A new process for the continuous production of carbamazepine

Abstract

The application discloses a new process for continuously preparing carbamazepine, and comprises the following steps: (1) dissolving indole in an organic solvent as raw material liquid I, filling a copper catalyst and the like in a tubular reactor, and reacting the raw material liquid I through the tubular reactor to obtain a reaction liquid, and distilling the reaction liquid to obtain 1-phenylindole; (2) dissolving 1-phenylindole and an acid catalyst in organic solvents respectively as raw material liquids II and III, mixing and reacting the raw material liquids II and III through a tubular reactor to obtain a reaction liquid, and recrystallizing the reaction liquid to obtain imino stilbene; (3) dissolving imino stilbene and triphosgene in organic solvents as raw material liquids IV and V, mixing and reacting the raw material liquids IV and V through a tubular reactor, mixing and reacting the reaction liquid with ammonia water again, and finally recrystallizing the reaction liquid to obtain carbamazepine; the process has three steps of reaction in total, the yield of each step is above 85%, the reaction speed is fast, the side reaction is less, the mass transfer and heat transfer efficiency is high, the safety is high, the waste is less, the cost is low, and the post-treatment is convenient.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and in particular relates to a novel process for the continuous preparation of carbamazepine. Background Technology

[0002] Carbamazepine, chemically named 5H-dibenzo[b,f]azapyro-5-carboxamide, is currently used for anti-epileptic, anti-manic-depressive, anti-arrhythmic, trigeminal neuralgia, diabetes insipidus, and depression treatment, and has a wide range of clinical applications.

[0003] There are many methods for preparing carbamazepine. Currently, the main industrial production method is the o-nitrotoluene process (as reported by Zhou Yiguo et al., Pharmaceutical Industry, 1972(2):4-9). The specific synthetic route is as follows: o-nitrotoluene is used as the starting material. Coupling is carried out under strong base conditions, followed by catalytic hydrogenation to reduce the nitro group. Then, a ring-closing reaction is carried out at ultra-high temperature to obtain iminodibenzyl. After acylation, bromination, elimination, and amination, a total of seven steps are taken to obtain the product carbamazepine. This process has the advantages of mature technology, cheap raw materials, and low production cost, but it also has disadvantages such as long reaction steps, complex post-treatment, a large amount of waste, and the use of dangerous processes such as hydrogenation or ultra-high temperature reactions.

[0004]

[0005] CN118459407A discloses a continuous preparation method for carbamazepine, which involves mixing iminostilbene chloride and chlorobenzene to obtain a raw material solution; using a constant flow pump, the raw material solution and ammonia water are separately introduced into a preheating module for mixing and preheating, and then introduced into a microchannel device for reaction to obtain a reaction solution; the reaction solution is post-processed to obtain the carbamazepine product. This process studies the microchannel continuous process of the ammoniation reaction, but using iminostilbene chloride as the starting material is expensive.

[0006] Andrew V. Stachulski's research group (Organic & Biomolecular Chemistry, 2014, 45(17):8426-8434.) proposed an indole synthesis process. Using indole and iodobenzene as raw materials, L-proline as a ligand, cuprous iodide as a catalyst, and DMSO as a solvent, an arylation reaction was carried out for 24 hours to obtain 1-phenylindole. Then, a rearrangement and cyclization reaction was catalyzed with 40 equivalents of polyphosphoric acid for 36 hours to obtain iminostilbene (the yield of this step was only 67%). Finally, a one-pot reaction was carried out with phosgene and ammonia, resulting in carbamazepine in four steps. This process has advantages such as short reaction steps and relatively mild reaction conditions, but it also has disadvantages such as expensive raw materials, low yield of the key rearrangement reaction, long reaction time, and excessive waste acid production.

[0007] In summary, both the first and third processes are currently batch production processes. The first process, due to its long reaction steps and complex post-processing, lacks value for continuous process research. The third process, also due to its long reaction time and low yield of key reactions, is difficult to implement as a continuous tubular reaction. The second process is only a continuous process for the final amination step in the synthesis of carbamazepine; the raw materials are expensive, and in the batch synthesis processes reported in the literature, the final acylation and amination steps often employ a "one-pot" process. Therefore, this continuous process has limited practical value. Summary of the Invention

[0008] In view of this, and addressing the aforementioned technical problems, this invention has creatively researched a third process, providing a novel tubular continuous preparation process for carbamazepine. This process overcomes the shortcomings of existing processes, achieving advantages such as high yield, low cost, short reaction steps, short reaction time, simple post-processing, minimal waste, and process safety. It is a green, safe, and efficient new process. This new process has not been reported in the literature and possesses innovative and industrial production value.

