Preparation method of lamidetan succinate intermediate

Abstract

The invention discloses a preparation method of lamidipine succinate intermediate 2-amino-6-(1-methylpiperidine-4-yl acyl)-pyridine dihydrochloride, Boc anhydride is introduced in the reaction process, the preparation method is simple in preparation process and low in cost, and the obtained product is high in purity, high in yield and suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to a preparation method of a chemical raw material, specifically a preparation method of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride, an intermediate of ramelteon succinate. Background Art

[0002] Migraine is a common and recurrent chronic neurovascular disease with a high global incidence. Symptoms include headache, photophobia, phonophobia, hallucinations, and nausea. According to the 2019 Global Burden of Disease (GBD) study, the cause of migraine alone ranks second among the causes of disability. Another study found that the overall prevalence of headache disorders globally is approximately 52%, and the prevalence of migraine is approximately 14%.

[0003] Ramelteon succinate, with the chemical name 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate, has the structure shown in Formula IV below. It is the first approved selective 5-hydroxytryptamine 1F (5-HT1F) receptor agonist drug for the treatment of adult acute migraine. It was approved by the US FDA for market on October 12, 2019, under the trade name Reyvow, and the original research company is Eli Lilly.

[0004]

[0005] According to research, there are multiple synthetic routes for ramelteon succinate, among which 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine or its salt is an important intermediate for the preparation of this drug. The structure of the compound 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine is shown in Formula V below. After acylation reaction with 2,3,6-trifluorobenzoyl chloride and then salification, the final product ramelteon succinate can be obtained, which is the mainstream synthetic route for the synthesis of ramelteon succinate at present.

[0006]

[0007] For example, the original patent CN100352817C discloses a preparation method of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride using 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine and NH3 / ethylene glycol as raw materials and cuprous oxide as a catalyst. This method requires reaction under high temperature and high pressure conditions in a sealed autoclave, with cumbersome operation steps, high requirements for reaction conditions, and troublesome post-treatment of the product, requiring multiple extractions and multiple salification steps, resulting in low yields and purities of the final product dihydrochloride.

[0008] The patent application CN113637003 improved the reaction conditions on the basis of the original preparation method. The product 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine can be obtained without pressure. However, its post-treatment is troublesome, requiring repeated extraction operations with a large amount of solvent, resulting in a large process loss and long time consumption. During the actual experiment process, those skilled in the art also found that under these reaction conditions, the product could not be obtained after 2 hours of reaction. Even when the reaction time was increased, the yield of the obtained product was still low, and the obtained product was a liquid oil with unstable quality.

[0009] Patent CN110386918B discloses a preparation route for synthesizing 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine using 2,3-butanedione and 2-chloropropenenitrile as starting materials for reaction, through a series of reactions such as addition, pyridine cyclization, hydroxyethylation, sulfonation esterification, and condensation. Although the raw materials of this route are easily available, highly toxic ethylene oxide is used in the synthesis process, posing a safety hazard. Moreover, this reaction route has a long reaction step, complex operation, and long time consumption.

[0010] Patent CN111004214B discloses a synthesis method of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine using 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine and tert-butyl carbamate as reaction raw materials, through a catalytic coupling reaction of a metal catalyst and BINAP, and then deprotecting the group. Although the conditions of this synthesis method are relatively mild and the yield of the prepared product is relatively high, the reaction requires high temperature and nitrogen protection, and precious metal catalyst palladium acetate and expensive organophosphorus reagent BINAP are required, resulting in a high preparation cost and being not conducive to industrial production.

[0011] In summary, there are still a series of problems in the current preparation of ramelteon succinate intermediate or its salt, such as high requirements for process conditions, cumbersome steps, low product yield and purity, high production cost, and long time consumption. Therefore, there is an urgent need to research and obtain a preparation method of ramelteon succinate intermediate suitable for industrial large-scale production with mild preparation conditions, simple operation, high product yield and purity, and low process cost. Summary of the Invention

[0012] Aiming at the above-mentioned disadvantages existing in the prior art, the main purpose of the present invention is to provide a preparation method of ramelteon succinate intermediate 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride with a simple synthesis route, low cost, high product yield and purity. Compared with the prior art, the present invention significantly improves the yield of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine. After salification, the yield of the dihydrochloride product can still be stably increased to 80% or above. At the same time, the reaction raw materials adopted in the present invention are simple, cheap, clean and safe, greatly reducing the process production cost.

