A process for the synthesis of a remegapant intermediate
By employing the nucleophilic substitution reaction of 2-amino-3-chloropyridine with 4-bromopiperidine, followed by amination and CDI cyclization steps, the problems of high cost and poor safety in the preparation of rimexam intermediates have been solved, enabling efficient and safe industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NANTONG CHANGYOO PHARMATECH CO LTD
- Filing Date
- 2023-06-16
- Publication Date
- 2026-05-26
AI Technical Summary
Existing methods for preparing rimex intermediates are costly, involve long process routes, complex post-processing, have low yields, and pose safety risks, making them unsuitable for industrial production.
The compound of formula III was prepared by nucleophilic substitution reaction of 2-amino-3-chloropyridine and 4-bromopiperidine in the presence of a base. Then, the compound of formula I was prepared by amination reaction in the presence of a catalyst and ammonia solution, followed by cyclization by CDI and salt formation by hydrogen chloride solution.
It reduces production costs, simplifies the process, increases yield, enhances reaction safety, avoids environmental pollution, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical organic synthesis technology, and more specifically, to a method for synthesizing a retinoic acid intermediate. Background Technology
[0002] Rimegepant, also known as Rimegepan or Rimegepan in Chinese, is a CGRP antagonist used for the acute treatment of migraines in adults. It was approved by the FDA in February 2020. Its chemical structure is shown below:
[0003] ; 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one is one of the key intermediates in the synthetic route of retamipine, and its chemical structural formula is shown in Formula I below:
[0004] .
[0005] Traditional methods, such as those disclosed in patent documents US2007 / 259851A1, WO2004 / 92166A2, and WO2012 / 37226A1, all involve the reductive amination of compounds a and b to obtain compound c, followed by CDI cyclization to obtain compound d. Compound d is then subjected to deBoc removal to obtain compound I. The synthetic route is as follows:
[0006] , The above preparation method uses compound a as the starting material, which has high raw material costs. Furthermore, the reductive amination step generates impurities, resulting in high preparation costs and making it unsuitable for industrial production.
[0007] While existing research on methods for preparing compounds of formula I has reduced the cost of starting materials to some extent, it still requires high-cost raw materials during the reaction process and suffers from complex post-processing, long process routes, generally low yields, and limited reaction safety, easily causing environmental pollution and hindering industrial-scale production. Specifically, patent documents such as CN114957247A disclose methods for preparing compounds of formula I, which involve a substitution reaction of 3-amino-2-pyridine to obtain compound 1, followed by reductive amination to obtain compound 2, deprotection to obtain compound 3, CDI cyclization to obtain compound 4, and finally deBoc to obtain compound I. The synthetic route is as follows:
[0008] , The above preparation methods require the use of palladium on carbon or hydrogen for reduction reactions, which are expensive, pose safety risks, have long process routes, and result in low yields. For example, patent documents WO2007 / 120590A2, US2009 / 124799A1, and US2018 / 50992A1, etc., have the following synthetic routes:
[0009] , The above preparation method requires the use of chlorosulfonyl isocyanate reaction, which is expensive and highly toxic, produces many reaction impurities, has a long process route, and results in a low overall synthetic yield. It is also environmentally unfriendly and unsuitable for industrialization.
[0010] Therefore, a new technical solution is needed to solve the above-mentioned technical problems. Summary of the Invention
[0011] The purpose of this invention is to provide a method for synthesizing the intermediate of rimexam, namely 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, to solve the technical problems of the prior art mentioned in the background, which are high cost, long process route, complicated post-processing, general yield, and general reaction safety, which are very likely to cause environmental pollution and are not conducive to industrial production.
[0012] To achieve the above objectives, the present invention adopts the following technical solution:
[0013] A method for synthesizing a rimex intermediate, the process route is as follows:
[0014] .
[0015] Furthermore, the specific synthesis method includes the following steps:
[0016] S1. In the presence of a base, 2-amino-3-chloropyridine and 4-bromopiperidine undergo a nucleophilic substitution reaction in solvent A to prepare compound III, namely 3-chloro-N-(piperidin-4-yl)pyridine-2-amine. The molar ratio of 2-amino-3-chloropyridine, 4-bromopiperidine and base is 1:1.05:1.1 to 1:1.6:2.0. The base is one of potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine. Solvent A is one of tetrahydrofuran, acetonitrile, 1,4-dioxane, and 2-methyltetrahydrofuran. The reaction temperature is 0 to 20 °C, and the reaction time is 3 to 10 h.