[0009] The specific process route of this invention is as follows:

[0010]

[0011] The specific process of this invention is as follows: using indole and halobenzene as starting materials, a copper / alkali catalytic system is packed into a centimeter-scale tubular fixed-bed catalytic reactor and reacted for several minutes to obtain 1-phenylindole; the intermediate and acid are dissolved in solvents respectively and reacted for several minutes in a centimeter-scale tubular liquid-phase reactor to obtain iminostilbene; the intermediate, solid phosgene and ammonia are dissolved in solvents respectively and reacted twice in a centimeter-scale tubular liquid-phase reactor for several minutes each time, to carry out a "one-pot" reaction to obtain the product carbamazepine.

[0012] The technical solution adopted by this invention to solve its technical problem is:

[0013] A novel process for the continuous preparation of carbamazepine includes the following steps:

[0014] Step 1: Continuous preparation of 1-phenylindole; Indole is dissolved in an organic solvent, which is also a reactant, and the solution is heated to obtain raw material solution I; Copper catalyst and acid-binding agent are mixed evenly and packed into a tubular reactor; Raw material solution I is introduced, and then mixed and preheated in a preheater before entering the tubular reactor for reaction to obtain reaction solution ①; Reaction solution ① is distilled to obtain 1-phenylindole.

[0015] Step 2: Continuous preparation of iminostilbene; 1-phenylindole is dissolved in an organic solvent to obtain raw material solution II; acid catalyst is dissolved in an organic solvent to obtain raw material solution III; raw material solutions II and III are introduced into a preheater for mixing and preheating, and then introduced into a tubular reactor for reaction to obtain reaction solution ②; reaction solution ② is subjected to solvent removal and recrystallization to obtain iminostilbene.

[0016] Step 3: Continuous preparation of carbamazepine; dissolve iminostilbene in an organic solvent to obtain raw material solution IV; dissolve triphosgene in an organic solvent to obtain raw material solution V; introduce raw material solutions IV and V, mix and preheat in a preheater, and then react in a tubular reactor to obtain reaction solution ③; introduce reaction solution ③ and ammonia water into a preheater for mixing and preheating, and then react in a tubular reactor to obtain reaction solution ④; after solvent removal and recrystallization, reaction solution ④ yields carbamazepine.

[0017] Furthermore, in step one, the tubular reactor is made of stainless steel hollow column with an inner diameter ranging from 0.1 to 1.5 cm and a length ranging from 1 to 20 cm; in steps two and three, the tubular reactor has an inner diameter ranging from 0.1 to 1.0 cm and a length ranging from 0.5 to 5 m.

[0018] Furthermore, in step one, the copper catalyst is one of copper oxide, cuprous oxide, cuprous chloride, cuprous chloride dihydrate, copper iodide, cuprous iodide, copper bromide, and cuprous bromide, preferably cuprous iodide; the acid-binding agent is one of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, and triethylamine, preferably potassium carbonate; the organic solvent is one of fluorobenzene, chlorobenzene, bromobenzene, and iodobenzene, preferably bromobenzene.

[0019] Furthermore, in step one, the preheating and reactor temperature is 120–160°C; the reaction time is 1–5 minutes.

[0020] Furthermore, in step one, the mass ratio of the indole to the organic solvent, the acid-binding agent, and the copper catalyst is 1:(5-15):(1.5-3.5):(0.01-0.2), preferably 1:10:2.5:0.1.

[0021] Furthermore, in step two, the acid catalyst is a protic acid or a sulfonamide compound, wherein the protic acid is selected from trifluoromethanesulfonic acid, fluorosulfonic acid, chlorosulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, and polyphosphoric acid; wherein the sulfonamide is selected from bis(trifluoromethanesulfonyl)imide, bis(fluorosulfonyl)imide, bis(benzenesulfonyl)imide, and trifluoromethanesulfonamide, preferably trifluoromethanesulfonic acid; and the organic solvent is selected from toluene, chlorobenzene, bromobenzene, acetonitrile, dichloroethane, n-heptane, N,N-dimethylformamide, and dimethyl sulfoxide, preferably chlorobenzene.

[0022] Furthermore, in step two, the mass ratio of 1-phenylindole to organic solvent and acid catalyst is 1:(5-15):(1-4), preferably 1:12:2; in step two, the preheating and reactor temperature is 80-120°C, and the reaction time is 5-10 minutes.

[0023] Furthermore, in step three, the organic solvent is one of toluene, chlorobenzene, fluorobenzene, iodobenzene, bromobenzene, acetonitrile, and n-butanol, preferably chlorobenzene, and the ammonia water is ammonia water with a mass fraction of 20-50%.