[0013] The main technical solution of the present invention is as follows:

[0014] A preparation method of a ramelteon succinate intermediate shown in Formula III, the method comprising: Step 1: Using the compound of Formula I, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine as a reaction raw material, carrying out an ammoniation reaction, then adding Boc anhydride. After the reaction is completed, the organic phase is extracted to obtain the compound of Formula II, tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate; Step 2: After Step 1 is completed, reacting with a hydrogen chloride ethanol solution to obtain the compound of Formula III, 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine dihydrochloride. The preparation route is as follows:

[0015]

[0016] Wherein, in Step 1, the reagents used in the ammoniation reaction are ammonium salt, base, catalyst and solvent; adding Boc anhydride is carried out under alkaline conditions, and the alkaline conditions are adding an aqueous solution of sodium hydroxide or potassium hydroxide, and adjusting the pH to 9-14.

[0017] Further, in the above preparation method, in Step 1, the ammonium salt used in the ammoniation reaction is selected from ammonium chloride, ammonium sulfate, ammonium carbonate, the base is selected from sodium hydroxide, potassium hydroxide, the catalyst is selected from cuprous oxide, copper oxide, and the solvent is selected from one or a combination of ethylene glycol and propylene glycol. Preferably, the reagents used in the ammoniation reaction are ammonium chloride, sodium hydroxide, cuprous oxide, and ethylene glycol.

[0018] The temperature of the ammoniation reaction is ≥60 °C, preferably 80-95 °C, more preferably 85-90 °C.

[0019] The ammoniation reaction is carried out for ≥6 hours, preferably for ≥8 hours, more preferably for ≥16 hours.

[0020] Further, in the above preparation method, the reagents used in the ammoniation reaction are preferably ammonium chloride, sodium hydroxide, cuprous oxide, and ethylene glycol, the preferred reaction temperature is 85-90 °C, and the preferred reaction time is ≥16 hours.

[0021] Further, in the above preparation method, in Step 1, the molar ratio of the added Boc anhydride to the compound of Formula I is (1.5-3.5):1, preferably (2.5-3.0):1, more preferably 3.0:1. The addition of Boc anhydride is carried out at room temperature.

[0022] The extraction solvent used for extraction is selected from one or a combination of methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and dichloromethane. Preferably, it is methyl tert-butyl ether and ethyl acetate, and more preferably methyl tert-butyl ether. The number of extractions does not exceed 3 times.

[0023] In step 2, after adding the hydrogen chloride ethanol solution for reaction, it further includes filtration, rinsing, and drying; preferably, the drying temperature is 50°C, and the drying method is vacuum drying.

[0024] The present invention provides a preparation method of a lamotrigine succinate intermediate shown in Formula III, and the method includes:

[0025] Step 1: Dissolve the compound of Formula I, ammonium chloride, sodium hydroxide, and cuprous oxide in ethylene glycol, then heat to 85-90°C and react for 16 hours; after the reaction is completed, cool the reaction solution to room temperature, add an aqueous sodium hydroxide solution and Boc anhydride to continue the reaction; then add methyl tert-butyl ether for extraction, drying, and concentration to obtain the compound of Formula II;

[0026] Step 2: Dissolve the compound of Formula II in ethanol, add the hydrogen chloride ethanol solution, filter, rinse, and vacuum dry at 50°C to obtain the compound of Formula III.

[0027] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0028] (1) The synthetic route is simple, the conditions are mild, no high pressure or nitrogen protection is required, and the extraction step in the post-treatment is simple, with fewer extraction times and less loss, thereby reducing the preparation time, lowering the cost, and being more suitable for large-scale industrial production.

[0029] (2) The dihydrochloride product obtained through this synthetic route has fewer impurities, high purity (≥99%), and high yield, which is further beneficial to the synthesis and preparation of lamotrigine succinate.

[0030] (3) The synthesized product 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride is a solid, which is more stable in quality than the free product in liquid form, and is more convenient for production, storage, and transportation. Detailed implementation mode

[0031] The present invention will be further illustrated by way of examples below, but the present invention is not limited to the scope of the examples described herein.

[0032] The typical synthetic method for preparing 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride in the examples of the present invention is as shown in the following synthetic route:

[0033]

[0034] Example 1

[0035] Synthesis step 1: Preparation of tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate (II)

[0036] At room temperature, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (20.0 g, 70.67 mmol, 1 equiv), ethylene glycol (100 mL), ammonium chloride (22.7 g, 424 mmol), sodium hydroxide (17.0 g, 424 mmol), and cuprous oxide (1.0 g, 7.1 mmol) were added to a reaction flask. After addition, the reaction solution was heated to 85 - 90 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 30% aqueous sodium hydroxide solution (40 mL) and Boc anhydride (46.3 g, 212 mmol) were added. After addition, the mixture was stirred at room temperature for 2 hours. Methyl tert-butyl ether (50 mL × 2) was added to the reaction solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate, which was directly used in the next step of the reaction.

