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. The target product is prepared through an amide reaction of 1-(3-methoxypropyl)-4-piperidinol and finally acidolysis. The method can effectively avoid the operation of the dangerous catalytic hydrogenation technology and the application of the reducing reagent in the prior art, is safe in operation, avoids the introduction of a Ts-protecting group, shortens the reaction steps, reduces production man-hours, and is simple in operation and suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing a prucalopride intermediate. 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 literature Synthesis of Prucalopride, Pharmaceutical and Clinical Research, 2011, Aug; 19(4):306-307, etc., in which 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is used as the starting material or key intermediate and reacted with 1-(3-methoxypropyl)-4-piperidineamine to prepare it.

[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-piperidineamine to obtain the target product.

[0007]

[0008] Similarly, patent CN109232544A obtains the target product by oxidative dehydrogenation coupling of (4-amino-5-chloro-2,3-dihydrobenzofuran-7-yl)methanol with 1-(3-methoxypropyl)-4-piperidineamine through a multi-step reaction.

[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 a variety of synthetic strategies. Therefore, 1-(3-methoxypropyl)-4-piperidinamine directly affects the production, market supply and quality of this drug.

[0011]

[0012] Currently, the main methods for preparing 1-(3-methoxypropyl)-4-piperidineamine include the following:

[0013] Patent CN102295594B uses 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 acidolysis (HBt or TMSI); acetyl and propionyl groups are usually removed by alkaline hydrolysis or acidolysis] to obtain the target product. However, this method uses expensive starting materials and is basically not competitive in the market.

[0014]

[0015] Patent CN102898356B uses 4-piperidinone hydrochloride monohydrate as a starting material, reacting it with 1-substituted-3-methoxypropane under alkaline conditions to prepare 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.

[0016]

[0017] Patent CN103193699B uses 4-piperidinone as a starting material, reacting it with 1-bromo-3-methoxypropane under alkaline conditions of K2CO3 to prepare 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 highly polar nature of the target product, the final reaction step is incomplete, making it difficult to remove intermediates and byproducts, and purification is challenging.

[0018]

[0019] 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. In the literature "Synthesis of Pucapride Succinate," *China Pharmaceutical Industry Magazine*, 2012, 43(1):5-8, a methanol solution saturated with ammonia is used as a solvent, and the carbonyl group is directly converted to an amino group in one step via 10% Pd / C catalytic hydrogenation to obtain the target product.

[0020] Patent CN103508939A uses the key intermediate 1-(3-methoxypropyl)-4-piperidinone in the above process as the starting material and heats and refluxes with hydroxylamine hydrochloride to dehydrate and obtain the key intermediate 1-(3-methoxypropyl)-4-piperidinoxime, and finally obtains the target product by catalytic (Raney Ni) hydrogenation.

[0021]

[0022] 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.

[0023] In addition, the patent CN1143858A (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 through Hofmann rearrangement. However, the prices of the two starting materials in this process are relatively high, and the stability and safety issues of the high-valent iodine compound have always restricted its large-scale industrial production.

[0024]

[0025] The synthesis of prucalopride succinate, patent CN106146386A and literature, "China Pharmaceutical Industry Magazine", 2015, 46(11):1158-1160, uses inexpensive and readily available 4-piperidinecarboxylic acid as a raw material. It is esterified in thionyl chloride-methanol to obtain methyl 4-piperidinecarboxylate hydrochloride; then, it undergoes alkylation with 1-methoxy-3-bromopropane to obtain methyl 1-(3-methoxypropyl)piperidine-4-carboxylate; subsequently, it is ammonolyzed in ammonia water to obtain 1-(3-methoxypropyl)piperidine-4-carboxamide; finally, it reacts with dibromohydantoin under alkaline conditions to undergo Hofmann rearrangement to obtain a crude product, which is then purified by distillation to obtain the target product with a purity greater than 99.5%. The total yield of the four steps is 56%. However, this process requires distillation purification, which is cumbersome.

[0026]

[0027] Patent CN103351329A also uses 1-(3-methoxypropyl)-4-piperidinone as the starting material, and obtains the target product by using sodium triacetoxyborohydride as a reducing agent under the conditions of ammonia in methanol solution or ammonium formate salt.

[0028]

[0029] Patent CN103848777A (WO2015139332) also uses 1-(3-methoxypropyl)-4-piperidinone as the starting material, reacts with substituted or unsubstituted benzylamine in the presence of a reducing agent to generate N-(3-methoxypropyl)-4-benzylaminopiperidine, and finally reduces it with palladium on carbon to obtain the target product.

[0030]

[0031] Furthermore, patent CN103804281A uses 1-(3-methoxypropyl)-4-piperidinone as the starting material. The carbonyl group is first reduced with NaBH4 to obtain 1-(3-methoxypropyl)-4-piperidinol, then esterified with p-toluenesulfonyl chloride to obtain 1-(3-methoxypropyl)-4-p-methylbenzenesulfonate piperidine, and finally reacted with phthalimide and then hydrazolyzed under alkaline conditions to obtain the target product. However, this process uses NaBH4 to reduce the carbonyl group, which has low safety during industrial scale-up. At the same time, the use of genotoxic substances to activate the hydroxyl group of toluenesulfonyl chloride greatly prolongs the synthesis steps and makes the operation more complicated.