[0017] S2. In the presence of a catalyst and ammonia solution, compound III, namely 3-chloro-N-(piperidin-4-yl)pyridine-2-amine, undergoes an amination reaction in solvent B to prepare compound II, namely N-(piperidin-4-yl)pyridine-2,3-diamine. The molar ratio of compound III, ammonia solution, and catalyst is 1:3:0.05 to 1:10:0.2. The catalyst is one of potassium iodide, sodium iodide, potassium bromide, and sodium bromide. The ammonia solution is one of ammonia-methanol solution, ammonia-tetrahydrofuran solution, and ammonia water. Solvent B is one of methanol, ethanol, isopropanol, and n-butanol. The reaction temperature is 30–60℃, and the reaction time is 10–20 h.
[0018] S3. Compound S2, namely N-(piperidin-4-yl)pyridine-2,3-diamine, is dissolved in solvent C and sequentially cyclized by CDI and salted by hydrogen chloride solution to prepare compound I, namely 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one. The molar ratio of compound S2 to CDI is 1:1.05 to 1:2. The hydrogen chloride solution is one of hydrochloric acid ethanol solution, hydrochloric acid methanol solution, or hydrochloric acid 1,4-dioxane solution. Solvent C is one of dichloromethane, ethyl acetate, tetrahydrofuran, or toluene. The reaction temperature is 0 to 30°C, and the reaction time is 2 to 5 h.
[0019] Compared with the prior art, the beneficial effects of the present invention are:
[0020] 1. This invention uses 2-amino-3-chloropyridine as the starting material, which undergoes a nucleophilic substitution reaction with 4-bromopiperidine to generate compound III. Compound III is then amination to obtain compound II. Compound II undergoes CDI cyclization and salt formation to obtain compound I, namely 1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. The raw materials and excipients for the entire synthesis process have been industrially produced, are inexpensive and readily available, effectively reducing production costs. The post-processing is simple, the reaction conditions are mild, and there is no need to meet harsh reaction requirements such as extreme cold or extreme heat. Compound I can be prepared in only three steps, which greatly simplifies the synthesis process of compound I and significantly improves the overall yield. Furthermore, it eliminates the need for expensive and potentially dangerous excipients such as palladium on carbon, hydrogen, or chlorosulfonyl isocyanate, effectively improving reaction safety, avoiding environmental pollution, and facilitating industrial production.
[0021] 2. The reaction mechanism for preparing intermediates such as compounds of formula III and formula II is relatively simple, the reaction process is stable and controllable, side reactions are not easy to occur, and good separation effect can be achieved by simple extraction after the reaction is completed. The post-processing is extremely simple. Detailed Implementation
[0022] To enhance understanding of the present invention, the invention will be further described in detail below with reference to embodiments.
[0023] All raw materials used in this invention are commercially available. Example 1
[0024] Preparation of S1, Formula III compound (3-chloro-N-(piperidin-4-yl)pyridine-2-amine):
[0025] In a 1000 ml reaction flask, 58 g (451.15 mmol) of 2-amino-3-chloropyridine, 580 ml of anhydrous tetrahydrofuran, and 93.52 g (676.73 mmol) of anhydrous potassium carbonate were added. The mixture was then cooled to 0 °C, and 81.41 g (496.27 mmol) of 4-bromopiperidine was added dropwise. After the addition was complete, the mixture was stirred and reacted for 4 hours. TLC showed that the reaction was complete. The tetrahydrofuran was removed by vacuum distillation at 40 °C. Then, 500 ml of ethyl acetate and 500 ml of tap water were added and the mixture was stirred to separate the phases. The aqueous phase was extracted with 200 ml of ethyl acetate. All ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under vacuum at 50 °C to give 90.1 g of a pale yellow solid. The yield was 94.3%.
[0026] LC-MS[M+H] + =211.69.
[0027] Preparation of S2, Formula II compound (N-(piperidin-4-yl)pyridine-2,3-diamine):
[0028] In a 1000 ml reaction flask, 50 g (236.2 mmol) of compound III, namely 3-chloro-N-(piperidin-4-yl)pyridine-2-amine, 250 ml of methanol, 82 ml (708.6 mmol) of ammonia-methanol solution, 1.96 g (11.81 mmol) of potassium iodide, and 5 g of copper were added. The mixture was heated to 35 °C and stirred for 12 hours. After the reaction was confirmed to be complete by TLC, the temperature was lowered to 25 °C, and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure at 50 °C to obtain a yellow solid. The residue was dissolved in 100 ml of acetone by reflux, and then cooled to 5 °C with stirring to induce crystallization for 1 hour. The solid was filtered, washed, and dried under reduced pressure at 45 °C to obtain 38.6 g of a pale yellow solid. The yield was 85.2%.
