A method for synthesizing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to a method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride. This method uses inexpensive and readily available 4-hydroxypiperidine as a reaction raw material, chlorinates it, and reacts it with methenamine to form an amino group, thereby producing the compound 1-(3-methoxypropyl)-4-piperidinamine. The preparation method is safe and simple to operate, features high atom utilization, operates under mild reaction conditions, and is environmentally friendly. The target product obtained has a high yield and purity, making it suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine. Background Art

[0002] Prucalopride succinate, chemically known as 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide succinate, is a new generation of highly selective, high-affinity 5-hydroxytryptamine 4 (5-HT4) receptor agonists developed by Movetis, a Belgian company. It restores impaired intestinal motility by directly acting on the intestinal wall. Its chemical structure is as follows:

[0003]

[0004] Currently, there are many methods disclosed 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, etc., which use 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as a starting material or key intermediate and 1-(3-methoxypropyl)-4-piperidinamine to prepare the product through amidation reaction.

[0005]

[0006] Patent CN108976216A prepares 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxaldehyde through a multi-step reaction, and then couples it with 1-(3-methoxypropyl)-4-piperidinamine through oxidative dehydrogenation to obtain the target product.

[0007]

[0008] Similarly, patent CN109232544A prepares (4-amino-5-chloro-2,3-dihydrobenzofuran-7-yl)methanol through a multi-step reaction, and then couples it with 1-(3-methoxypropyl)-4-piperidinamine through oxidative dehydrogenation to obtain the target product.

[0009]

[0010] As can be seen from the above, 1-(3-methoxypropyl)-4-piperidinamine is used as a key intermediate in the preparation of prucalopride in various synthetic strategies. Therefore, 1-(3-methoxypropyl)-4-piperidinamine directly affects the production, market supply, and quality of this drug. Its specific structural formula is as follows:

[0011]

[0012] At present, the synthesis methods of 1-(3-methoxypropyl)-4-piperidinamine mainly include the following according to the different "amino group construction":

[0013] ①Constructed with substituted aminopiperidine.

[0014] Patent CN102295594B uses N-protected aminopiperidine as a starting material, reacts it with 1-substituted-3-methoxypropane under alkaline conditions, and then deprotects it. Deprotection of the benzyloxycarbonyl (Cbz) group is typically achieved by hydrogenolysis or acidic cleavage (HBt or TMSI); acetyl and propionyl groups are typically removed by alkaline hydrolysis or acidic decomposition. However, this method uses relatively expensive starting materials, making it largely uncompetitive.

[0015]

[0016] ② Using N-substituted-4-piperidinone compounds as starting materials, it is constructed through a reductive amination strategy.

[0017] Patent CN102898356B uses 4-piperidone hydrochloride monohydrate as the starting material, reacting it with 1-substituted-3-methoxypropane under alkaline conditions to produce 1-(3-methoxypropyl)-4-piperidone. The product is then reacted in an organic ammonia solution in the presence of hydrogen and a catalyst (Raney Ni and / or Pd / C) to produce the target product. This route has a long reaction time (>15 hours) for the first step, and the second step uses high-pressure hydrogenation, which is difficult to control. Furthermore, the high-cost heavy metal catalyst palladium-carbon or the flammable and highly toxic Raney Ni is required, which poses a risk of heavy metal residues in the API, prucalopride.

[0018]

[0019] Patent CN103193699B uses 4-piperidone as the starting material, reacting it with 1-bromo-3-methoxypropane under alkaline conditions of K2CO3 to produce 1-(3-methoxypropyl)-4-piperidone. The target product is then produced after reflux reaction at 110°C for 8 hours in a formic acid / ammonium formate system. This process has a long reaction time at high temperature and high energy consumption. Furthermore, due to the high polarity of the target product, the final step of the process is incomplete, making it difficult to remove intermediates and byproducts, making purification more challenging.

[0020]

[0021] Another document, 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 document Synthesis of Prucalopride Succinate, Chinese Journal of Pharmaceutical Industry, 2012, 43(1):5-8, uses a saturated ammonia solution in methanol as a solvent and 10% Pd / C catalytic hydrogenation to directly convert the carbonyl group to an amino group to obtain the target product.