[0024] Furthermore, in step three, the temperature of the first preheating and reactor is 100-130°C, and the reaction time is 2-10 minutes; the temperature of the second preheating and reactor is 60-90°C, and the reaction time is 1-8 minutes.

[0025] Furthermore, in step three, the mass ratio of iminostilbene to triphosgene, organic solvent, and ammonia is 1:(0.5-1.5):(5-15):(1.5-4.5), preferably 1:0.7:10:2.5.

[0026] The novel process for the continuous preparation of carbamazepine in this invention employs a high-efficiency catalytic system coupled with a centimeter-scale tubular reactor. The highly active catalyst system exists in molecular or nanoscale form, and the centimeter-scale tubular reactor exhibits excellent mass and heat transfer performance. Optimized reaction parameters at low pressure and medium temperature for each step ensure high-efficiency reaction, achieving high yield, extremely short reaction time, few side reactions, and simple post-processing. The yield of key reactions reaches 85%, and both the catalyst and solvent can be recovered and reused. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments, but the scope of protection of the present invention is not limited thereto.

[0028] Example 1

[0029] Step 1: Weigh out 10g of indole, 100g of bromobenzene, 1.5g of cuprous iodide, and 25g of potassium carbonate. Dissolve indole in bromobenzene (bromobenzene is also a reactant) and heat to dissolve, obtaining raw material solution I. Mix cuprous iodide and potassium carbonate evenly and pack into a tubular reactor (inner diameter 1.0cm, length 10cm). Heat the preheater and tubular reactor to 155℃. Introduce raw material solution I into the preheater for preheating, then into the tubular reactor for reaction, controlling the reaction time to 3 minutes, to obtain reaction solution ①. After reaction solution ① cools, dismantle the tubular reactor, remove the mixed solids, separate the cuprous iodide, and recover it for reuse. Distill reaction solution ① under reduced pressure to recover the solvent bromobenzene, obtaining 15.68g of pale yellow oily liquid 1-phenylindole, with a yield of 95.06% and a purity of 99.9%.

[0030] Example 2

[0031] In Example 1, the copper catalyst cuprous iodide was replaced with cuprous oxide in step one, and the rest was the same as in Example 1. Finally, 15.26 g of 1-phenylindole was obtained, with a yield of 92.47% and a purity of 99.9%.

[0032] Example 3

[0033] In Example 1, the copper catalyst cuprous iodide was replaced with cuprous bromide in step one, and the rest was the same as in Example 1. Finally, 14.09 g of 1-phenylindole was obtained, with a yield of 85.42% and a purity of 99.9%.

[0034] Example 4

[0035] In Example 1, potassium carbonate was replaced with potassium hydroxide as the acid-binding agent in step one, and the rest was the same as in Example 1. Finally, 14.77 g of 1-phenylindole was obtained, with a yield of 89.51% and a purity of 99.9%.

[0036] Example 5

[0037] In Example 1, the temperature of the preheater and tubular reactor in step one was replaced with 150°C, while other parameters remained the same as in Example 1. Finally, 15.07 g of 1-phenylindole was obtained, with a yield of 91.31% and a purity of 99.9%.

[0038] Example 6

[0039] In Example 1, the temperature of the preheater and tubular reactor in step one was replaced with 140°C, while other parameters remained the same as in Example 1. Finally, 13.66 g of 1-phenylindole was obtained, with a yield of 82.76% and a purity of 99.9%.

[0040] Example 7

[0041] In Example 1, the solvent bromobenzene was replaced with iodobenzene in step one, and the rest was the same as in Example 1. Finally, 15.67 g of 1-phenylindole was obtained, with a yield of 94.98% and a purity of 99.9%.

[0042] Example 8

[0043] The inner diameter of the tubular reactor in step one of Example 1 was adjusted to 1.5 cm, and the rest was the same as in Example 1. Finally, 13.98 g of 1-phenylindole was obtained, with a yield of 84.71% and a purity of 99.9%.

[0044] Example 9

[0045] The reaction time in step one of Example 1 was adjusted to 2 minutes, while other steps remained the same as in Example 1. Finally, 14.61 g of 1-phenylindole was obtained, with a yield of 88.53% and a purity of 99.9%.