[0029] LC-MS[M+H] + =192.27.
[0030] Preparation of S3, Formula I compound (1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one):
[0031] In a 1000 ml reaction flask, 50 g (260.05 mmol) of compound II, N-(piperidin-4-yl)pyridine-2,3-diamine, and 500 ml of dichloromethane were added. The mixture was cooled to 0 °C, and then 44.2 g (273.05 mmol) of CDI, N,N-carbonyldiimidazole, was added. The reaction was maintained at this temperature for 2 hours. After the reaction was complete by TLC, 50 ml of hydrochloric acid ethanol solution was added to adjust the pH to 1-2, and the mixture was stirred for another 30 minutes. The mixture was then filtered, washed, and dried under reduced pressure at 45 °C to obtain 51.1 g of a pale yellow solid. The yield was 90.1%.
[0032] LC-MS[M+H] + =291.13;
[0033] 1 H-NMR (400 MHz, DMSO-d6): δ 11.77 (broad s,1H), 8.32 (broads, 3H), 7.95(d,1H), 7.93(s,1H), 7.06(dd,1H), 4.60(m,1H), 3.39(d,2H) ,3.07(q,2H) ,3.65(dq,2H) ,1.86(d,2H) . Example 2
[0034] Preparation of S1, Formula III compound (3-chloro-N-(piperidin-4-yl)pyridine-2-amine):
[0035] In a 1000 ml reaction flask, 60 g (466.71 mmol) of 2-amino-3-chloropyridine, 600 ml of anhydrous acetonitrile, and 77.5 g (766.96 mmol) of triethylamine were added. The mixture was cooled to 10 °C, and 80 g (606.72 mmol) of 4-bromopiperidine was added dropwise. After the addition was complete, the mixture was stirred and reacted for 7 hours. The reaction was completed by TLC. The acetonitrile was removed by vacuum distillation at 40 °C. Then, 500 ml of ethyl acetate and 500 ml of tap water were added and the mixture was stirred to separate the phases. The aqueous phase was extracted with 200 ml of ethyl acetate. All ethyl acetate phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness at 50 °C to obtain 88.9 g of a pale yellow solid. The yield was 90.2%.
[0036] Preparation of S2, Formula II compound (N-(piperidin-4-yl)pyridine-2,3-diamine):
[0037] 60 g (283.43 mmol) of compound III, namely 3-chloro-N-(piperidin-4-yl)pyridine-2-amine, 300 ml of ethanol, 130 ml (1984.01 mmol) of ammonia-tetrahydrofuran solution, 3.37 g (28.34 mmol) of potassium bromide and 6 g of copper were added to a 1000 ml reaction flask. The mixture was heated to 45 °C and stirred for 16 hours. After the reaction was confirmed to be complete by TLC, the temperature was lowered to 25 °C, and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure at 50 °C to obtain a yellow solid. The residue was dissolved in 100 ml of acetone and heated to reflux. The mixture was then cooled to 5 °C and stirred to induce crystallization for 1 hour. The crystals were filtered, washed, and dried under reduced pressure at 45 °C to obtain 46.9 g of a pale yellow solid. The yield was 86.1%.
[0038] Preparation of S3, Formula I compound (1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one):
[0039] In a 1000 ml reaction flask, 60 g (312.06 mmol) of compound II, N-(piperidin-4-yl)pyridine-2,3-diamine, and 600 ml of ethyl acetate were added. The mixture was cooled to 15 °C, and then 55.66 g (343.27 mmol) of CDI, N,N-carbonyldiimidazole, was added. The reaction was maintained at this temperature for 4 hours. After the reaction was completed by TLC, the mixture was cooled to 10 °C, and 60 ml of hydrochloric acid-ethanol solution was added to adjust the pH to 1-2. The mixture was stirred for another 30 minutes, filtered, washed, and dried under reduced pressure at 45 °C to obtain 62.66 g of a pale yellow solid. The yield was 92.2%. Example 3
[0040] Preparation of S1, Formula III compound (3-chloro-N-(piperidin-4-yl)pyridine-2-amine):
[0041] In a 1000 ml reaction flask, 50 g (388.92 mmol) of 2-amino-3-chloropyridine, 500 ml of anhydrous 1,4-dioxane, and 100.5 g (766.73 mmol) of DIPEA were added. The mixture was cooled to 20 °C, and 95.7 g (583.38 mmol) of 4-bromopiperidine was added dropwise. After the addition was complete, the mixture was stirred and reacted for 10 hours. TLC showed that the reaction was complete. The mixture was cooled to 40 °C and 1,4-dioxane was removed by vacuum distillation. Then, 500 ml of ethyl acetate and 500 ml of tap water were added and the mixture was stirred to separate the phases. The aqueous phase was extracted with 200 ml of ethyl acetate. All ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 °C to give 72.5 g of a pale yellow solid. Yield: 88.1%.
