Process for the preparation of a prucalopride intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a prucalopride intermediate 4-acetylamino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester. The method uses 4-acetylamino-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester (SM-1) as a starting material, and the target product is prepared through dehalogen coupling, which can effectively solve the problem of low operation safety of sodium metal dehalogen coupling, and can also solve the problem of long production time of the zinc powder coupling technical scheme, and is suitable for industrialized scale production. The obtained product has high yield and purity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 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, mainstream processes all use 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid as the key intermediate in the preparation of prucalopride, as reported in patents CN1164233A (CN1071332C) and CN103664912B, which involve the reaction of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid with 1-(3-methoxypropyl)-4-piperidinamine. The reaction route is as follows:

[0005]

[0006] Most processes involve obtaining methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (I) via various routes, followed by hydrolysis to obtain the target product. Therefore, methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate is also a key intermediate in the preparation of prucalopride, directly affecting the production, market supply, and quality of this drug. The reaction route is as follows:

[0007]

[0008] Studies have shown that the current difficulty in preparing prucalopride lies in the construction of intermediates related to the benzofuran ring. The method using 1,2-dibromoethane as a key reagent for this construction is as follows:

[0009] The literature, "Research on the Synthesis Process of 4-Amino-5-chloro-2,3-dihydro-7-benzofuranbenzoic Acid, a Key Intermediate of Prucalopride," *China Pharmaceutical Industry*, 2016, 25(2), 38-40, describes a multi-step reaction process using methyl 2-methoxy-4-acetamido-5-chlorobenzoate as the starting material. However, this process, in addition to using highly toxic bromine for bromination, also employs a highly hazardous sodium metal in diethyl ether for dehalogenation coupling via the Wutz reaction. The coupling step yield is 88.7%, and the operation and post-processing are dangerous, making large-scale production difficult. The reaction route is as follows:

[0010]

[0011] The literature *Chemical Process Research*, Vol. 870, Chapter 8, Washington: American Chemical Society, 2003, pp. 125-139 describes a process using methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate) as a starting material, involving bromination, bromoethylation, cyclization, and hydrolysis. The reaction conditions are mild, and the overall yield is 29%. However, this process only achieves a 60% yield in the dehalogenation coupling step, resulting in high production costs and making industrial-scale production difficult. The reaction route is as follows:

[0012] The synthesis of purcapride succinate, *China Pharmaceutical Industry Magazine*, 2012, 43(1), 5-8, uses para-aminosalicylic acid as the starting material and obtains the target product through a multi-step reaction. However, this process uses bromine for bromination, which is highly toxic, and also uses highly corrosive sulfonyl chloride for chlorination. In addition, the dehalogenation coupling preparation uses a large amount of excess zinc powder and reacts at 50℃ for 20 h. After treatment with hydrochloric acid, a slightly red crude product is obtained with low purity. The reaction route is as follows:

[0013]

[0014] In addition, patent CN107337658A recrystallizes the crude product with propylene glycol monomethyl ether to obtain I. However, this process also requires an excess of zinc powder, and the inorganic salt ZnCl2 obtained from the post-processing is difficult to recover and reuse, resulting in serious pollution. Furthermore, the reaction time (20h) is relatively long, leading to a long production cycle.

[0015] Given the many shortcomings in the current preparation of methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate, finding a simple, mild, safe, and convenient process suitable for the industrial production of methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate remains a problem that needs to be solved. Summary of the Invention

[0016] To address the numerous problems existing in the current preparation of methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate, a related intermediate of prucalopride, this invention provides a method for preparing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and yield.

[0017] The specific technical solution of the present invention is as follows:

[0018] A method for preparing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, an intermediate related to prucalopride as shown in formula (I), specifically includes the following steps:

[0019] At room temperature, SM-1 was added to the reaction solvent, followed by an alkyltin compound, palladium catalyst, base, and phase transfer catalyst. The temperature was controlled until the reaction was complete, and the target product I was obtained after post-treatment. The reaction route is as follows:

[0020]

[0021] Preferably, the molar ratio of SM-1 to the alkyltin catalyst, palladium catalyst, base catalyst, and phase transfer catalyst is 1:0.8-1.5:5%-20%:1.0-2.0:1.0-2.0, and more preferably 1:1.1:10%:1.5:1.5.

