Preparation method of N-Boc-3-pyrroline

Abstract

The invention discloses a preparation method of N-Boc-3-pyrroline, and belongs to the technical field of medical intermediates. The method comprises the following steps: by taking 1, 3-butadiene and N, N-dihalogenated tert-butyl carbamate as raw materials, carrying out 1, 4-cis addition reaction with high stereoselectivity under the catalysis of B (C6F5) 3 to generate (4-halogenated butyl-2-ene-1-yl) tert-butyl carbamate which is mainly cis; and then carrying out ring closing on the cis-(4-halogenated butyl-2-ene-1-yl) tert-butyl carbamate under the action of a phase transfer catalyst and alkali, so as to prepare the N-Boc-3-pyrroline. The preparation method is high in yield, low in cost, simple in technological operation and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates technology, specifically relating to a method for preparing N-Boc-3-pyrrolidine. Background Technology

[0002] N-Boc-3-pyrroline, CAS: 73286-60-1, is a white, low-melting-point solid or liquid. It can be used as a precursor for many natural products and is also an important intermediate in the preparation of drugs containing pyrrole structures.

[0003] The preparation methods for this compound are currently reported in the literature as follows:

[0004] The first method uses tert-butyl carbamate and cis-1,4-dichloro-2-butene as raw materials. Sodium hydrogen attacks the hydrogen in the amide in DMF, followed by cyclization to obtain the product (see Tetrahedron Astrometry, 2001, 12, 21, 2989-2997, EP1849781). This method uses sodium hydrogen and DMF, is highly hazardous, has a low yield, and is not suitable for industrial production.

[0005] The second method involves cyclization of N,N-diallylcarbamate tert-butyl esters under a Grubbs catalyst (see Journal of Organic Chemistry, 1998, 63, 9904-9909; Organic Letters, 2010, 12, 984-987; CN113185440). However, this method uses expensive Grubbs catalysts, resulting in high raw material costs and making it unsuitable for industrial production.

[0006] The third method involves a Delépine reaction using hexamethylenetetramine and cis-1,4-dichloro-2-butene as raw materials. After hydrolysis in concentrated hydrochloric acid, the product undergoes cyclization with (Boc)₂O in the presence of potassium carbonate (refer to Organic Process Research and Development, 2009, 13, 638-640). However, hexamethylenetetramine, the raw material used in this method, is a potentially explosive and hazardous chemical with limited availability, making it unsuitable for industrial production.

[0007] Summary of the Invention:

[0008] To overcome the above problems, this invention discloses a method for preparing N-Boc-3-pyrrololine. Using 1,3-butadiene and tert-butyl N,N-dihalocarbamate as raw materials, a 1,4-cis-addition reaction with high stereoselectivity occurs under B(C6F5)3 catalysis to generate cis-dominant (4-halobut-2-en-1-yl)carbamate tert-butyl ester; subsequently, cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester undergoes cyclization under the action of a phase transfer catalyst and a base to obtain N-Boc-3-pyrrololine. This preparation method has high yield, low cost, and simple operation, making it suitable for industrial production.

[0009] The present invention provides a method for preparing N-Boc-3-pyrrolidine, comprising the following steps:

[0010] In the first step, 1,3-butadiene and N,N-dihalocarbamate tert-butyl ester undergo a 1,4-cis addition reaction in toluene solution under the catalysis of B(C6F5)3. The reaction is quenched by a reducing agent aqueous solution, and the mixture is separated into layers to obtain a toluene solution of cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester.

[0011] In the second step, a phase transfer catalyst, potassium carbonate, and potassium hydroxide were added to a toluene solution of cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester, and the mixture was heated to 80-90℃ to react and obtain the product N-Boc-3-pyrrololine.

[0012] The equation is expressed as follows:

[0013]

[0014] Furthermore, in the first step, tert-butyl N,N-dihalocarbamate is selected from tert-butyl N,N-dichlorocarbamate or tert-butyl N,N-dibromocarbamate, preferably tert-butyl N,N-dibromocarbamate.

[0015] Furthermore, in the first step, the reducing agent is selected from sodium thiosulfate, sodium sulfite, or sodium bisulfite.

[0016] Furthermore, in the first step, the molar ratio of 1,3-butadiene, tert-butyl N,N-dihalocarbamate to B(C6F5)3 is 1.1-1.3:1.0:0.03-0.05.

