A method for the continuous synthesis of N-Boc-2,5-dihydro-1H-pyrrole

Abstract

The present invention discloses a method for the continuous synthesis of N-Boc-2,5-dihydro-1H-pyrrole. The method includes the steps of dissolving cis-1,4-dichloro-2-butene in an organic solvent to prepare solution A, dissolving urotropin in an organic solvent to prepare solution B, feeding solution A and solution B into a first continuous reactor, transferring the product overflow system of the first continuous reactor to a second continuous reactor and simultaneously feeding concentrated hydrochloric acid, transferring the product overflow system of the second continuous reactor to a third continuous reactor and simultaneously feeding potassium carbonate, transferring the product overflow system of the third continuous reactor to a fourth continuous reactor and simultaneously feeding Boc anhydride solution, and continuously separating the product of the fourth continuous reactor into solid and liquid, concentrating and distilling to obtain N-Boc-2,5-dihydro-1H-pyrrole. The technical solution of the present invention can avoid the route involving high-risk materials, and the continuous method can increase production capacity and yield.

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical chemical industry, specifically to a continuous synthesis method for N-Boc-2,5-dihydro-1H-pyrrole. [Background technology]

[0002] N-Boc-2,5-dihydro-1H-pyrrole (also known as N-Boc-3-pyrroline, cas: 73286-70-1) is a widely demanded raw material and an important heterocyclic block in medicinal chemistry. However, due to the long synthetic route and complicated process, the production cost is high. Therefore, it is very valuable and necessary to improve the process and reduce its production cost.

[0003] Currently, the main synthetic routes for N-Boc-2,5-dihydro-1H-pyrrole include the following route reported in the literature Practical One-Pot and Large-Scale Synthesis of N-(tert-Butyloxycarbonyl)-3-pyrroline (Organic Process Research & Development 2009,13,638-640).

[0004] [ka]

[0005] Here, hexamethylenetetramine is cyclic hexamethylenetetramine, Reflux is reflux, and Conc.HCl is concentrated hydrochloric acid.

[0006] This route avoids the use of dangerous reducing agents, but no study was done on the subsequent cyclopropanation. In addition, the report also found that oxidation and coupling impurities were found during a 1000L batch scale-up, but this was attributed to the transformation of an unstable intermediate during multi-step work-up, and the yield was only 85%. However, the literature did not propose any follow-up solutions.

[0007] Ring-Closing Metathesis in Methanol and Water, Thomas A. Kirkland (J. Org. Chem. 1998, 63, 9904-9909) reported that the shortest route is directly synthesized using Grubbs reagent according to olefin metathesis. However, this method is not cost-effective because the raw material cost is high and ruthenium chloride and expensive ligands are required to prepare the Grubbs reagent. In addition, the reaction produces ethylene, a flammable gas, which makes the process less safe when scaled up. The synthesis route is as follows:

[0008] [ka]

[0009] However, Tolene is toluene.

[0010] Although various other routes have been reported, they all suffer from the problem of high raw material costs. Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention aims to provide a continuous synthesis method for N-Boc-2,5-dihydro-1H-pyrrole so as to reduce production costs and increase yields. [Means for solving the problem]

[0012] To achieve the above object, according to one aspect of the present invention, there is provided a method for continuous synthesis of N-Boc-2,5-dihydro-1H-pyrrole. The method includes the steps of dissolving cis-1,4-dichloro-2-butene in an organic solvent to prepare solution A; dissolving urotropin in an organic solvent to prepare solution B; feeding solution A and solution B into a first continuous reactor using a continuous feeding system; transferring the product overflow system of the first continuous reactor to a second continuous reactor, and simultaneously feeding concentrated hydrochloric acid into the second continuous reactor; transferring the product overflow system of the second continuous reactor to a third continuous reactor, and simultaneously feeding potassium carbonate into the third continuous reactor; transferring the product overflow system of the third continuous reactor to a fourth continuous reactor, and simultaneously feeding Boc anhydride solution into the fourth continuous reactor; and continuously separating, concentrating and distilling the product of the fourth continuous reactor to prepare N-Boc-2,5-dihydro-1H-pyrrole.