[0022] Patent CN103508939A uses 1-(3-methoxypropyl)-4-piperidone, a key intermediate in the above process, as a starting material. The process then heats it with hydroxylamine hydrochloride, refluxes it, and dehydrates it to produce the key intermediate 1-(3-methoxypropyl)-4-piperidinoxime. The target product is then produced through catalytic hydrogenation (using Raney Ni). This process uses expensive starting materials and a highly toxic Raney Ni catalyst, making it unsuitable for industrial production.

[0023]

[0024] Furthermore, Chinese patent CN1143858 (US6479487) also uses the above strategy to prepare the key intermediate 1-(3-methoxypropyl)-4-piperidinyl oxime, followed by reduction with lithium aluminum tetrahydride to obtain the corresponding product. However, lithium aluminum tetrahydride requires a strictly oxygen- and water-free environment during experimental operation, resulting in complex post-processing and difficulty in filtration. Therefore, industrialization of this method is difficult.

[0025] Patent CN103351329A also uses 1-(3-methoxypropyl)-4-piperidone as a starting material, and produces the target product using sodium triacetoxyborohydride as a reducing agent in the presence of ammonia in methanol or ammonium formate.

[0026]

[0027] Patent CN103804281A also uses 1-(3-methoxypropyl)-4-piperidone as the starting material. The carbonyl group is first reduced with NaBH4 to obtain 1-(3-methoxypropyl)-4-piperidinol, which is then esterified with p-toluenesulfonyl chloride to obtain 1-(3-methoxypropyl)-4-p-toluenesulfonate piperidine. Finally, it reacts with phthalimide and undergoes hydrazinolysis under alkaline conditions to obtain the target product. However, this process uses the genotoxic substance p-toluenesulfonyl chloride to activate the hydroxyl group and simultaneously uses the Gabriel reaction to prepare the primary amine group, resulting in poor atom economy. The phthalic hydrazide generated by the hydrazinolysis method has high polarity and is difficult to post-process. In addition, the use of the highly toxic substance hydrazine hydrate has poor operational safety.

[0028]

[0029] Patent CN103848777A (WO2015139332) also uses 1-(3-methoxypropyl)-4-piperidone as the starting material, which reacts with substituted or unsubstituted benzylamine under the action of a reducing agent to produce N-(3-methoxypropyl)-4-benzylaminopiperidine, and finally undergoes palladium-carbon catalytic reduction to obtain the target product.

[0030]

[0031] ③ Using 4-carboxamidopiperidine as the starting material or key intermediate, it is constructed through Hofmann rearrangement reaction.

[0032] Patent CN1143858 (US6479487) uses 4-carboxamidopiperidine as a raw material, which undergoes an alkylation reaction with 1-methoxy-3-bromopropane. The target product is then generated via a Hofmann rearrangement in the presence of the hypervalent iodine compound bis(trifluoroacetyloxy)iodobenzene [PhI(O2CCF3)2]. This process is both expensive for the raw materials and the hypervalent iodine compound, and stability and safety issues with the compound have hindered its large-scale industrial production.

[0033]

[0034] Patent CN106146386A and the literature on the synthesis of prucalopride succinate, Chinese Journal of Pharmaceutical Industry, 2015, 46(11):1158-1160, use cheap and readily available 4-piperidinic acid as a raw material, esterify it in thionyl chloride-methanol to obtain 4-piperidinic acid methyl ester hydrochloride; then react it with 1-methoxy-3-bromopropane to obtain 1-(3-methoxypropyl)piperidin-4-carboxylic acid methyl ester through alkylation; then aminolysis in aqueous ammonia to obtain 1-(3-methoxypropyl)piperidin-4-carboxamide; finally, react it with dibromohydantoin under alkaline conditions to obtain a crude product, which is then distilled to obtain the target product with a purity greater than 99.5%. However, the total yield of this process is only 56%, and distillation and purification are required, which is cumbersome.

[0035]

[0036] In summary, the current process for preparing 1-(3-methoxypropyl)-4-piperidinamine mainly has the following problems:

[0037] 1. The high prices of the starting materials and various reagents used increase production costs and make the product basically uncompetitive in the market.

