A preparation method of prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine. The method uses 4-acylpiperidine as a starting material, and first reacts with 3-substituted propyl methyl ether, then constructs an amide group under the action of a catalyst, and finally, the intermediate 1-(3-methoxypropyl)-4-piperidinamine is obtained through amide bond hydrolysis. The target product prepared through the method has high yield and purity, and can effectively avoid the complex and dangerous operation in the prior art, is safe and simple to operate, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing 1-(3-methoxypropyl)-4-piperidineamine, an intermediate of prucalopride. Background Technology

[0002] Prucalopride succinate, chemically named 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofuran carboxamide succinate, is a new generation selective, high-affinity 5-hydroxytryptamine 4 (5-HT4) receptor agonist developed by Movetis AG of Belgium. It restores impaired intestinal motility through direct action on the intestinal wall. It was approved by the EU for the treatment of chronic constipation in October 2009, launched in Germany in January 2010, and in the UK in March of the same year. It was approved by the FDA in October 2012. Clinical studies have shown that this drug has consistent efficacy and safety in patients with severe chronic constipation. Its chemical structure is as follows:

[0003]

[0004] Currently, there are many publicly disclosed methods for the preparation of prucalopride, such as patents CN1164233A (CN1071332C), CN103664912B, and the literature "Synthesis of Prucalopride," *Pharmaceutical and Clinical Research*, 2011, Aug; 19(4):306-307. In these methods, 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is used as the starting material or key intermediate in the reaction with 1-(3-methoxypropyl)-4-piperidinamine. The synthetic route is shown below:

[0005]

[0006] Patent CN108976216A describes a multi-step reaction to prepare 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxaldehyde, followed by oxidative dehydrogenation coupling with 1-(3-methoxypropyl)-4-piperidinamine to obtain the target product. The synthetic route is shown below:

[0007]

[0008] Similarly, patent CN109232544A describes a multi-step reaction to obtain (4-amino-5-chloro-2,3-dihydrobenzofuran-7-yl)methanol, followed by oxidative dehydrogenation coupling with 1-(3-methoxypropyl)-4-piperidinamine to yield the target product. The synthetic route is shown below:

[0009]

[0010] As shown above, 1-(3-methoxypropyl)-4-piperidinamine is used as a key intermediate in the preparation of prucalopride in various synthetic strategies. Its chemical structural formula is shown below:

[0011]

[0012] Depending on the starting materials and the construction method of the primary amine, the preparation methods of 1-(3-methoxypropyl)-4-piperidinamine mainly include the following:

[0013] ①The target product is obtained by using 4-piperidinone or 1-(3-methoxypropyl)-4-piperidinone obtained by its alkylation as raw material, reacting it with a nitrogen source (organic solution of ammonia, ammonium formate, hydroxylamine hydrochloride) to form an imine, and then reducing it with a hydrogen source (catalytic hydrogenation, metal hydride, formic acid).

[0014] Specifically, patent CN102898356B uses 4-piperidinone hydrochloride monohydrate as the starting material, reacting it with 1-substituted-3-methoxypropane under alkaline conditions to obtain 1-(3-methoxypropyl)-4-piperidinone. Finally, the target product is obtained by reacting it in an organic solution under ammonia atmosphere with hydrogen and a catalyst (Raney Ni and / or Pd / C). This route involves more difficult-to-control high-pressure reaction conditions and requires the use of expensive heavy metal catalysts such as palladium on carbon, which also poses a risk of heavy metal residues to the active pharmaceutical ingredient, procapapride. The synthetic route is shown below:

[0015]

[0016] Patent CN103193699B uses 4-piperidinone as the starting material, reacting it with 1-bromo-3-methoxypropane under alkaline conditions of K2CO3 to obtain 1-(3-methoxypropyl)-4-piperidinone. Finally, the target product is obtained by reflux reaction at 110°C for 8 hours in a formic acid / ammonium formate system. However, this process requires high temperature and long reaction time, resulting in high energy consumption. Furthermore, due to the very high polarity of the target product, the final step of this method is incomplete, making it difficult to remove intermediates and byproducts, thus posing a significant purification challenge. The synthetic route is shown below:

[0017]

[0018] Another literature, Tetrahedron Lett, 2001, 42(25):4257-4259, uses Pd / C as a catalyst and ammonium formate as a nitrogen and hydrogen source to directly reduce the carbonyl group to an amino group. The literature, Synthesis of Pucapride Succinate, *China Pharmaceutical Industry Magazine*, 2012, 43(1):5-8, uses a methanol solution saturated with ammonia as a solvent and a 10% Pd / C catalytic hydrogenation step to directly convert the carbonyl group to an amino group to obtain the target product.

[0019] Patent CN103508939A uses the key intermediate 1-(3-methoxypropyl)-4-piperidinone in the above process as a starting material and dehydrates it with hydroxylamine hydrochloride under reflux to obtain the key intermediate 1-(3-methoxypropyl)-4-piperidinoxime. Finally, the target product is obtained by catalytic (Raney Ni) hydrogenation. The synthetic route is shown below:

[0020]

[0021] In addition, Chinese patent CN1143858 (US6479487) also uses the above strategy to prepare the key intermediate 1-(3-methoxypropyl)-4-piperidine oxime, and then uses lithium aluminum hydride to reduce it to obtain the corresponding product. However, this method uses lithium aluminum hydride, the experimental operation requires an oxygen-free and anhydrous environment, and it is not easy to filter during post-processing. Therefore, the industrialization of this method is quite difficult.

[0022] Patent CN103351329A also uses 1-(3-methoxypropyl)-4-piperidinone as the starting material, and obtains the target product by means of sodium triacetoxyborohydride as a reducing agent under conditions of ammonia in methanol solution or ammonium formate. The synthetic route is shown below:

[0023]

[0024] However, the above processes use catalytic hydrogenation or metal hydrides for reduction, which results in low operational safety.

[0025] ② After 1-(3-methoxypropyl)piperidine-4-carboxamide was prepared by different routes, the target product was obtained by Hofmann rearrangement reaction under the action of oxidant.

[0026] Specifically, patent CN1143858 (US6479487) also uses 4-formamide piperidine and the high-valent iodine compound di(trifluoroacetoxy)iodobenzene [PhI(O2CCF3)2] as raw materials to generate the target product via Hofmann rearrangement. However, the prices of both starting materials in this process are relatively high, and the stability and safety issues of the high-valent iodine compound have always limited its large-scale industrial production. The synthetic route is shown below:

[0027]

[0028] In addition, patent CN106146386A and literature Synthesis of Prucalopride Succinate, "China Pharmaceutical Industry Magazine", 2015, 46(11):1158-1160, use inexpensive and readily available 4-piperidinecarboxylic acid as raw material, esterification in thionyl chloride-methanol to obtain methyl 4-piperidinecarboxylate hydrochloride; then alkylation reaction with 1-methoxy-3-bromopropane to obtain methyl 1-(3-methoxypropyl)piperidine-4-carboxylate; then ammonolysis in ammonia water to obtain 1-(3-methoxypropyl)piperidine-4-carboxamide; finally react with dibromohydantoin under alkaline conditions to undergo Hofmann rearrangement to obtain crude product, and then distillation to obtain the target product with a purity greater than 99.5%, with an overall yield of 56% in 4 steps. However, this process requires distillation purification, which is cumbersome. The synthetic route is as follows:

[0029]

[0030] ③ Using N-protected aminopiperidine as the starting material, the target product was obtained by substitution reaction with 1-substituted-3-methoxypropane and then deprotection.