[0013] Furthermore, the first continuous reactor, the second continuous reactor, the third continuous reactor, and the fourth continuous reactor are each a continuous CSTR reactor or a continuous tubular reactor.

[0014] Furthermore, the concentration is carried out in a continuous thin film evaporator, and preferably, the concentration is carried out at 40 to 50°C.

[0015] Furthermore, the organic solvent is one or more selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, methanol, ethanol, and isopropanol.

[0016] Furthermore, the reaction temperature in the first continuous reactor is 50° C. to 70° C., and the retention time is 1 to 4 hours, preferably 2 hours.

[0017] Furthermore, the reaction temperature in the second continuous reactor is 50° C. to 60° C., and the retention time is 10 to 60 minutes, preferably 30 minutes.

[0018] Furthermore, the reaction temperature in the third continuous reactor is 50° C. to 60° C., and the retention time is 10 to 60 minutes, preferably 30 minutes.

[0019] Furthermore, the reaction temperature in the fourth continuous reactor is 20° C. to 40° C., and the retention time is 0.5 to 4 hours, and preferably 1 hour.

[0020] Furthermore, the mass volume percent concentration of cis-1,4-dichloro-2-butene in solution A is 10-20.2%, the mass volume percent concentration of urotropine in solution B is 21.8%, and the supply mass ratio of solution A to solution B is 1:1.0-2.0.

[0021] Furthermore, the proportion of Boc anhydride in the Boc anhydride solution is 20 to 80%. Effect of the Invention

[0022] By applying the technical solution of the present invention, the route involving high-risk materials can be avoided, and a continuous multi-step reaction continuous input production process can be realized in a continuous manner, which reduces the safety risks of traditional batch processes, reduces the amount of materials used, reduces the destruction of unstable intermediates, eliminates multi-step post-treatment, and increases production capacity and yield. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] In addition, unless there is a conflict, the embodiments and features in the embodiments in the present application can be combined with each other.

[0024] In order to address the technical problems of the prior art synthesis of N-Boc-2,5-dihydro-1H-pyrrole, such as long synthetic route, complicated process, high cost, and unstable intermediates, the present invention proposes the following technical solution:

[0025] [ka]

[0026] The present invention is based on the policy of minimizing the destruction of intermediates by selecting a route that avoids high-risk materials and using a process that can realize continuous all steps, and directly synthesizes the highly stable intermediate N-Boc-2,5-dihydro-1H-pyrrole. As a result, a highly efficient and high-yield process has been developed.

[0027] According to an exemplary embodiment of the present invention, a method for the continuous synthesis of N-Boc-2,5-dihydro-1H-pyrrole is provided. The method includes the steps of dissolving cis-1,4-dichloro-2-butene in an organic solvent to prepare solution A; dissolving urotropin in an organic solvent to prepare solution B; feeding solution A and solution B into a first continuous reactor using a continuous feeding system; transferring the product overflow system of the first continuous reactor to a second continuous reactor, and simultaneously feeding concentrated hydrochloric acid into the second continuous reactor; transferring the product overflow system of the second continuous reactor to a third continuous reactor, and simultaneously feeding potassium carbonate into the third continuous reactor; transferring the product overflow system of the third continuous reactor to a fourth continuous reactor, and simultaneously feeding Boc acid (tert-butoxycarboxylic acid) anhydride solution into the fourth continuous reactor; and continuously separating, concentrating and distilling the product of the fourth continuous reactor to prepare N-Boc-2,5-dihydro-1H-pyrrole.

[0028] By applying the technical solution of the present invention, the route involving high-risk materials can be avoided, and a continuous multi-step reaction continuous input production process can be realized in a continuous manner, which reduces the safety risks of traditional batch processes, reduces the amount of materials used, reduces the destruction of unstable intermediates, eliminates multi-step post-treatment, and increases production capacity and yield.