[0046] Example 10

[0047] Step 2: Weigh 10g of 1-phenylindole obtained in Example 1 and 20g of trifluoromethanesulfonic acid. Dissolve 1-phenylindole in 120g of chlorobenzene to obtain raw material solution II; dissolve trifluoromethanesulfonic acid in 120g of chlorobenzene to obtain raw material solution III; the temperature of the preheater and tubular reactor is 105℃. Raw material solutions II and III are introduced into the preheater for mixing and preheating, and then enter the tubular reactor (inner diameter 8mm, length 3m) for reaction. The reaction time is controlled at 8 minutes to obtain reaction solution ②; after the reaction solution ② is cooled, it is subjected to vacuum distillation to recover the solvent chlorobenzene. The solid is recrystallized to obtain 8.531g of yellow crystalline iminostilbene, with a yield of 85.31% and a purity of 99.8%.

[0048] Example 11

[0049] In step two of Example 10, the acid catalyst trifluoromethanesulfonic acid was replaced with bis(trifluoromethanesulfonyl)imide, and the rest was the same as in Example 10. Finally, 8.027 g of iminostilbene was obtained, with a yield of 80.27% and a purity of 99.8%.

[0050] Example 12

[0051] In step two of Example 10, the acid catalyst trifluoromethanesulfonic acid was replaced with difluorosulfonyl imide, and the rest was the same as in Example 10. Finally, 7.327 g of iminostilbene was obtained, with a yield of 73.27% and a purity of 99.8%.

[0052] Example 13

[0053] In Example 10, the temperature of the preheater and tubular reactor in step two was replaced with 100°C, while other parameters remained the same as in Example 10. Finally, 8.344 g of iminostilbene was obtained, with a yield of 83.44% and a purity of 99.8%.

[0054] Example 14

[0055] In Example 10, the preheater and tubular reactor in step two were replaced with 95°C, while other steps remained the same as in Example 10. Finally, 7.887 g of iminostilbene was obtained, with a yield of 78.87% and a purity of 99.8%.

[0056] Example 15

[0057] In step two of Example 10, the solvent chlorobenzene was replaced with bromobenzene, and the rest was the same as in Example 10. Finally, 8.107 g of iminostilbene was obtained, with a yield of 81.07% and a purity of 99.8%.

[0058] Example 16

[0059] In step two of Example 10, the inner diameter of the tubular reactor was adjusted to 10 mm, while other steps remained the same as in Example 10. Finally, 7.67 g of iminostilbene was obtained, with a yield of 76.83% and a purity of 99.8%.

[0060] Example 17

[0061] The reaction time in step two of Example 10 was adjusted to 6 minutes, while other steps remained the same as in Example 10. Finally, 8.142 g of iminostilbene was obtained, with a yield of 81.42% and a purity of 99.8%.

[0062] Example 18

[0063] Step 3: Weigh 10g of iminostilbene prepared in Example 10, 7g of triphosgene, and 25g of 25% ammonia water; dissolve iminostilbene in 100g of chlorobenzene to obtain raw material solution IV; dissolve triphosgene in 100g of chlorobenzene to obtain raw material solution V; the temperature of the first preheater and tubular reactor is 120℃, and raw material solutions IV and V are introduced into the preheater for mixing and preheating, and then enter the tubular reactor (inner diameter 8mm, length 3m) for reaction, controlling the reaction time to 5 minutes to obtain reaction solution ③. When the temperature of reaction solution ③ drops to 80℃, and the temperature of the second preheater and the tubular reactor is 80℃, reaction solution ③ and ammonia water are introduced and mixed and preheated in the second preheater. Then, it enters the tubular reactor (with an inner diameter of 8mm and a length of 3m) for reaction. The reaction time is controlled at 3 minutes to obtain reaction solution ④. After the reaction solution ④ is cooled, it is washed with water, separated, dried, filtered, and the organic phase is subjected to vacuum distillation to recover the solvent chlorobenzene. Recrystallization yields 11.15g of white carbamazepine powder, with a yield of 91.2% and a purity of 99.8%.

[0064] Example 19

[0065] In step 3 of Example 18, the solvent chlorobenzene was replaced with bromobenzene, and the rest was the same as in Example 18. Finally, 10.80 g of carbamazepine was obtained, with a yield of 88.35% and a purity of 99.8%.

[0066] Example 20

[0067] In step three of Example 18, the temperature of the first preheater and tubular reactor was replaced with 115°C, while other parameters remained the same as in Example 18. Finally, 10.87 g of carbamazepine was obtained, with a yield of 88.87% and a purity of 99.8%.

[0068] Example 21

[0069] In step three of Example 18, the temperature of the second preheater and tubular reactor was replaced with 75°C, while other parameters remained the same as in Example 18. Finally, 10.97 g of carbamazepine was obtained, with a yield of 89.72% and a purity of 99.8%.