[0017] Furthermore, in the first step, the reaction temperature is -80℃ to -65℃.

[0018] Furthermore, in the second step, the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium fluoride, preferably tetrabutylammonium bromide.

[0019] Furthermore, in the second step, the molar ratio of cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester, phase transfer catalyst, potassium carbonate, and potassium hydroxide is 1.0:0.05-0.1:1.5-2.0:3.0-4.0.

[0020] This invention has the following advantages:

[0021] 1. The materials used are inexpensive and readily available, avoiding the use of highly hazardous chemicals. The two-step reaction uses a single solvent, toluene, which is easy to recycle and reuse, reducing waste and ensuring safety and environmental protection.

[0022] 2. Under the catalysis of B(C6F5)3, 1,3-butadiene and N,N-dihalocarbamate tert-butyl ester undergo a highly stereoselective 1,4-cis addition reaction, with the target product cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester containing 94-95% in the reaction solution.

[0023] 3. The two-step reaction can be completed in one pot. After the first step reaction is separated into layers, the toluene layer of cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester remains in the reactor. Other reaction materials for the second step can be added directly. The operation is simple and suitable for industrial scale-up production.

[0024] 4. This method has mild reaction conditions, is safe and controllable, has high yield and stable quality, and has advantages in cost and route. Attached Figure Description

[0025] Figure 1 The image shows the 1H NMR spectrum of N-Boc-3-pyrrolline in Example 1. Specific Implementation

[0026] Example 1

[0027] Step 1: Under nitrogen protection, add 55.0 g (0.20 mol) of N,N-dibromocarbamate tert-butyl ester, 3.07 g (0.006 mol) of B(C6F5)3, and 550 g of toluene to a reaction flask. Add 64.9 g (0.24 mol) of 20% 1,3-butadiene-toluene solution dropwise at -78°C, controlling the temperature to not exceed -65°C during the addition. After the addition is complete, maintain the reaction temperature between -80°C and -65°C for 4 hours. Then add 320 g of... 20% sodium thiosulfate was added dropwise, and the mixture was kept at 0-10℃ with stirring for 1 hour. GC analysis (excluding solvent) showed: cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester 94.2%, trans-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester 1.0%, and (2-bromobut-3-en-1-yl)carbamate tert-butyl ester 4.8%. After separation, 653 g of cis-(4-bromobut-2-en-1-yl))carbamate tert-butyl ester toluene solution (7.16 wt%, 0.187 mol) was obtained, with a yield of 93.5%.

[0028] In the second step, tetrabutylammonium bromide (6.1 g, 0.019 mol), potassium carbonate (38.8 g, 0.281 mol), and potassium hydroxide (31.4 g, 0.561 mol) were added to the 653 g cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (7.16 wt%, 0.187 mol) obtained in the previous step. The mixture was heated to 80-90 °C and kept at that temperature for 8 hours. The feed content was controlled to be <0.5% during GC. The mixture was then cooled to room temperature, filtered, and the filtrate was washed once with 100 g of water. The organic layer was concentrated under reduced pressure to remove toluene. The toluene was then distilled under reduced pressure to obtain 29.8 g of colorless liquid N-Boc-3-pyrrolline. The solid was allowed to solidify at room temperature. GC: 99.1%, yield 94.1%, mp: 42-44 °C. 1 H-NMR characterization spectra as follows Figure 1 As shown.

[0029] Example 2

[0030] Step 1: Under nitrogen protection, add tert-butyl N,N-dichlorocarbamate (37.2 g, 0.20 mol), B(C6F5)3 (5.12 g, 0.01 mol), and 550 g of toluene to a reaction flask. Add 70.2 g of 20% 1,3-butadiene-toluene solution (0.26 mol) dropwise at -78°C, controlling the temperature to not exceed -65°C during the addition. After the addition is complete, maintain the reaction temperature between -80°C and -65°C for 5 hours. Then add 260 g of... 20% sodium sulfite was added dropwise, and the mixture was kept at 0-10℃ with stirring for 1 hour. GC analysis (excluding solvent) showed: cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester 94.0%, trans-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester 1.4%, and (2-chlorobut-3-en-1-yl)carbamate tert-butyl ester 4.6%. After separation, 648 g of cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (5.90 wt%, 0.186 mol) was obtained, with a yield of 93.1%.