[0031] Specifically, patent CN102295594B uses 4-N-protected aminopiperidine as the starting material, reacts it with 1-substituted-3-methoxypropane under alkaline conditions, and finally deprotects it [the deprotection conditions for benzyloxycarbonyl (Cbz) are generally hydrogenolysis or acid cleavage (HBt or TMSI); acetyl and propionyl groups are usually removed by alkaline or acidic hydrolysis] to obtain the target product. However, this method requires the 4-amino group of 4-aminopiperidine to be monosubstituted for protection, resulting in poor reaction selectivity and a tendency to produce 1,4-dual-protected 4-aminopiperidine or 1-N-protected aminopiperidine, which are difficult to separate and purify, making the starting material expensive and basically uncompetitive in the market. The synthetic route is shown below:

[0032]

[0033] Furthermore, patent CN103848777A (WO2015139332) describes the self-construction of the relevant benzyl protecting group, using 1-(3-methoxypropyl)-4-piperidinone as the starting material. It reacts with substituted or unsubstituted benzylamine in the presence of a reducing agent to generate N-(3-methoxypropyl)-4-benzylaminopiperidine, which is then reduced by palladium on carbon to obtain the target product. The synthetic route is shown below:

[0034] ④ The primary amine group is prepared by the Gabriel reaction of phthalimide.

[0035] Patent CN103804281A also uses 1-(3-methoxypropyl)-4-piperidinone as the starting material, but first reduces the carbonyl group with NaBH4 to obtain 1-(3-methoxypropyl)-4-piperidinol, then esterifies it with TsCl to obtain 1-(3-methoxypropyl)-4-p-methylbenzenesulfonate piperidine, and finally reacts it with phthalimide and then hydrazinolyses it under alkaline conditions to obtain the target product. However, this process uses a genotoxic substance to activate the hydroxyl group of toluenesulfonyl chloride, and uses the Gabriel reaction to prepare the primary amine group, resulting in poor atom economy. It also uses the highly toxic substance hydrazine hydrate, leading to poor operational safety. The synthetic route is shown below:

[0036]

[0037] In summary, the current process for preparing 1-(3-methoxypropyl)-4-piperidinamine mainly has the following problems:

[0038] 1. The high cost of the starting materials and reagents used increases production costs, making the company essentially uncompetitive in the market.

[0039] 2. The preparation of the target product by catalytic hydrogenation is difficult to control under high-pressure reaction conditions. It requires the use of high-cost heavy metal catalysts such as palladium on carbon or flammable and highly toxic catalysts such as Raney Ni, which poses a risk of heavy metal residues to the active pharmaceutical ingredient, procapapride.

[0040] 3. The need for high-temperature, long-duration reactions results in high energy consumption.

[0041] 4. The reaction requires anhydrous and oxygen-free conditions, or the target product requires distillation purification, which makes the operation cumbersome.

[0042] 5. The reaction requires activation of the hydroxyl group by p-toluenesulfonyl chloride and preparation of the primary amine group using the Gabriel reaction, resulting in poor atom economy.

[0043] 6. The use of hydrazine hydrate and catalytic hydrogenation or hydrides for reduction results in lower operational safety.

[0044] Given the many shortcomings in the current preparation of 1-(3-methoxypropyl)-4-piperidineamine, finding a simple, safe, mild reaction process with high yield and purity suitable for industrial production of 1-(3-methoxypropyl)-4-piperidineamine remains a problem that needs to be solved. Summary of the Invention

[0045] To address the numerous problems existing in the current preparation of 1-(3-methoxypropyl)-4-piperidinamine, this invention provides a novel method for preparing 1-(3-methoxypropyl)-4-piperidinamine. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and high yield.

[0046] The specific technical solution of the present invention is as follows:

[0047] A method for preparing 1-(3-methoxypropyl)-4-piperidinamine as shown in formula (I) specifically includes the following steps:

[0048] Step A: At room temperature, SM-1, 3-substituted propyl methyl ether, and a base are added to reaction solvent A. The temperature is controlled until the reaction is complete, and after post-treatment, intermediate I-1 is obtained. The reaction route is as follows:

[0049]

[0050] The preferred embodiment is the 3-substituted propyl methyl ether described in step A. X is one of Cl, Br, I, MsO, and TsO, with Br being particularly preferred.

[0051] In a preferred embodiment, the alkali mentioned in step A includes, but is not limited to, one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, and piperidine, with potassium carbonate being particularly preferred.