[0070] Example 22

[0071] In step three of Example 18, the inner diameter of the tubular reactor was uniformly adjusted to 10 mm, and other parameters were the same as in Example 18. Finally, 10.57 g of carbamazepine was obtained, with a yield of 86.43% and a purity of 99.8%.

[0072] Example 23

[0073] In step three of Example 18, the reaction time of the first tubular reactor was adjusted to 4 minutes, while other steps remained the same as in Example 18. Finally, 10.68 g of carbamazepine was obtained, with a yield of 87.31% and a purity of 99.8%.

[0074] Example 24

[0075] In step three of Example 18, the reaction time of the second tubular reactor was adjusted to 2 minutes, while other steps remained the same as in Example 18. Finally, 10.43 g of carbamazepine was obtained, with a yield of 85.31% and a purity of 99.8%.

[0076] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A novel process for the continuous preparation of carbamazepine, characterized in that, The steps are as follows: Step 1: Continuous preparation of 1-phenylindole; Indole is dissolved in an organic solvent and heated to obtain raw material solution I; Copper catalyst and acid-binding agent are mixed evenly and packed into a tubular reactor; Raw material solution I is introduced, mixed and preheated in a preheater, and then introduced into the tubular reactor for reaction to obtain reaction solution ①; Reaction solution ① is distilled to obtain 1-phenylindole; Step 2: Continuous preparation of iminostilbene; 1-phenylindole is dissolved in an organic solvent to obtain raw material solution II; an acid catalyst is dissolved in an organic solvent to obtain raw material solution III; raw material solutions II and III are introduced into a preheater for mixing and preheating, and then introduced into a tubular reactor for reaction to obtain reaction solution ②; reaction solution ② is subjected to solvent removal and recrystallization to obtain iminostilbene. Step 3: Continuous preparation of carbamazepine; dissolve iminostilbene in an organic solvent to obtain raw material solution IV; dissolve triphosgene in an organic solvent to obtain raw material solution V; introduce raw material solutions IV and V into a preheater for mixing and preheating, then introduce them into a tubular reactor for reaction to obtain reaction solution ③; introduce reaction solution ③ and ammonia water into a preheater for mixing and preheating, then introduce them into a tubular reactor for reaction to obtain reaction solution ④; reaction solution ④ undergoes solvent removal and recrystallization to obtain carbamazepine; In step one, the copper catalyst is one of cuprous oxide, cuprous chloride, cuprous iodide, and cuprous bromide, and the organic solvent is one of bromobenzene and iodobenzene; In step two, the acid catalyst is selected from one of bis(trifluoromethanesulfonyl)imide and bis(fluorosulfonyl)imide.

2. The novel process for continuous preparation of carbamazepine according to claim 1, characterized in that, In step one, the tubular reactor is made of stainless steel hollow column with an inner diameter ranging from 0.1 to 1.5 cm and a length ranging from 1 to 20 cm; in steps two and three, the tubular reactor has an inner diameter ranging from 0.1 to 1.0 cm and a length ranging from 0.5 to 5 m.

3. The novel process for continuous preparation of carbamazepine according to claim 1, characterized in that, In step one, the preheating and reactor temperature is 120–160°C; the reaction time is 1–5 minutes.

4. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step one, the mass ratio of indole to organic solvent, acid-binding agent, and copper catalyst is 1:(5-15):(1.5-3.5):(0.01-0.2).

5. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step one, the acid-binding agent is one of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, and triethylamine.

6. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step two, the organic solvent is one of toluene, chlorobenzene, bromobenzene, acetonitrile, dichloroethane, n-heptane, N,N-dimethylformamide, and dimethyl sulfoxide.

7. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step two, the mass ratio of 1-phenylindole to organic solvent and acid catalyst is 1:(5-15):(1-4); in step two, the preheating and reactor temperature is 80-120℃, and the reaction time is 5-10 minutes.

8. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step three, the organic solvent is one of toluene, chlorobenzene, fluorobenzene, iodobenzene, bromobenzene, acetonitrile, and n-butanol, and the ammonia water is ammonia water with a mass fraction of 20-50%.

9. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step three, the temperature of the first preheater and reactor is 100-130℃, and the reaction time is 2-10 minutes. The temperature of the second preheater and reactor is 60-90℃, and the reaction time is 1-8 minutes.

10. A novel process for the continuous preparation of carbamazepine according to claim 1, characterized in that, In step three, the mass ratio of iminostilbene to triphosgene, organic solvent, and ammonia is 1:(0.5-1.5):(5-15):(1.5-4.5).

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