[0022] Preferably, the alkyltin compound is one or a combination of hexamethyldistin and hexabutyldistin, and more preferably hexabutyltin.

[0023] Preferably, the palladium catalyst is one or a combination of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, with Pd(dppf)Cl2 being more preferred.

[0024] Preferably, the alkali is one or a combination of Li2CO3, K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc, with Li2CO3 being more preferred.

[0025] Preferably, the phase transfer catalyst is one or a combination of Me4NCl, Me4NBr, Me4NI, Et4NCl, Et4NBr, Et4NI, Pr4NCl, Pr4NBr, Pr4NI, Bu4NCl, Bu4NBr, and Bu4NI, with Bu4NBr being more preferred.

[0026] Preferably, the reaction solvent is one or a combination of dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, and toluene, with toluene being more preferred.

[0027] Preferably, the reaction temperature is 80–110°C, and more preferably 100–105°C.

[0028] In the preferred embodiment, after the reaction is confirmed to be complete, the post-processing steps are as follows: filter the reaction solution onto diatomaceous earth, pour the filtrate into purified water, extract with an organic solvent, wash with saturated saline solution, and concentrate under reduced pressure to dryness to obtain the target product.

[0029] Preferably, the organic solvent used for extraction is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being more preferred.

[0030] The beneficial effects of this invention are:

[0031] 1. This invention provides a simple and efficient method for preparing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, an intermediate related to prucalopride. The entire synthetic method is simple to operate and suitable for industrial production.

[0032] 2. Using methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1) as the starting material, the target product is prepared via dehalogenation coupling. This effectively solves the problem of low safety in dehalogenation coupling using metallic sodium, and also addresses the issue of long production time in zinc powder coupling technology. It is suitable for industrial-scale production.

[0033] 3. The product yield and purity obtained by the reaction completed through this scheme are both high. Detailed Implementation

[0034] 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.

[0035] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0036] Example 1

[0037] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutylditin (63.81 g, 0.11 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), Li2CO3 (11.08 g, 0.15 mol), and Bu4NBr (48.36 g, 0.15 mol) were added to toluene (400 ml). The reaction was carried out at 100–105 °C for about 6 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (4 L). The solution was extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 95.2%, and the HPLC purity was 99.7%.

[0038] Example 2

[0039] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutylditin (46.41 g, 0.08 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), K2CO3 (20.73 g, 0.15 mol), and Bu4NCl (41.69 g, 0.15 mol) were added to toluene (400 ml). The reaction was carried out at 105–110 °C for about 4 hours. After the reaction was confirmed to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was poured into purified water (4 L), extracted with chloroform (1000 ml × 3), washed with saturated brine (1000 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 93.4%, and the HPLC purity was 99.3%.

[0040] Example 3

[0041] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutylditin (40.61 g, 0.07 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), Li2CO3 (11.08 g, 0.15 mol), and Me4NI (30.16 g, 0.15 mol) were added to dimethyl sulfoxide (400 ml). The reaction was carried out at 105–110 °C for about 6 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (4 L). The solution was extracted with dichloromethane (1500 ml × 3), washed with saturated brine (1500 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 92.1%, and the HPLC purity was 99.4%.

[0042] Example 4

[0043] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexamethyldistin (49.14 g, 0.15 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), Na2CO3 (15.90 g, 0.15 mol), and Et4NBr (31.52 g, 0.15 mol) were added to toluene (400 ml). The reaction was carried out at 90–95 °C for about 7 h. After the reaction was confirmed to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was poured into purified water (4 L), extracted with ethyl acetate (1000 ml × 3), washed with saturated brine (1000 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product with a yield of 92.5% and an HPLC purity of 99.1%.

[0044] Example 5

[0045] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexamethylditin (52.42 g, 0.16 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), Li2CO3 (11.08 g, 0.15 mol), and Et4NI (38.56 g, 0.15 mol) were added to N,N-dimethylformamide (400 ml). The mixture was reacted at 80–85 °C for approximately 8 hours. After the reaction was confirmed to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was poured into purified water (4 L), extracted with methyl tert-butyl ether (1500 ml × 3), washed with saturated brine (1500 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 90.4%, and the HPLC purity was 99.0%.