[0052] In a preferred embodiment, the reaction solvent A in step A includes, but is not limited to, one or a combination of acetonitrile, butanone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, with acetonitrile being particularly preferred.

[0053] In a preferred embodiment, the molar ratio of SM-1 to 3-substituted propyl methyl ether and alkali in step A is 1:1.1 to 1.4:1.2 to 2.0, with a particularly preferred ratio of 1:1.15:1.5.

[0054] In a preferred embodiment, the reaction temperature in step A is 60–90°C, with a particularly preferred temperature of 75–80°C.

[0055] In the preferred embodiment, the post-processing in step A is as follows: after the reaction is complete, filter, concentrate the filtrate under reduced pressure to dryness, add purified water, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate I-1.

[0056] Step B:

[0057] At room temperature, I-1, hydroxylamine hydrochloride, base, and molecular sieve are added to reaction solvent B, and the temperature is controlled at T. B1After the reaction was detected as complete, the solution was filtered. Then, the catalyst PTSA and Lewis acid were added to the filtrate, and the temperature was maintained at T. B2 After the reaction is complete, post-processing yields intermediate I-2. The reaction route is as follows:

[0058]

[0059] In a preferred embodiment, the alkali mentioned in step B is one or a combination of sodium acetate, potassium acetate, triethylamine, potassium carbonate, and sodium carbonate, with potassium carbonate being particularly preferred.

[0060] In the preferred embodiment, the molecular sieve type mentioned in step B is: One or a combination thereof, wherein particularly preferred

[0061] In a preferred embodiment, the reaction solvent B in step B is one or a combination of tetrahydrofuran, acetonitrile, and 1,4-dioxane, with acetonitrile being particularly preferred.

[0062] In a preferred embodiment, the Lewis acid mentioned in step B is one of ZnBr2, ZnCl2, SnCl4, FeCl3, and InCl2, with ZnCl2 being particularly preferred.

[0063] In a preferred embodiment, the molar ratio of compound I-1 in step B to hydroxylamine hydrochloride, alkali, PTSA, and Lewis acid is 1:1.2-1.8:1.2-1.8:2%-15%:2%-15%, with a particularly preferred ratio of 1:1.4:1.4:8%:8%.

[0064] In a preferred embodiment, the mass ratio of I-1 to molecular sieve in step B is 1:0.05 to 0.3, with a particularly preferred ratio of 1:0.1.

[0065] In the preferred embodiment, the reaction temperature T mentioned in step B... B1 The temperature range is 60–90°C, with a particularly preferred range of 75–80°C; the reaction temperature T B2 The temperature range is 60–90℃, with 75–80℃ being particularly preferred.

[0066] In the preferred embodiment, the post-treatment in step B is as follows: after the reaction is completed, the reaction is quenched with saturated sodium bicarbonate solution, extracted with organic solvent, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain I-2.

[0067] In a preferred embodiment, the extractant in step B is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being particularly preferred.

[0068] Step C:

[0069] At room temperature, dissolve I₂ in dry reaction solvent C, and control the temperature T under inert gas protection. C1 Add boron trifluoride diethyl ether and continue to control the temperature T. C2 After the reaction is detected as complete, the temperature T is controlled. C3 Add pre-cooling temperature T C3 A saturated sodium bicarbonate solution, with temperature controlled at T. C3 The reaction proceeded, and after detection of its completion, post-processing yielded the target product I. The reaction route is as follows:

[0070]

[0071] In a preferred embodiment, the reaction solvent C in step C is one or a combination of dichloromethane and chloroform, with dichloromethane being particularly preferred.

[0072] In a preferred embodiment, the molar ratio of compound I-2 to boron trifluoride diethyl ether in step C is 1:1.0 to 1.2, with a particularly preferred ratio of 1:1.05.

[0073] In the preferred embodiment, the reaction temperature T mentioned in step C is... C1 and reaction temperature T C3 The temperature range is -5 to 10°C, with a particularly preferred range of 0 to 5°C; the reaction temperature T C2 The temperature ranges from 15 to 40°C, with 20 to 25°C being particularly preferred.