[0042] Preparation of S2, Formula II compound (N-(piperidin-4-yl)pyridine-2,3-diamine):
[0043] In a 1000 ml reaction flask, 50 g (236.2 mmol) of compound III, namely 3-chloro-N-(piperidin-4-yl)pyridine-2-amine, 250 ml of n-butanol, 150 ml (2362 mmol) of ammonia, 4.86 g (47.24 mmol) of sodium bromide, and 5 g of copper were added. The mixture was heated to 60 °C and stirred for 20 hours. After the reaction was confirmed to be complete by TLC, the temperature was lowered to 25 °C, and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure at 50 °C to obtain a yellow solid. The residue was dissolved in 100 ml of acetone by reflux, and then cooled to 5 °C with stirring to induce crystallization for 1 hour. The crystals were filtered, washed, and dried under reduced pressure at 45 °C to obtain 40.8 g of a pale yellow solid. The yield was 90%.
[0044] Preparation of S3, Formula I compound (1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one):
[0045] In a 1000 ml reaction flask, 58 g (301.66 mmol) of N-(piperidin-4-yl)pyridine-2,3-diamine, 580 ml of tetrahydrofuran, and 58.7 g (362 mmol) of CDI (N,N-carbonyldiimidazole) were added. The mixture was then heated to 30 °C and kept at that temperature for 5 hours. After the reaction was complete by TLC, the temperature was lowered to 10 °C, and 58 ml of hydrochloric acid-ethanol solution was added to adjust the pH to 1-2. The mixture was stirred for another 30 minutes, filtered, washed, and dried under reduced pressure at 45 °C to obtain 57.95 g of a pale yellow solid. The yield was 88.2%.
Claims
1. A process for the synthesis of a remegapant intermediate characterized in that, Includes the following steps: S1. In the presence of a base, 2-amino-3-chloropyridine and 4-bromopiperidine undergo a nucleophilic substitution reaction in solvent A to prepare compound III, wherein the molar ratio of 2-amino-3-chloropyridine, 4-bromopiperidine and base is 1:1.05:1.1 to 1:1.6:2.0, the base is one of potassium carbonate, sodium carbonate, triethylamine, and diisopropylethylamine, and solvent A is one of tetrahydrofuran, acetonitrile, 1,4-dioxane, and 2-methyltetrahydrofuran; S2. In the presence of a catalyst and an ammonia solution, compound III undergoes an amination reaction in solvent B to prepare compound II. The molar ratio of compound III, ammonia solution, and catalyst is 1:3:0.05 to 1:10:0.
2. The catalyst is one of potassium iodide, sodium iodide, potassium bromide, or sodium bromide. The ammonia solution is one of ammonia-methanol solution, ammonia-tetrahydrofuran solution, or ammonia water. Solvent B is one of methanol, ethanol, isopropanol, or n-butanol. S3 and Compound II are dissolved in solvent C, and then subjected to cyclization with CDI and salt formation with hydrogen chloride solution to prepare Compound I. The molar ratio of Compound II to CDI is 1:1.05 to 1:
2. The hydrogen chloride solution is one of hydrochloric acid ethanol solution, hydrochloric acid methanol solution, or hydrochloric acid 1,4-dioxane solution. Solvent C is one of dichloromethane, ethyl acetate, tetrahydrofuran, or toluene. The process route is as follows: 。 2. The method of claim 1, wherein the remegapant intermediate is of formula (I): ###0001### (I) or a salt thereof. In step S1, the reaction temperature is 0–20°C and the reaction time is 3–10 h.
3. The process for synthesis of a remegelt intermediate as claimed in claim 1, wherein, In step S2, the reaction temperature is 30–60°C and the reaction time is 10–20 h.
4. The method for synthesizing a retinoic acid intermediate according to claim 1, characterized in that, In step S3, the reaction temperature is 0–30°C and the reaction time is 2–5 h.