[0037] Synthesis step 2: Preparation of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride (III)

[0038] The intermediate tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate obtained in the previous step was dissolved in ethanol, and 30% ethanolic hydrogen chloride solution (34.4 g, 282 mmol) was added. After stirring at room temperature for 2 hours, the mixture was cooled to 0 - 5 °C and stirred for another 2 hours. The mixture was filtered, the filter cake was rinsed with 10 mL of ethanol, and then dried in vacuo at 50 °C to obtain 16.9 g of a white solid, which was 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride, with a yield of 82.04% and HPLC purity of 99.1%.

[0039] Example 2

[0040] Synthesis step 1: Preparation of tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate (II)

[0041] At room temperature, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (20.0 g, 70.67 mmol, 1 equiv), ethylene glycol (100 mL), ammonium chloride (22.7 g, 424 mmol), sodium hydroxide (17.0 g, 424 mmol), and copper(I) oxide (1.0 g, 7.1 mmol) were added to a reaction flask. After addition, the reaction solution was heated to 85 - 90 °C and reacted for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and 30% aqueous sodium hydroxide solution (40 mL) and Boc anhydride (38.6 g, 177 mmol) were added. After addition, the mixture was stirred at room temperature for 2 h. Ethyl acetate (50 mL × 2) was added to the reaction solution, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate, which was directly used in the next step of the reaction.

[0042] Synthesis Step 2: Preparation of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride (III)

[0043] The intermediate tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate obtained in the previous step was dissolved in ethanol, and 30% ethanolic hydrogen chloride solution (34.4 g, 282 mmol) was added. After stirring at room temperature for 2 h, the mixture was filtered. The filter cake was rinsed with 10 mL of ethanol and then dried in vacuo at 50 °C to obtain 16.6 g of a white solid, which was 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride, with a yield of 80.28% and HPLC purity of 99.6%.

[0044] Comparative Example 1: Preparation of 2-amino(6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride

[0045] A solution of 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (20 g, 70.67 mmol, 1 equiv) in 73.6 mL of 7 M NH₃ / ethylene glycol (530 mmol, 7.5 equiv) was placed in a 130 mL autoclave, and Cu₂O (101 mg, 0.706 mmol, 0.01 equiv) was added as a catalyst. The autoclave was sealed and the reaction mixture was heated at 85 °C and a pressure of about 50 psi (345 kPa) for 20 h. The reaction mixture was cooled to room temperature, and the organic layer was transferred to a 250 mL flask. The flask was placed under reduced pressure to remove ammonia. Water (70 mL) and 30% NaOH (38 mL) were added, and then the mixture was extracted with methyl tert-butyl ether (MTBE) (5 × 100 mL). The organic portions were combined, then dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain the crude product of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (18.5 g).

[0046] The crude product of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (14.5 g, 66.2 mmol) was resuspended in ethanol, 2.5 M HCl / ethanol (100 mL) was added, the mixture was stirred for 30 minutes, and then the solvent was removed under reduced pressure. The resulting solid was resuspended in 125 mL of isopropanol and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, the precipitate was filtered off, rinsed with 20 mL of isopropanol, and dried in vacuo at 50 °C to obtain 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride (11 g, 56.9% yield).

[0047] Comparative Example 2: Preparation of 2-amino(6-(1-methylpiperidin-4-ylcarbonyl)pyridine

[0048] At room temperature, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (20.0 g, 70.67 mmol, 1 equiv), ethylene glycol (100 mL), ammonium chloride (22.7 g, 424 mmol), sodium hydroxide (17.0 g, 424 mmol), and copper(I) oxide (1.0 g, 7.1 mmol) were added to a reaction flask. After addition, the reaction solution was heated to 85 - 90 °C and reacted for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the insoluble matter was removed by suction filtration under reduced pressure. 30% aqueous sodium hydroxide solution (40 mL) was added to the filtrate, and the mixture was extracted once with methyl tert-butyl ether (100 mL). After standing for phase separation, the lower layer was further extracted 4 times with methyl tert-butyl ether, 100 mL each time. The organic phases were combined, dried over 20.0 g of anhydrous sodium sulfate, and the sodium sulfate was removed by suction filtration under reduced pressure. The filtrate was concentrated under reduced pressure at 40 - 50 °C, and 10.1 g of a brown oil was obtained, which was 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine, yield: 65.10%, HPLC: 70.3%.

[0049] Comparative Example 3: Preparation of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine

[0050] At room temperature, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (20.0 g, 70.67 mmol, 1 equivalent), ethylene glycol (100 mL), ammonium chloride (30.4 g, 565 mmol), sodium hydroxide (22.7 g, 565 mmol), and copper(I) oxide (1.0 g, 7.1 mmol) were added to a reaction flask. After addition, the reaction solution was heated to 85 - 90 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the insoluble substances were removed by suction filtration under reduced pressure. 30% aqueous sodium hydroxide solution (40 mL) was added to the filtrate, and extraction was carried out once with methyl tert-butyl ether (100 mL). After standing and separating the layers, the lower layer was continuously extracted 4 times with methyl tert-butyl ether, 100 mL each time. The organic phases were combined, dried over 20.0 g of anhydrous sodium sulfate, and the sodium sulfate was removed by suction filtration under reduced pressure. The filtrate was concentrated under reduced pressure at 40 - 50 °C, and after concentration, 10.8 g of a brown oil was obtained, which was 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine, yield: 69.68%, HPLC: 72.6%.