[0074] In the preferred embodiment, the post-processing in step C is as follows: after the reaction is completed, the organic phase is separated, washed with purified water, washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain the target product I.

[0075] In a preferred embodiment, the inert gas mentioned in step C is one or a combination of argon, nitrogen, and carbon dioxide, with argon being particularly preferred.

[0076] The beneficial effects of this invention are:

[0077] 1. This invention provides a simple and efficient method for preparing 1-(3-methoxypropyl)-4-piperidineamine, an intermediate related to prucalopride. The method uses 4-acetylpiperidine as a starting material, reacts it with 3-substituted propyl methyl ether, constructs an amino group through a Beckmann rearrangement, and finally removes the acetyl group under the catalysis of boron trifluoride diethyl ether to obtain 1-(3-methoxypropyl)-4-piperidineamine.

[0078] 2. The entire synthesis method is simple to operate, the conditions are relatively mild, it is environmentally friendly, and it is suitable for industrial production.

[0079] 3. Using inexpensive and readily available hydroxylamine hydrochloride as the nitrogen source can effectively avoid the dangerous operation of existing catalytic hydrogenation technology, ensuring safe operation.

[0080] 4. The target product obtained by this process has a high yield and purity. Attached Figure Description

[0081] Figure 1 It is the proton NMR spectrum of 1-(3-methoxypropyl)-4-piperidinamine;

[0082] Figure 2 This is the carbon spectrum of 1-(3-methoxypropyl)-4-piperidinamine;

[0083] Figure 3 This is the mass spectrum of 1-(3-methoxypropyl)-4-piperidineamine. Detailed Implementation

[0084] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0085] This invention uses GC to determine the purity of 1-(3-methoxypropyl)-4-piperidinamine. The chromatographic conditions are as follows:

[0086] Fixative: 14% cyanopropylphenyl-36% dimethyl polysiloxane or similar polarity (DB-1701, 30m × 0.53mm, 1.5μm);

[0087] Inlet temperature: 210℃;

[0088] Detection temperature: 250℃;

[0089] Flow rate: 4.0 ml / min;

[0090] Flow split ratio: 15:1;

[0091] Gradient heating: Start at 60℃, hold for 5 min, increase to 210℃ at 15℃ / min, hold for 5 min, increase to 250℃ at 10℃ / min, hold for 10 min.

[0092] The retention time of 1-(3-methoxypropyl)-4-piperidineamine is approximately 14.34 min.

[0093] Structural analysis: See attached diagram for details.

[0094] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0095] Synthesis of I-1:

[0096] Example 1

[0097] At room temperature, 4-acetylpiperidine (SM-1, 25.44 g, 0.20 mol), 3-bromopropyl methyl ether (X = Br, 35.19 g, 0.23 mol), and potassium carbonate (41.46 g, 0.30 mol) were added to acetonitrile (200 ml). The reaction was carried out at 75–80 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 96.1% and a GC purity of 99.38%.

[0098] Example 2

[0099] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-bromopropyl methyl ether (X = Br, 33.66 g, 0.22 mol), and potassium carbonate (41.46 g, 0.30 mol) were added to N,N-dimethylformamide (200 ml). The reaction was carried out at 85–90 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and dichloromethane (300 ml × 3) was added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 95.0% and a GC purity of 99.35%.

[0100] Example 3

[0101] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-bromopropyl methyl ether (X = Br, 30.60 g, 0.20 mol), and pyridine (23.73 g, 0.30 mol) were added to acetonitrile (200 ml) and reacted at 75–82 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 91.2% and a GC purity of 99.15%.

[0102] Example 4

[0103] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-bromopropyl methyl ether (X = Br, 42.85 g, 0.28 mol), and triethylamine (30.36 g, 0.30 mol) were added to acetonitrile (200 ml) and reacted at 75–80 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 95.7% and a GC purity of 98.98%.

[0104] Example 5

[0105] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-bromopropyl methyl ether (X = Br, 45.91 g, 0.30 mol), and potassium bicarbonate (30.03 g, 0.30 mol) were added to acetonitrile (200 ml). The reaction was carried out at 75–80 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 92.7% and a GC purity of 98.18%.