[0038] 2. The target product is prepared by catalytic hydrogenation, and the related high-pressure reaction conditions are difficult to control. It requires the use of high-cost heavy metal catalysts such as palladium carbon or flammable and highly toxic catalysts such as Raney Ni, which brings the risk of heavy metal residues in the raw material drug prucalopride.

[0039] 3. It requires high temperature and long time reaction, resulting in high energy consumption.

[0040] 4. The reaction needs to be anhydrous and oxygen-free or the target product needs to be purified by distillation, which makes the operation complicated.

[0041] 5. The reaction requires p-toluenesulfonyl chloride to activate the hydroxyl group and the Gabriel reaction to prepare the primary amine group, resulting in poor atom economy.

[0042] 6. The use of hydrazine hydrate and catalytic hydrogenation or hydride for reduction results in a problem of low operational safety.

[0043] Given that there are many deficiencies in the current preparation of 1-(3-methoxypropyl)-4-piperidinamine, it is still a problem that needs to be solved to find a preparation process that is simple and safe to operate, has mild reaction conditions, and has high product yield and high purity and is suitable for the industrial production of 1-(3-methoxypropyl)-4-piperidinamine. Summary of the Invention

[0044] To address the numerous problems currently encountered in the synthesis of prucalopride-related intermediate 1-(3-methoxypropyl)-4-piperidinamine, the present invention provides a novel method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine. This method offers mild reaction conditions, a safe and simple operation, and produces a target product with high purity and yield.

[0045] The present invention is specifically implemented through the following technical solutions:

[0046] A method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride, comprises: using 4-hydroxypiperidine as a reaction raw material, subjecting it to a substitution reaction with 3-substituted propyl methyl ether to obtain an intermediate I-1; then subjecting it to a chlorination reaction with SOCl2 in the presence of a base to obtain an intermediate I-2; and reacting the intermediate I-2 with methenamine in the presence of a catalyst to obtain the compound 1-(3-methoxypropyl)-4-piperidinamine. The reaction formula is as follows:

[0047]

[0048] Among them 3-substituted propyl methyl ether wherein X is selected from one of Cl, Br, I, MsO, and TsO, preferably Br.

[0049] A method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride as shown in Formula I, comprises the following steps:

[0050] Step 1. Add 4-hydroxypiperidine, 3-substituted propyl methyl ether, and a base to an organic solvent A, control the temperature until the reaction is complete, and perform post-treatment to obtain an intermediate I-1;

[0051] Step 2. Dissolve the intermediate I-1 in anhydrous organic solvent B and stir. Dilute the mixture of benzotriazole and SOCl2 to 1.5M with anhydrous organic solvent B and add it to the reaction solution. Control the temperature until the reaction is complete, and then perform post-treatment to obtain the intermediate I-2.

[0052] Step 3. Add intermediate I-2, hexamethylenetetramine and a catalyst to organic solvent C, control the temperature until the reaction is complete, and obtain compound I through post-treatment.

[0053] Preferably, the base in step 1 is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, piperidine or a combination thereof, preferably potassium carbonate.

[0054] Preferably, the organic solvent A in step 1 is selected from one or a combination of acetonitrile, butanone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, preferably acetonitrile.

[0055] Preferably, the molar ratio of 4-hydroxypiperidine to 3-substituted propyl methyl ether in step 1 is 1:1.1 to 1.5, preferably 1:1.3.

[0056] Preferably, the molar ratio of 4-hydroxypiperidine to the base in step 1 is 1:1.2 to 2.0, preferably 1:1.6.

[0057] Preferably, the reaction temperature in step 1 is 60-90°C, preferably 75-80°C.

[0058] In a preferred embodiment, the post-treatment steps described in step 1 are as follows: after the reaction is completed, the reaction is filtered, the filtrate is concentrated to dryness under reduced pressure, dichloromethane is added, and the mixture is washed 1 to 2 times with 0.5 to 2 M dilute hydrochloric acid. The organic layer is collected, dried, and concentrated under reduced pressure to obtain intermediate I-1.

[0059] Preferably, the molar ratio of benzotriazole to SOCl2 in step 2 is 1:1.

[0060] Preferably, the molar ratio of I-1 to SOCl2 in step 2 is 1:1.1 to 1.5, preferably 1:1.2.