[0031] In the second step, tetrabutylammonium chloride (5.0 g, 0.018 mol), potassium carbonate (51.3 g, 0.372 mol), and potassium hydroxide (41.7 g, 0.744 mol) were added to 648 g of the cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester toluene solution obtained in the previous step. The mixture was heated to 80-90 °C and kept at that temperature for 8 hours. The GC concentration was controlled at <0.5%. The mixture was cooled to room temperature, filtered, and the filtrate was washed once with 100 g of water. The organic layer was concentrated under reduced pressure to remove toluene. The toluene was then distilled under reduced pressure to obtain 29.5 g of colorless liquid N-Boc-3-pyrrolline. The solidified into a white solid at room temperature. The GC concentration was 98.7%, and the yield was 93.6%.

[0032] Example 3

[0033] Step 1: Under nitrogen protection, add tert-butyl N,N-dichlorocarbamate (37.2 g, 0.20 mol), B(C6F5)3 (3.07 g, 0.006 mol), and 550 g of toluene to a reaction flask. Add 20% 1,3-butadiene-toluene solution (59.4 g, 0.22 mol) dropwise at -78°C, controlling the temperature to not exceed -65°C during the addition. After the addition is complete, maintain the reaction temperature at -80°C to -65°C for 5 hours. Then add 320 g of... 20% sodium thiosulfate was added dropwise, and the mixture was kept at 0-10℃ with stirring for 1 hour. GC analysis (excluding solvent) showed: cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester 92.8%, trans-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester 2.0%, and (2-chlorobut-3-en-1-yl)carbamate tert-butyl ester 5.2%. After separation, 631 g of cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (5.93 wt%, 0.182 mol) was obtained, with a yield of 91.0%.

[0034] In the second step, tetrabutylammonium bromide (2.9 g, 0.009 mol), potassium carbonate (37.7 g, 0.273 mol), and potassium hydroxide (30.6 g, 0.546 mol) were added to 631 g of the cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (5.93 wt%, 0.182 mol) obtained in the previous step. The mixture was heated to 80-90 °C and kept at that temperature for 8 hours. The raw material content was controlled to be <0.5% during GC. The mixture was then cooled to room temperature, filtered, and the filtrate was washed once with 100 g of water. The organic layer was concentrated under reduced pressure to remove toluene. The toluene was then distilled under reduced pressure to obtain 28.6 g of colorless liquid N-Boc-3-pyrrolline. The solid was allowed to solidify at room temperature. The GC yield was 98.4%, and the yield was 92.9%.

[0035] Example 4

[0036] In the first step, under nitrogen protection, 440.0 g (1.6 mol) of N,N-dibromocarbamate tert-butyl ester, 41.0 g (0.08 mol) of B(C6F5)3, and 4.4 kg of toluene were added to the reaction flask. A 20% 1,3-butadiene-toluene solution (519.2 g, 1.92 mol) was added dropwise at -78°C, with the temperature controlled to not exceed -65°C during the addition. After the addition was complete, the reaction was maintained at -80°C to -65°C for 4 hours. Then, 2.56 kg of [unspecified substance] was added dropwise. 20% sodium thiosulfate was added dropwise, and the mixture was kept at 0-10℃ with stirring for 1 hour. GC analysis (excluding solvent) showed: cis-(4-chlorobut-2-en-1-yl)carbamate tert-butyl ester 94.6%, trans-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester 0.9%, and (2-bromobut-3-en-1-yl)carbamate tert-butyl ester 4.5%. After separation, 5.25 kg of cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (7.14 wt%, 1.50 mol) was obtained, with a yield of 93.8%.

[0037] In the second step, tetrabutylammonium bromide (48.3 g, 0.15 mol), potassium carbonate (414 g, 3.0 mol), and potassium hydroxide (336 g, 6.0 mol) were added to the 5.25 kg cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (7.14 wt%, 1.50 mol) obtained in the previous step. The mixture was heated to 80-90 °C and kept at that temperature for 8 hours. The raw material concentration was controlled to be <0.5% during GC. The mixture was then cooled to room temperature, filtered, and the filtrate was washed once with 800 g of water. The organic layer was concentrated under reduced pressure to obtain toluene. The toluene was then distilled under reduced pressure to obtain 240.1 g of colorless liquid N-Boc-3-pyrrolline. The solid was allowed to solidify at room temperature. The GC concentration was 99.3%, and the yield was 94.6%.