[0046] Example 6

[0047] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutyltin (63.81 g, 0.11 mol), Pd(PPh3)4 (5.78 g, 0.005 mol), KOAc (14.72 g, 0.15 mol), and Pr4NBr (39.94 g, 0.15 mol) were added to toluene (400 ml). The reaction was carried out at 105–110 °C for about 7 h. After the reaction was confirmed to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was poured into purified water (4 L), extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 91.5%, and the HPLC purity was 99.1%.

[0048] Example 7

[0049] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutyltin (63.81 g, 0.11 mol), Pd(PPh3)2Cl2 (14.04 g, 0.02 mol), Na3PO4 (24.59 g, 0.15 mol), and Pr4NI (46.99 g, 0.15 mol) were added to 1,4-dioxane (400 ml). The mixture was refluxed under controlled temperature for about 5 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (4 L). The solution was extracted with dichloromethane (1500 ml × 3), washed with saturated brine (1500 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 90.9%, and the HPLC purity was 99.3%.

[0050] Example 8

[0051] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutylditin (63.81 g, 0.11 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), K3PO4 (21.23 g, 0.1 mol), and Bu4NI (36.94 g, 0.1 mol) were added to N,N-dimethylacetamide (400 ml). The reaction was carried out at 105–110 °C for about 6 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was poured into purified water (4 L). The solution was extracted with dichloromethane (1500 ml × 3), washed with saturated brine (1500 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 89.9%, and the HPLC purity was 99.2%.

[0052] Example 9

[0053] At room temperature, methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (SM-1, 42.95 g, 0.1 mol), hexabutylditin (63.81 g, 0.11 mol), Pd(dppf)Cl2 (7.32 g, 0.01 mol), NaOAc (16.41 g, 0.2 mol), and Me4NBr (30.81 g, 0.2 mol) were added to toluene (400 ml). The reaction was carried out at 95–100 °C for about 6 hours. After the reaction was confirmed to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was poured into purified water (4 L), extracted with dichloromethane (1000 ml × 3), washed with saturated brine (1000 ml × 2), and concentrated to dryness under reduced pressure to obtain the target product. The yield was 92.7%, and the HPLC purity was 99.4%.

Claims

1. A method for preparing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, an intermediate related to prucalopride as shown in formula (I), characterized in that, Specifically, the following steps are included: At room temperature, SM-1 was added to the reaction solvent, followed by an alkyltin compound, palladium catalyst, base, and phase transfer catalyst. The temperature was controlled until the reaction was complete, and the target product I was obtained after post-treatment. The reaction route is as follows: ； The alkyltin compound is one or a combination of hexamethyldistin and hexabutyldistin. The palladium catalyst is one or a combination of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2.

2. The preparation method according to claim 1, characterized in that, The molar ratio of SM-1 to alkyltin catalyst, palladium catalyst, base catalyst and phase transfer catalyst is 1:0.8-1.5:5%-20%:1.0-2.0:1.0-2.

0.

3. The preparation method according to claim 1, characterized in that, The alkali is one or a combination of Li2CO3, K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc.

4. The preparation method according to claim 1, characterized in that, The phase transfer catalyst is one or a combination of Me4NCl, Me4NBr, Me4NI, Et4NCl, Et4NBr, Et4NI, Pr4NCl, Pr4NBr, Pr4NI, Bu4NCl, Bu4NBr, and Bu4NI.

5. The preparation method according to claim 1, characterized in that, The reaction solvent is dimethyl sulfoxide. N , N -Dimethylformamide, 1,4-dioxane, N , N - One or a combination of dimethylacetamide, toluene, or dimethylacetamide.

6. The preparation method according to claim 1, characterized in that, The reaction temperature is 80–110°C.

7. The preparation method according to claim 1, characterized in that, The post-processing steps are as follows: filter the reaction liquid into diatomaceous earth, pour the filtrate into purified water, extract with organic solvent, wash with saturated saline, and concentrate under reduced pressure to dryness to obtain the target product.

8. The preparation method according to claim 7, characterized in that, The organic solvent used for extraction is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

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