[0061] Preferably, the organic solvent B in step 2 is selected from one of dichloromethane and chloroform or a combination thereof, preferably dichloromethane.

[0062] Preferably, the reaction temperature in step 2 is 10-30°C, preferably 20-25°C.

[0063] In a preferred embodiment, the post-treatment steps in step 2 are as follows: after the reaction is completed, filtering, washing the filtrate with saturated sodium bicarbonate solution, washing with purified water, drying, filtering, and concentrating the filtrate to dryness under reduced pressure to obtain intermediate I-2.

[0064] Preferably, the organic solvent C in step 3 is selected from one of methanol, ethanol, isopropanol, n-butanol, tert-butanol or a combination thereof, preferably ethanol.

[0065] Preferably, the catalyst in step 3 is selected from sodium iodide, potassium iodide or a combination thereof, preferably potassium iodide.

[0066] Preferably, the molar ratio of the intermediate I-2 to hexamethylenetetramine in step 3 is 1:1.05 to 1.5, preferably 1:1.2.

[0067] Preferably, the molar ratio of the intermediate I-2 to the catalyst in step 3 is 1:0.05 to 0.1, preferably 1:0.08.

[0068] Preferably, the reaction temperature in step 3 is 30-60°C, preferably 45-50°C.

[0069] In a preferred embodiment, the post-treatment steps in step 3 are as follows: after the reaction is completed, the reaction solution is cooled to room temperature, concentrated hydrochloric acid is added dropwise to a pH of 1 to 2, stirred until a large amount of solid is precipitated, filtered, and the filter cake is washed with a small amount of organic solvent C and dried to obtain the hydrochloride of the target product I; the reaction mixture is stirred at room temperature for 1 to 2 hours in the presence of a base using methanol or ethanol as a solvent, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain the target product I; preferably, the base is selected from one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof, preferably potassium carbonate; preferably, the amount of the base added is 1.5 to 3 times the molar amount of the intermediate I-2.

[0070] Beneficial effects of the present invention:

[0071] The present invention provides a simple and efficient method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride. This method uses inexpensive and readily available 4-hydroxypiperidine as a starting material. After chlorination, it reacts with methenamine to directly construct the amino group to produce Compound I. Compared with existing technologies, this method effectively avoids the hazardous catalytic hydrogenation techniques, is safe to operate, has high atom utilization, and reduces production costs. The entire synthetic process is simple to operate, operates under relatively mild conditions, is environmentally friendly, and is suitable for industrial production. The target product produced by this process has a high yield and purity. DETAILED DESCRIPTION

[0072] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0073] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0074] Synthesis of I-1:

[0075] Example 1

[0076] 4-Hydroxypiperidine (40.46 g, 0.40 mol), 3-bromopropyl methyl ether (X = Br, 79.57 g, 0.52 mol), and potassium carbonate (88.45 g, 0.64 mol) were added to acetonitrile (400 ml) and the reaction was controlled at 75-80°C. After the reaction was completed, it was filtered and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (500 ml) was added and the mixture was washed 1-2 times with 1M dilute hydrochloric acid (150 ml). The organic layer was dried and concentrated under reduced pressure to obtain intermediate I-1 with a yield of 96.4% and a purity of 99.3%.

[0077] Example 2

[0078] 4-Hydroxypiperidine (40.45 g, 0.40 mol), 3-iodopropyl methyl ether (X=I, 88.01 g, 0.44 mol), and triethylamine (64.76 g, 0.64 mol) were added to N,N-dimethylformamide (400 ml) and the reaction was controlled at 80-85°C. After the reaction was completed, it was filtered and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (500 ml) was added and the mixture was washed 1-2 times with 2M dilute hydrochloric acid (150 ml). The organic layer was dried and concentrated under reduced pressure to obtain intermediate I-1 with a yield of 93.7% and a purity of 99.4%.

[0079] Example 3

[0080] 4-Hydroxypiperidine (40.43 g, 0.40 mol), 3-chloropropyl methyl ether (X=Cl, 64.82 g, 0.60 mol), and sodium bicarbonate (53.76 g, 0.64 mol) were added to butanone (400 ml) and the reaction was controlled at 75-80°C. After the reaction was completed, it was filtered and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (500 ml) was added and the mixture was washed 1-2 times with 0.5 M dilute hydrochloric acid (150 ml). The organic layer was dried and concentrated under reduced pressure to obtain intermediate I-1 with a yield of 95.9% and a purity of 98.1%.