[0029] Preferably, the first, second, third and fourth continuous reactors are continuous CSTR reactors or continuous tubular reactors, respectively. In this route, the intermediate has the characteristic that it cannot stably exist for a long time, so the continuous technology reduces the risk of its destruction and deterioration, and it is transferred to the next reaction stage as soon as it is produced, and finally forms a stable target product. In order to make the process more favorable for industrial production, the concentration is carried out in a continuous thin film evaporator, and preferably, the concentration is carried out at 40-50°C. Thin film concentration has a negative pressure effect, and can be concentrated at a low temperature to prevent the destruction of the product due to high temperature, and thin film concentration is a continuous technology, which can shorten the heating time of the product, which is also an important factor in increasing the yield.

[0030] According to a typical embodiment of the present invention, the organic solvent is one or more selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, methanol, ethanol and isopropanol, and preferably, the organic solvent is methanol, which has better solubility in both the aqueous phase and the organic phase at the same time, and therefore promotes the reaction rate between the two phases. Moreover, methanol is cheap, easy to concentrate, and easy to post-treat.

[0031] Preferably, in one embodiment of the present invention, the reaction temperature in the first continuous reactor is 50°C-70°C, and the retention time is 2h. The reaction temperature in the second continuous reactor is 50°C-60°C, and the retention time is 30min. The reaction temperature in the third continuous reactor is 50°C-60°C, and the retention time is 30min. The reaction temperature in the fourth continuous reactor is 20°C-40°C, and the retention time is 1h. More preferably, the mass volume percent concentration of cis-1,4-dichloro-2-butene in solution A is 10-20.2%, the mass volume percent concentration of urotropine in solution B is 21.8%, the supply mass ratio of solution A to solution B is 1:1.0-2.0, and the proportion of Boc acid anhydride in the Boc acid anhydride solution is 20-80%. EXAMPLES

[0032] The beneficial effects of the present invention will be further illustrated below with reference to examples. Example 1 Solution A was prepared by dissolving 2 kg of cis-1,4-dichloro-2-butene in 10 L of methanol. Solution B was prepared by dissolving 2.2 kg of urotropine in 10 L of methanol. Next, using a continuous feed system, the two solutions were fed into the first continuous CSTR reactor at feed rates of 10.0 g / min and 10.2 g / min, respectively, and the temperature of the first continuous CSTR reactor was controlled at 50°C to 70°C and the retention time was controlled at 2 h. The overflow system was then transferred to the second continuous CSTR reactor, and concentrated hydrochloric acid was simultaneously fed at a rate of 6.2 g / min, and the temperature of the second continuous CSTR reactor was controlled at 50°C to 60°C and the retention time was controlled at 30 min. Further, the reaction system overflowed into the third continuous CSTR reactor, and at the same time, potassium carbonate was fed into the third continuous CSTR reactor using a continuous solid feeder, with the rate being 10.5g / min, the temperature being 50℃-60℃, and the retention time being 30min. Then, the overflow system was transferred to the fourth continuous CSTR reactor, and at the same time, a methanol solution of Boc acid anhydride (3.49kg of Boc acid anhydride dissolved in 2L of methanol) was fed, with the feed rate being 5.2g / min, the temperature being 20℃-40℃, and the retention time being 1h. The reaction system was continuously solid-liquid separated, and the mother liquor was concentrated by thin film, and concentrated at 40℃-50℃ to a crude product of 2V, and then continuously distilled to prepare pure intermediate 5, the mass of which was 2.53kg, and the yield was 95%.