[0106] Example 6

[0107] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-chloropropylmethyl ether (X = Cl, 24.85 g, 0.23 mol), and cesium carbonate (78.20 g, 0.24 mol) were added to acetonitrile (200 ml). The reaction was carried out at 80–85 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 95.6% and a GC purity of 99.15%.

[0108] Example 7

[0109] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-iodopropyl methyl ether (X = I, 46.00, 0.23 mol), and potassium carbonate (30.41 g, 0.22 mol) were added to acetonitrile (200 ml). The reaction was carried out at 80–85 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 92.2% and a GC purity of 98.87%.

[0110] Example 8

[0111] At room temperature, 4-acetylpiperidine (SM-1-1, 25.44 g, 0.20 mol), 3-methoxypropyl methanesulfonic acid (X = MsO, 38.69 g, 0.23 mol), and sodium carbonate (42.40 g, 0.40 mol) were added to dimethyl sulfoxide (200 ml). The reaction was carried out at 70–75 °C. After the reaction was detected to be complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-1, with a yield of 95.7% and a GC purity of 98.97%.

[0112] Synthesis of I-2:

[0113] Example 9

[0114] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (9.73 g, 0.14 mol), and potassium carbonate (19.35 g, 0.14 mol) were added. Molecular sieve (1.99 g) was added to acetonitrile (200 ml), and the reaction was carried out at 75–80 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 1.38 g, 0.008 mol) and ZnCl2 (1.09 g, 0.008 mol) were added to the filtrate, and the reaction was continued at 75–80 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 93.5% and a GC purity of 99.56%.

[0115] Example 10

[0116] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (8.34 g, 0.12 mol), potassium carbonate (16.58 g, 0.12 mol), Molecular sieve (1.00 g) was added to acetonitrile (200 ml), and the reaction was carried out at 75–80 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 1.38 g, 0.008 mol) and ZnBr (1.80 g, 0.008 mol) were added to the filtrate, and the reaction was continued at 75–80 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with chloroform (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 91.6% and a GC purity of 99.43%.

[0117] Example 11

[0118] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (7.64 g, 0.11 mol), potassium carbonate (15.20 g, 0.11 mol), Molecular sieve (1.99 g) was added to 1,4-dioxane (200 ml) and reacted at a controlled temperature of 85–90 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 1.38 g, 0.008 mol) and SnCl4 (2.08 g, 0.008 mol) were added to the filtrate, and the reaction was continued at a controlled temperature of 85–90 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 90.3% and a GC purity of 99.32%.

[0119] Example 12

[0120] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (12.50 g, 0.18 mol), and potassium carbonate (24.88 g, 0.18 mol) were added. Molecular sieve (5.98 g) was added to acetonitrile (200 ml), and the reaction was carried out at 75–80 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 1.38 g, 0.008 mol) and FeCl3 (1.30 g, 0.008 mol) were added to the filtrate, and the reaction was continued at 75–80 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with ethyl acetate (150 ml × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 92.8% and a GC purity of 99.38%.

[0121] Example 13

[0122] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (13.20 g, 0.19 mol), and potassium carbonate (26.26 g, 0.19 mol) were added. Molecular sieve (1.99 g) was added to tetrahydrofuran (200 ml), and the reaction was carried out at a controlled temperature of 65–70 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 1.38 g, 0.008 mol) and InCl2 (1.49 g, 0.008 mol) were added to the filtrate, and the reaction was continued at a controlled temperature of 65–70 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 93.1% and a GC purity of 99.02%.

[0123] Example 14

[0124] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (9.73 g, 0.14 mol), and sodium acetate (11.48 g, 0.14 mol) were added. Molecular sieve (1.99 g) was added to 1,4-dioxane (200 ml) and reacted at a controlled temperature of 85–90 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 0.34 g, 0.002 mol) and ZnCl2 (0.27 g, 0.002 mol) were added to the filtrate, and the reaction was continued at a controlled temperature of 85–90 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 92.5% and a GC purity of 99.35%.