[0081] Example 4

[0082] 4-Hydroxypiperidine (40.46 g, 0.40 mol), 3-methoxypropyl methanesulfonate (X = MsO, 87.47 g, 0.52 mol), and potassium bicarbonate (48.05 g, 0.48 mol) were added to dimethyl sulfoxide (400 ml) and the reaction was controlled at 85-90°C. After the reaction was completed, it was filtered and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (500 ml) was added and the mixture was washed 1-2 times with 1M dilute hydrochloric acid (150 ml). The organic layer was dried and concentrated under reduced pressure to obtain intermediate I-1 with a yield of 94.0% and a purity of 99.2%.

[0083] Example 5

[0084] 4-Hydroxypiperidine (40.45 g, 0.40 mol), 3-methoxypropyl p-toluenesulfonate (X=TsO, 127.04 g, 0.52 mol), and sodium carbonate (84.79 g, 0.80 mol) were added to acetonitrile (400 ml) and the reaction was controlled at 70-75°C. After the reaction was completed, it was filtered and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (500 ml) was added and the mixture was washed 1-2 times with 1M dilute hydrochloric acid (150 ml). The organic layer was dried and concentrated under reduced pressure to obtain intermediate I-1 with a yield of 94.3% and a purity of 98.5%.

[0085] Synthesis of I:

[0086] Example 6

[0087] Intermediate I-1 (51.98 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (42.89 g, 0.36 mol) and SOCl2 (42.83 g, 0.36 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 20-25 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0088] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (50.47 g, 0.36 mol), and potassium iodide (3.99 g, 0.024 mol) were added to ethanol (250 ml) and reacted at 45-50°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in ethanol (200 ml), potassium carbonate (82.92 g, 0.60 mol) was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 95.2% and the purity was 99.6%.

[0089] Example 7

[0090] Intermediate I-1 (51.96 g, 0.30 mol) was dissolved in anhydrous chloroform (200 ml) and stirred. A mixture of benzotriazole (39.31 g, 0.33 mol) and SOCl2 (39.26 g, 0.33 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 25-30 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0091] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (41.39 g, 0.31 mol), and potassium iodide (3.97 g, 0.024 mol) were added to methanol (250 ml) and the reaction was controlled at 40-45°C. After the reaction was detected to be complete, it was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to pH = 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. This was dissolved in ethanol (200 ml), potassium carbonate (82.94 g, 0.60 mol) was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 93.2% and the purity was 99.3%.

[0092] Example 8

[0093] Intermediate I-1 (51.95 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (53.60 g, 0.45 mol) and SOCl2 (53.53 g, 0.45 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 15-20 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2), washed with purified water (150 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0094] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (63.09 g, 0.45 mol), and sodium iodide (3.60 g, 0.024 mol) were added to isopropyl alcohol (250 ml) and the reaction was carried out at a temperature of 50-55°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in ethanol (200 ml) and sodium carbonate (63.60 g, 0.60 mol) was added. The mixture was stirred at room temperature for 1.5 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 94.5% and the purity was 98.4%.

[0095] Example 9

[0096] Intermediate I-1 (52.00 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (42.89 g, 0.36 mol) and SOCl2 (42.83 g, 0.36 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 20-25 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0097] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (44.16 g, 0.30 mol), and potassium iodide (4.00 g, 0.024 mol) were added to ethanol (250 ml) and reacted at 45-50°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in methanol (200 ml), and potassium bicarbonate (60.05 g, 0.60 mol) was added. The mixture was stirred at room temperature for 1.5 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 92.4% and the purity was 99.0%.

[0098] Example 10

[0099] Intermediate I-1 (51.99 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (42.90 g, 0.36 mol) and SOCl2 (42.85 g, 0.36 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 20-25 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0100] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (75.70 g, 0.54 mol), and sodium iodide (3.60 g, 0.016 mol) were added to isopropanol (250 ml) and reacted at 50-55°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in methanol (200 ml), and sodium bicarbonate (50.40 g, 0.60 mol) was added. The mixture was stirred at room temperature for 2.0 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 92.9% and the purity was 98.5%.