[0033] Example 2 Solution A was prepared by dissolving 2 kg of cis-1,4-dichloro-2-butene in 10 L of methanol. Solution B was prepared by dissolving 2.2 kg of urotropine in 10 L of methanol. Next, using a continuous feed system, the two solutions were fed into the first continuous CSTR reactor at feed rates of 10.0 g / min and 10.2 g / min, respectively, and the temperature of the first continuous CSTR reactor was controlled at 50°C to 70°C and the retention time was controlled at 1 h. Then, the overflow system was transferred to the second continuous CSTR reactor, and concentrated hydrochloric acid was fed at a rate of 6.2 g / min at the same time, and the temperature of the second continuous CSTR reactor was controlled at 50°C to 60°C and the retention time was controlled at 10 min. Further, the reaction system overflowed into the third continuous CSTR reactor, and at the same time, potassium carbonate was fed into the third continuous CSTR reactor using a continuous solid feeder, with the rate being 10.5g / min, the temperature being 50℃-60℃, and the retention time being 10min. Then, the overflow system was transferred to the fourth continuous CSTR reactor, and at the same time, a methanol solution of Boc acid anhydride (3.49kg of Boc acid anhydride dissolved in 2L of methanol) was fed, with the feed rate being 5.2g / min, the temperature being 20℃-40℃, and the retention time being 0.5h. The reaction system was continuously solid-liquid separated, and the mother liquor was concentrated by thin film, and concentrated at 40℃-50℃ to a crude product of 2V, and then continuously distilled to prepare pure intermediate 5, with a mass of 2.4kg and a yield of 90%.

[0034] Example 3 Solution A was prepared by dissolving 2 kg of cis-1,4-dichloro-2-butene in 10 L of methanol. Solution B was prepared by dissolving 2.2 kg of urotropine in 10 L of methanol. Next, using a continuous feed system, the two solutions were fed into the first continuous CSTR reactor at feed rates of 10.0 g / min and 10.2 g / min, respectively, and the temperature of the first continuous CSTR reactor was controlled at 50°C to 70°C and the retention time was controlled at 4 h. The overflow system was then transferred to the second continuous CSTR reactor, and concentrated hydrochloric acid was simultaneously fed into the second continuous CSTR reactor at a rate of 6.2 g / min, and the temperature of the second continuous CSTR reactor was controlled at 50°C to 60°C and the retention time was controlled at 60 min. Further, the reaction system overflowed into the third continuous CSTR reactor, and at the same time, potassium carbonate was fed into the third continuous CSTR reactor using a continuous solid feeder, with the rate being 10.5g / min, the temperature being 50℃-60℃, and the retention time being 60min. Then, the overflow system was transferred to the fourth continuous CSTR reactor, and at the same time, a methanol solution of Boc acid anhydride (3.49kg of Boc acid anhydride dissolved in 2L of methanol) was fed, with the feed rate being 5.2g / min, the temperature being 20℃-40℃, and the retention time being 4h. The reaction system was continuously solid-liquid separated, and the mother liquor was concentrated by thin film, and concentrated at 40℃-50℃ to a crude product of 2V, and then continuously distilled to prepare pure intermediate 5, with a mass of 2.51kg and a yield of 94%.

[0035] Example 4 Solution A was prepared by dissolving 2 kg of cis-1,4-dichloro-2-butene in 10 L of ethanol. Solution B was prepared by dissolving 2.2 kg of urotropine in 10 L of ethanol. Next, using a continuous feed system, the two solutions were fed into the first continuous CSTR reactor at feed rates of 10.0 g / min and 10.2 g / min, respectively, and the temperature of the first continuous CSTR reactor was controlled at 50°C to 70°C and the retention time was controlled at 2 h. The overflow system was then transferred to the second continuous CSTR reactor, and concentrated hydrochloric acid was simultaneously fed at a rate of 6.2 g / min, and the temperature of the second continuous CSTR reactor was controlled at 50°C to 60°C and the retention time was controlled at 30 min. Further, the reaction system overflowed into the third continuous CSTR reactor, and at the same time, potassium carbonate was fed into the third continuous CSTR reactor using a continuous solid feeder, with the rate being 10.5g / min, the temperature being 50℃-60℃, and the retention time being 30min. Then, the overflow system was transferred to the fourth continuous CSTR reactor, and at the same time, an ethanol solution of Boc acid anhydride (3.49kg of Boc acid anhydride dissolved in 2L of ethanol) was fed, with the feed rate being 5.2g / min, the temperature being 20℃-40℃, and the retention time being 1h. The reaction system was continuously solid-liquid separated, and the mother liquor was concentrated by thin film at 40℃-50℃ to a crude product of 2V, which was then continuously distilled to prepare pure intermediate 5, with a mass of 2.50kg and a yield of 94%.

