylate.

2. The preparation method according to claim 1, characterized in that In the step of preparing compound 4 from compound 3, (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, reaction solvent 1 and base are first added, the internal temperature is controlled and the substituted sulfonyl chloride is added. After the addition is completed, the reaction temperature is controlled to react. After the reaction is completed, the reaction liquid is cooled and the mixture containing compound 4 and residual substituted sulfonyl chloride is obtained after post-treatment, which can be directly added to the step of preparing compound 5 from compound 4.

3. The preparation method according to claim 2, characterized in that In the step of preparing compound 4 from compound 3, the internal temperature is controlled at 5-15°C when adding substituted sulfonyl chloride. After the addition is completed, the reaction temperature is controlled at 20-40°C and the reaction is carried out for 6-16 hours.

4. The preparation method according to any one of claims 1 or 2, characterized in that The base includes at least one of triethylamine, N,N-diisopropylethylamine, and 1,8-diazacyclo[5,4,0]undecene-7; and / or in the step of preparing compound 4 from compound 3, the molar ratio of (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, base, and substituted sulfonyl chloride is 1:1.2~1.5:1.1~1.

5.

5. The preparation method according to any one of claims 1 or 2, characterized in that The reaction solvent 1 includes at least one of dichloromethane, dichloroethane, and 2-methyltetrahydrofuran; and / or the mass volume ratio of the (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine and the reaction solvent 1 is 1:5-7 g / mL.

6. The preparation method according to any one of claims 1 or 2, characterized in that The phthalimide salt includes at least one of potassium phthalimide and sodium phthalimide; and / or the amount of the phthalimide salt is calculated based on (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine, and the molar ratio of (R)-1-tert-butyl carboxylate-3-hydroxypyrrolidine to the phthalimide salt is 1:1 to 2.

7. The preparation method according to any one of claims 1 or 2, characterized in that In the step of preparing compound 5 from compound 4, the high temperature reaction requires the addition of reaction solvent 2; the reaction solvent 2 includes at least one of N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, N-methylpyrrolidone, and dimethyl sulfoxide; and / or the amount of the reaction solvent 2 is calculated based on (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine, and the mass volume ratio of (R)-1-carboxylic acid tert-butyl ester-3-hydroxypyrrolidine and reaction solvent 2 is 1:7.0~9.5g / mL.

8. The preparation method according to any one of claims 1 or 2, characterized in that In the step of preparing compound 5 from compound 4, the high-temperature reaction needs to control the internal temperature to 80-140°C and react for 2-20 hours; and / or the purification includes: cooling, filtering, concentrating, adding ethyl acetate and water for washing, drying, filtering, concentrating, adding n-heptane for slurrying, filtering, and drying the filter cake to obtain compound 5.

9. The preparation method according to any one of claims 1 or 2, characterized in that In the step of preparing compound 1 from compound 5, the hydrazinolysis reaction requires the addition of reaction solvent 3. Compound 5 is reacted with hydrazine hydrate in reaction solvent 3 at 55-80° C. for 6-24 hours, cooled, filtered, concentrated, and toluene is added to obtain a filtrate by filtration. The solvent is removed, and the fraction is collected by vacuum distillation to obtain racemic tert-butyl 3-aminopyrrolidine-1-carboxylate. The molar ratio of the compound 5 to the hydrazine hydrate is 1:1 to 4; and / or the mass volume ratio of the compound 5 to the reaction solvent 3 is 0.08 to 0.2 g / mL; and / or the reaction solvent 3 is a 50% to 100% ethanol solution; and / or the hydrazine hydrate is a 70% to 90% hydrazine hydrate solution.

10. Use of tert-butyl 3-aminopyrrolidine-1-carboxylate prepared according to the method according to any one of claims 1 to 9, characterized in that: The tert-butyl 3-aminopyrrolidine-1-carboxylate is subjected to a reaction in which the tert-butyloxycarbonyl group is removed under the action of hydrogen chloride to prepare 3-aminopyrrolidine dihydrochloride; The molar ratio of tert-butyl 3-aminopyrrolidine-1-carboxylate to hydrogen chloride is 1:2-6; the hydrogen chloride is a 25-30% hydrogen chloride isopropanol solution; and / or the reaction solvent of the reaction is at least one of dichloromethane, ethyl acetate, and methyl tert-butyl ether, and the mass volume ratio of the tert-butyl 3-aminopyrrolidine-1-carboxylate to the reaction solvent is 0.08 to 0.3 g / mL; And / or the reaction temperature is 20-45° C., and the reaction time is 3-12 hours.

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