[0125] Example 15

[0126] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (9.73 g, 0.14 mol), and potassium acetate (13.74 g, 0.14 mol) were added. Molecular sieve (1.99 g) was added to acetonitrile (200 ml), and the reaction was carried out at 75–80 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 0.17 g, 0.001 mol) and ZnCl2 (0.14 g, 0.001 mol) were added to the filtrate, and the reaction was continued at 75–80 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with methyl tert-butyl ether (150 ml × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 89.8% and a GC purity of 99.11%.

[0127] Example 16

[0128] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (9.73 g, 0.14 mol), and triethylamine (14.17 g, 0.14 mol) were added. Molecular sieve (1.99 g) was added to tetrahydrofuran (200 ml), and the reaction was carried out at a controlled temperature of 65–70 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 2.58 g, 0.015 mol) and ZnCl2 (2.04 g, 0.015 mol) were added to the filtrate, and the reaction was continued at a controlled temperature of 65–70 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 93.3% and a GC purity of 95.18%.

[0129] Example 17

[0130] At room temperature, I-1 (19.92 g, 0.10 mol), hydroxylamine hydrochloride (9.73 g, 0.14 mol), sodium carbonate (14.84 g, 0.14 mol), Molecular sieve (1.99 g) was added to acetonitrile (200 ml), and the reaction was carried out at a controlled temperature of 75–80 °C. After the reaction was detected as complete, the mixture was filtered. Then, the catalysts p-toluenesulfonic acid (PTSA, 2.76 g, 0.016 mol) and ZnCl2 (2.18 g, 0.016 mol) were added to the filtrate, and the reaction was continued at a controlled temperature of 75–80 °C. After the reaction was detected as complete, the reaction was quenched with saturated sodium bicarbonate solution (200 ml), extracted with dichloromethane (150 ml × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a yield of 92.4% and a GC purity of 92.87%.

[0131] Synthesis of I:

[0132] Example 18

[0133] At room temperature, 10.72 g (0.05 mol) of I-2 was added to 60 ml of dry dichloromethane and stirred until dissolved. Under argon protection, boron trifluoride diethyl ether (7.45 g, 0.0525 mol) was added at 0–5 °C. After the addition was complete, the reaction was continued at 20–25 °C. Once the reaction was complete, 40 ml of pre-cooled saturated sodium bicarbonate solution (0–5 °C) was added at 0–5 °C. The mixture was stirred at 0–5 °C for 1 hour. The organic phase was separated, washed with purified water (20 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a colorless, transparent oily substance, which was I. The yield was 96.7%, and the GC purity was 99.78%.

[0134] Example 19

[0135] At room temperature, 10.72 g (0.05 mol) of I-2 was added to 60 ml of dry dichloromethane and stirred until dissolved. Under carbon dioxide protection, boron trifluoride diethyl ether (7.10 g, 0.05 mol) was added at 5–10 °C. After the addition was complete, the reaction was continued at 30–35 °C. Once the reaction was complete, 40 ml of pre-cooled saturated sodium bicarbonate solution (0–5 °C) was added at 0–5 °C. The mixture was stirred at 0–5 °C for 1 hour. The organic phase was separated, washed with purified water (20 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a colorless, transparent oily substance, which was I. The yield was 94.3%, and the GC purity was 99.73%.

[0136] Example 20

[0137] At room temperature, I-2 (10.72 g, 0.05 mol) was added to dry chloroform (60 ml). After stirring and dissolving, boron trifluoride diethyl ether (8.52 g, 0.06 mol) was added under argon protection at -5 to 0 °C. After the addition was complete, the reaction was continued at 15 to 20 °C. After the reaction was complete, saturated sodium bicarbonate solution (50 ml) pre-cooled to 0 to 5 °C was added at 0 to 5 °C. The mixture was stirred at 5 to 10 °C for 1 h. The organic phase was separated and washed with purified water (20 ml × 2), then washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a colorless, transparent oily substance, which was I, with a yield of 95.8% and a GC purity of 99.70%.