[0101] Example 11

[0102] Intermediate I-1 (51.95 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (42.86 g, 0.36 mol) and SOCl2 (42.80 g, 0.36 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 20-25 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0103] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (50.45 g, 0.36 mol), and potassium iodide (2.50 g, 0.015 mol) were added to n-butanol (250 ml) and the reaction was carried out at 35-40°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in ethanol (200 ml) and potassium carbonate (82.90 g, 0.60 mol) was added. The mixture was stirred at room temperature for 1.5 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 94.3% and the purity was 99.2%.

[0104] Example 12

[0105] Intermediate I-1 (51.98 g, 0.30 mol) was dissolved in anhydrous dichloromethane (200 ml) and stirred. A mixture of benzotriazole (42.89 g, 0.36 mol) and SOCl2 (42.83 g, 0.36 mol) was diluted to 1.5 M with anhydrous dichloromethane and added to the reaction solution. The temperature was controlled at 20-25 ° C. After the reaction was completed, it was filtered and the filtrate was washed with saturated sodium bicarbonate solution (150 ml × 2) and purified water (150 ml × 2), dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-2, which was directly used in the next reaction.

[0106] The intermediate I-2 obtained above (0.30 mol), hexamethylenetetramine (50.47 g, 0.36 mol), and potassium iodide (4.98 g, 0.030 mol) were added to tert-butanol (250 ml) and the reaction was carried out at 30-35°C. After the reaction was detected to be complete, the mixture was cooled to room temperature and concentrated hydrochloric acid (12 M) was added dropwise to a pH of 1-2. The mixture was stirred until a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with a small amount of ethanol and dried to obtain the hydrochloride salt of the target product I. The mixture was dissolved in ethanol (200 ml) and potassium carbonate (82.92 g, 0.60 mol) was added. The mixture was stirred at room temperature for 1.5 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound I. The total yield of the two-step reaction was 94.7% and the purity was 98.1%.

Claims

1. A method for synthesizing 1-(3-methoxypropyl)-4-piperidinamine, an intermediate of prucalopride, characterized in that: 4-Hydroxypiperidine is used as a reaction raw material, and a substitution reaction is carried out with 3-substituted propyl methyl ether to obtain intermediate I-1, which is then subjected to a chlorination reaction with SOCl2 to obtain intermediate I-2. Intermediate I-2 reacts with urotropine in the presence of a catalyst to obtain the compound 1-(3-methoxypropyl)-4-piperidinamine. The reaction formula is as follows: ， wherein X in the 3-substituted propyl methyl ether is selected from one of Cl, Br, I, MsO, and TsO; The specific steps of the synthetic method are as follows: Step 1. Add 4-hydroxypiperidine, 3-substituted propyl methyl ether, and a base to an organic solvent A, control the temperature until the reaction is complete, and perform post-treatment to obtain an intermediate I-1; Step 2. Dissolve the intermediate I-1 in anhydrous organic solvent B and stir. Dilute the mixture of benzotriazole and SOCl2 to 1.5M with anhydrous organic solvent B and add it to the reaction solution. Control the temperature until the reaction is complete, and then perform post-treatment to obtain the intermediate I-2. Step 3. Add intermediate I-2, hexamethylenetetramine, and a catalyst to organic solvent C, control the temperature until the reaction is complete, and perform post-treatment to obtain compound I; The base described in step 1 is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, and piperidine; the organic solvent A described in step 1 is selected from one or a combination of acetonitrile, butanone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the organic solvent B described in step 2 is selected from one or a combination of dichloromethane and chloroform; the catalyst described in step 3 is selected from one or a combination of sodium iodide and potassium iodide.

2. The synthesis method according to claim 1, wherein The molar ratio of I-1 to SOCl2 in step 2 is 1:1.1 to 1.

5.

3. The synthesis method according to claim 2, characterized in that The molar ratio of the intermediate I-2 to hexamethylenetetramine in step 3 is 1:1.05-1.

5.

4. The synthesis method according to claim 2, characterized in that The molar ratio of the intermediate I-2 to the catalyst in step 3 is 1:0.05 to 0.1.

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