[0038] Example 5

[0039] Step 1: Under nitrogen protection, add 55.0 g (0.20 mol) of N,N-dibromocarbamate tert-butyl ester and 550 g of toluene to a reaction flask. Add 64.9 g (0.24 mol) of 20% 1,3-butadiene-toluene solution dropwise at -78°C, controlling the temperature to not exceed -65°C during the addition. After the addition is complete, maintain the reaction temperature at -80°C to -65°C for 4 hours. Then add 320 g of... 20% sodium thiosulfate was added dropwise, and the mixture was kept at 0-10℃ with stirring for 1 hour. GC analysis (excluding solvent) showed the following: cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester 52.6%, trans-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester 21.1%, (2-bromobut-3-en-1-yl)carbamate tert-butyl ester 8.6%, and carbamate tert-butyl ester 17.7%. After separation, 647 g of cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (3.86 wt%, 0.10 mol) was obtained, with a yield of 51.8%.

[0040] In the second step, tetrabutylammonium bromide (3.2 g, 0.01 mol), potassium carbonate (27.6 g, 0.20 mol), and potassium hydroxide (22.4 g, 0.40 mol) were added to the 647 g cis-(4-bromobut-2-en-1-yl)carbamate tert-butyl ester toluene solution (3.86 wt%, 0.10 mol) obtained in the previous step. The mixture was heated to 80-90 °C and kept at that temperature for 8 hours. The raw material concentration was controlled to be <0.5% during GC. The mixture was then cooled to room temperature, filtered, and the filtrate was washed once with 100 g of water. The organic layer was concentrated under reduced pressure to remove toluene. The toluene was then distilled under reduced pressure to obtain 14.7 g of colorless liquid N-Boc-3-pyrrolline. The solid was allowed to solidify at room temperature. The GC concentration was 96.3%, and the yield was 87.1%.

[0041] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing N-Boc-3-pyrrolline, characterized in that, Includes the following steps: In the first step, 1,3-butadiene and N,N-dihalocarbamate tert-butyl ester undergo a 1,4-cis addition reaction in toluene solution under the catalysis of B(C6F5)3. The reaction is quenched by a reducing agent aqueous solution and the mixture is separated into layers to obtain a toluene solution of (4-halobut-2-en-1-yl)carbamate tert-butyl ester with cis as the main component. In the second step, a phase transfer catalyst, potassium carbonate, and potassium hydroxide were added to a toluene solution of (4-halobut-2-en-1-yl)carbamate tert-butyl ester, and the mixture was heated to 80-90℃ to react and obtain the product N-Boc-3-pyrrololine.

2. The method for preparing N-Boc-3-pyrrololine according to claim 1, characterized in that: In the first step, tert-butyl N,N-dihalocarbamate is selected from tert-butyl N,N-dichlorocarbamate or tert-butyl N,N-dibromocarbamate.

3. The method for preparing N-Boc-3-pyrrolidine according to claim 1, characterized in that: In the first step, the reducing agent is selected from sodium thiosulfate, sodium sulfite, or sodium bisulfite.

4. The method for preparing N-Boc-3-pyrrolidine according to claim 1, characterized in that: In the first step, the molar ratio of 1,3-butadiene, tert-butyl N,N-dihalocarbamate to B(C6F5)3 is 1.1-1.3:1.0:0.03-0.

05.

5. The method for preparing N-Boc-3-pyrrololine according to claim 1, characterized in that: In the first step, the reaction temperature is -80℃ to -65℃.

6. The method for preparing N-Boc-3-pyrrolline according to claim 1, characterized in that: In the second step, the phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylammonium fluoride.

7. The method for preparing N-Boc-3-pyrrolidine according to claim 1, characterized in that: In the second step, the molar ratio of cis-(4-halobut-2-en-1-yl)carbamate tert-butyl ester, phase transfer catalyst, potassium carbonate and potassium hydroxide is 1.0:0.05-0.1:1.5-2.0:3.0-4.0.

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