[0051] Example 3: Comparison of Product Yield and Purity

[0052] Table 1. Comparison of Product Yield and Purity of Examples 1 - 2 and Comparative Examples 1 - 3

[0053]

[0054] *Note: 1. The yield of Comparative Example 1 is cited from the salt formation yield of the original research patent CN100352817C, that is, the content of Comparative Example 1 above. There was an error in the calculation of this yield in the original text, which has been corrected in this invention when citing; the yields of other examples and comparative examples were all calculated from the input amount of Compound I.

[0055] 2. The difference calculation formula is: Difference = Yield - 56.9

[0056] 3. The ratio calculation formula is: Ratio = (Yield - 56.9) / 56.9 * 100%;

[0057] From the data in the above table, it can be seen that compared with Comparative Examples 1 - 3, the yields and purities of the dihydrochloride products prepared by the synthesis routes of Examples 1 and 2 are significantly improved. Compared with the original research Comparative Example 1, the ratio of the product yield is even increased by more than 40%. It can be seen that by using the synthesis route of this invention, the yields and purities of the succinate ramelteon intermediate 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride can be significantly improved, solving the problems of low product yield and low purity in the prior art.

Claims

1. A preparation method of a ramelteon succinate intermediate as shown in Formula III, the method comprising: Step 1: Using the compound of Formula I, 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine, as a reaction raw material, carrying out an ammoniation reaction, then adding Boc anhydride. After the reaction is completed, extracting the organic phase to obtain the compound of Formula II, tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate; Step 2: After Step 1 is completed, adding a hydrogen chloride ethanol solution for reaction to obtain the compound of Formula III, 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine dihydrochloride; The preparation route is as follows: Wherein, in Step 1, the reagents used in the ammoniation reaction are an ammonium salt, a base, a catalyst and a solvent; adding Boc anhydride is carried out under alkaline conditions, and the alkaline conditions are adding an aqueous solution of sodium hydroxide or potassium hydroxide, and adjusting the pH to 9-14.

2. The preparation method according to claim 1, characterized in that, The ammonium salt used in the ammoniation reaction is selected from ammonium chloride, ammonium sulfate, ammonium carbonate, the base is selected from sodium hydroxide, potassium hydroxide, the catalyst is selected from cuprous oxide, copper oxide, and the solvent is selected from one or a combination of ethylene glycol and propylene glycol.

3. The preparation method according to claim 1 or 2, characterized in that, The temperature of the ammoniation reaction is ≥60 °C.

4. The production method according to claim 1 or 2, characterized in that, The ammoniation reaction is carried out for ≥6 hours.

5. The preparation method according to claims 1-4, characterized in that, The reagents used in the ammoniation reaction are ammonium chloride, sodium hydroxide, cuprous oxide, ethylene glycol; the preferred reaction temperature is 85-90 °C; the preferred reaction is carried out for ≥16 hours.

6. The preparation method according to claim 5, characterized in that, The molar ratio of Boc anhydride to the compound of Formula I is (1.5-3.5):

1.

7. The preparation method according to claim 5, characterized in that, Adding Boc anhydride is carried out at room temperature.

8. The preparation method according to claim 5, characterized in that, The extraction solvent used for extraction is selected from one or a combination of methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and dichloromethane.

9. The preparation method according to any one of claims 1-8, characterized in that, In Step 2, after adding the hydrogen chloride ethanol solution for reaction, it further includes filtration, rinsing, and drying; preferably, the drying temperature is 50 °C, and the drying method is vacuum drying.

10. A preparation method of a ramelteon succinate intermediate as shown in Formula III, the method comprising: Step 1: Dissolving the compound of Formula I, ammonium chloride, sodium hydroxide, and cuprous oxide in ethylene glycol, then heating to 85-90 °C for reaction for 16 hours; after the reaction is completed, cooling the reaction solution to room temperature, adding an aqueous solution of sodium hydroxide and Boc anhydride to continue the reaction; then adding methyl tert-butyl ether for extraction, drying, and concentrating to obtain the compound of Formula II; Step 2: Dissolving the compound of Formula II in ethanol, adding a hydrogen chloride ethanol solution, filtering, rinsing, and drying in vacuo at 50 °C to obtain the compound of Formula III; The preparation route is as follows:

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