[0138] Example 21

[0139] At room temperature, I-2 (10.72 g, 0.05 mol) was added to 60 ml of dry dichloromethane and stirred until dissolved. Under nitrogen protection, boron trifluoride diethyl ether (9.23 g, 0.065 mol) was added at -10 to -5 °C. After the addition was complete, the reaction was continued at 15 to 20 °C. Once the reaction was complete, a pre-cooled saturated sodium bicarbonate solution (60 ml) was added at 0 to 5 °C. The mixture was stirred at -5 to 0 °C for 1 h. The organic phase was separated, washed with purified water (20 ml × 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a colorless, transparent oily substance, which was I. The yield was 95.3%, and the GC purity was 99.68%.

Claims

1. A method for preparing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride, characterized in that, The steps are as follows: Step A: At room temperature, add SM-1, 3-substituted propyl methyl ether, and base to reaction solvent A, control the temperature until the reaction is complete, and then perform post-treatment to obtain intermediate I-1; ； In the 3-substituted propyl methyl ether, X is selected from one of Cl, Br, I, MsO, and TsO; The alkali mentioned in step A is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, etc. N , N - One or a combination of diisopropylethylamine, pyridine; Step B: At room temperature, I-1, hydroxylamine hydrochloride, base, and molecular sieve are added to reaction solvent B, and the temperature is controlled at T. B1 After the reaction was detected as complete, the solution was filtered. Then, the catalyst PTSA and Lewis acid were added to the filtrate, and the temperature was maintained at T. B2 After the reaction is complete, post-processing yields intermediate I-2; ； Step C: At room temperature, dissolve I₂ in dry reaction solvent C, and control the temperature T under inert gas protection. C1 Add boron trifluoride diethyl ether and continue to control the temperature T. C2 After the reaction is detected as complete, the temperature T is controlled. C3 Add pre-cooling temperature T C3 A saturated sodium bicarbonate solution, with temperature controlled at T. C3 The reaction was completed, and after post-processing, the target product I was obtained. 。 2. The preparation method according to claim 1, characterized in that, The reaction solvent A mentioned in step A is acetonitrile, butanone, N , N -Dimethylformamide, N , N - One of dimethylacetamide and dimethyl sulfoxide.

3. The preparation method according to claim 1, characterized in that, The molar ratio of SM-1 to 3-substituted propyl methyl ether and alkali in step A is 1:1.1-1.4:1.2-2.

0.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in step A is 60–90°C.

5. The preparation method according to claim 1, characterized in that, The base mentioned in step B is one or a combination of sodium acetate, potassium acetate, triethylamine, potassium carbonate, and sodium carbonate; the reaction solvent B mentioned in step B is one or a combination of acetonitrile, tetrahydrofuran, and 1,4-dioxane.

6. The preparation method according to claim 1, characterized in that, The Lewis acid mentioned in step B is one of ZnBr2, ZnCl2, SnCl4, FeCl3, and InCl2.

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound I-1 in step B to hydroxylamine hydrochloride, alkali, PTSA, and Lewis acid is 1:1.2-1.8:1.2-1.8:2%-15%:2%-15%.

8. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step B B1 The temperature ranges from 60 to 90°C; the reaction temperature T B2 The temperature ranges from 60 to 90 degrees Celsius.

9. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step B B1 The temperature is 75–80℃; the reaction temperature T B2 The temperature is 75-80℃.

10. The preparation method according to claim 1, characterized in that, The molar ratio of compound I-2 to boron trifluoride diethyl ether in step C is 1:1.0 to 1.

2.

11. The preparation method according to claim 1, characterized in that, The molar ratio of compound I-2 to boron trifluoride diethyl ether in step C is 1:1.

05.

12. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step C C1 and reaction temperature T C3 The temperature ranges from -5 to 10℃; the reaction temperature T C2 The temperature ranges from 15 to 40 degrees Celsius.

13. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step C C1 and reaction temperature T C3 The temperature ranges from 0 to 5℃; the reaction temperature T C2 The temperature is 20-25℃.

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