[0036] From the above description, it can be seen that the above embodiments of the present invention can achieve the following technical effects: By applying the technical solution of the present invention, the route involving high-risk materials is avoided, and a continuous multi-step reaction continuous input production process is realized in a continuous manner, which reduces the safety risks of traditional batch processes, reduces the amount of materials used, reduces the destruction of unstable intermediates, omits multi-step post-treatment, and increases production capacity and yield.

[0037] The above content is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Those skilled in the art can make various modifications and changes to the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included within the protection scope of the present invention.

Claims

1. A continuous process for the synthesis of N-Boc-2,5-dihydro-1H-pyrrole, comprising the steps of: preparing a solution A by dissolving cis-1,4-dichloro-2-butene in an organic solvent; preparing solution B by dissolving urotropine in an organic solvent; driving said solution A and said solution B into a first continuous reactor utilizing a continuous feed system; transferring the product overflow system of the first continuous reactor to a second continuous reactor and simultaneously feeding concentrated hydrochloric acid into the second continuous reactor; transferring the product overflow system of the second continuous reactor to a third continuous reactor and simultaneously driving potassium carbonate into the third continuous reactor; transferring the product overflow system of the third continuous reactor to a fourth continuous reactor and simultaneously feeding a Boc anhydride solution into the fourth continuous reactor; and continuously subjecting the product of the fourth continuous reactor to solid-liquid separation, concentration and distillation to obtain the N-Boc-2,5-dihydro-1H-pyrrole.

2. 2. The method of claim 1, wherein the first continuous reactor, the second continuous reactor, the third continuous reactor, and the fourth continuous reactor are each a continuous CSTR reactor or a continuous tubular reactor.

3. 2. The method of claim 1, wherein the concentration is performed in a continuous thin film evaporator.

4. The method according to claim 3, wherein the concentration is carried out at 40°C to 50°C.

5. 2. The method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, methanol, ethanol, and isopropanol.

6. The method according to any one of claims 1 to 4, characterized in that the reaction temperature in the first continuous reactor is 50°C to 70°C, and the holding time is 1h to 4h.

7. 7. The method according to claim 6, wherein the retention time in the first continuous reactor is 2 h.

8. The method according to any one of claims 1 to 4, characterized in that the reaction temperature in the second continuous reactor is 50°C to 60°C, and the retention time is 10min to 60min.

9. 9. The method of claim 8, wherein the retention time in the second continuous reactor is 30 min.

10. The method according to any one of claims 1 to 4, wherein the reaction temperature in the third continuous reactor is 50°C to 60°C, and the retention time is 10min to 60min.

11. 11. The method according to claim 10, wherein the retention time in the third continuous reactor is 30 min.

12. 5. The method according to claim 1, wherein the reaction temperature in the fourth continuous reactor is 20° C. to 40° C., and the holding time is 0.5 h to 4 h.

13. 13. The method according to claim 12, wherein the retention time in the fourth continuous reactor is 1 h.

14. 2. The method of claim 1, wherein the mass percent concentration of cis-1,4-dichloro-2-butene in solution A is 10%-20.2%, the mass percent concentration of urotropine in solution B is 21.8%, and the feed mass ratio of solution A to solution B is 1:1.0-2.

0.

15. 2. The method according to claim 1, wherein the percentage of Boc anhydride in the Boc anhydride solution is 20% to 80%.

Images