[0032]

[0033] Given the many shortcomings in the current preparation of 1-(3-methoxypropyl)-4-piperidineamine, it remains a problem to be solved to find a simple, mild, safe and convenient preparation process that yields high-purity products suitable for industrial production of 1-(3-methoxypropyl)-4-piperidineamine. Summary of the Invention

[0034] To address the numerous problems existing in the current preparation of 1-(3-methoxypropyl)-4-piperidinamine, a related intermediate of prucalopride, 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 yield.

[0035] The specific technical solution of the present invention is as follows:

[0036] A method for preparing 1-(3-methoxypropyl)-4-piperidinamine, a prucalopride-related intermediate as shown in formula (I):

[0037]

[0038] In a preferred embodiment, R in SM-2 and I-1 is either SES or Tosyl, with SES being particularly preferred; the structural formula of the SM-2 related compound is shown below:

[0039]

[0040] A method for preparing 1-(3-methoxypropyl)-4-piperidinamine, a prucalopride-related intermediate as shown in Formula (I), specifically includes the following steps:

[0041] Step A: Under inert gas protection and light-proof conditions, dry SM-1, SM-2, and reducing phosphine reagents are added to anhydrous dry solvent. After all materials are dissolved, oxidizing azo reagent is added dropwise under controlled temperature. After the addition is complete, the temperature is controlled until the reaction is finished. The mixture is filtered, purified water is added to the filtrate, and the extractant is extracted. The mixture is washed with purified water, the organic phase is dried, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain intermediate I-1.

[0042] The reaction route is as follows:

[0043]

[0044] Where R is either SES or Tosyl.

[0045] In a preferred embodiment, the reducing phosphine reagent in step A is one or a combination of tri-n-butylphosphine (TBP), triphenylphosphine (TPP), 1,2-bis(diphenylphosphine ethane) (DPPE), diphenyl-(2-pyridyl)phosphine, 4-(dimethylamino)triphenylphosphine, and tris[4-(dimethylamino)phenyl]phosphine, with triphenylphosphine being particularly preferred.

[0046]

[0047] In a preferred embodiment, the solvent in step A is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, with N,N-dimethylformamide being particularly preferred.

[0048] In a preferred embodiment, the oxidizing azo reagent mentioned in step A is one or a combination of diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD), di-tert-butyl azodicarbonate (DBAD), di-p-chlorobenzyl azodicarbonate (DCAD), 1,1'-(azodicarbonyl)piperidine (ADDP), N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), N,N,N',N'-tetramethylazodicarboxamide (TMAD), and 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazaoctane-3,8-dione (DHTD), with diethyl azodicarbonate (DEAD) being particularly preferred.

[0049]

[0050] In a preferred embodiment, the molar ratio of SM-1 to SM-2, the reducing phosphine reagent, and the oxidizing azo reagent in step A is 1:1.1-1.6:1.4-2.8:1.4-2.8, with a particularly preferred ratio of 1:1.3:2.0:2.0.

[0051] In a preferred embodiment, the temperature at which the oxidizing azo reagent is added dropwise in step A is -10 to 10°C, particularly preferably 0 to 5°C; and the reaction temperature is 15 to 30°C, particularly preferably 20 to 30°C.

[0052] In the preferred embodiment, the extractant in step A is one of dichloromethane, chloroform, or ethyl acetate.

[0053] In this invention, the inert gas mentioned in step A is usually selected from nitrogen or argon, with argon being particularly preferred.

[0054] In this invention, the dried reagent mentioned in step A refers to anhydrous or water-containing reagents that do not affect the reaction, obtained by means of molecular sieve dehydration or distillation.

[0055] Step B: At room temperature, add compound I-1 and hydrochloric acid to the reaction solvent, control the temperature until the reaction is complete, adjust the pH of the reaction solution to 13-14 with sodium hydroxide or potassium hydroxide, add the extractant, wash with purified water, dry the organic phase, filter, and concentrate the filtrate under reduced pressure to dryness to obtain I;

[0056] The reaction route is as follows:

[0057]

[0058] Where R is either SES or Tosyl.

[0059] In a preferred embodiment, the concentration of hydrochloric acid in step B is 4–12 mol / L, with 6 mol / L being particularly preferred.

[0060] In a preferred embodiment, the molar ratio of compound I-1 to hydrochloric acid in step B is 1:6 to 18, with a particularly preferred ratio of 1:9.

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

[0062] In a preferred embodiment, the reaction temperature mentioned in step B is the reflux temperature of the solvent used.

[0063] In the preferred embodiment, the extractant in step B is one of dichloromethane, chloroform, or ethyl acetate.

[0064] The beneficial effects of this invention are:

[0065] 1. This invention provides a simple and efficient method for preparing prucalopride-related intermediate 1-(3-methoxypropyl)-4-piperidinamine. SM-1 and SM-2 react, and finally acid hydrolysis is performed to obtain the target product. The entire synthesis method is simple to operate and suitable for industrial production.

[0066] 2. It can effectively avoid the dangerous operation of existing catalytic hydrogenation technology and the use of reducing reagents, making operation safe.

[0067] 3. This process avoids the introduction of Ts-protecting groups by changing the reaction conditions, shortening the reaction steps and reducing production time.

[0068] 4. The target product obtained by this process has a high yield and purity. Detailed Implementation

[0069] 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.

[0070] This invention uses GC to determine the purity of 1-(3-methoxypropyl)-4-piperidinamine. The chromatographic conditions are as follows:

[0071] Fixative: 14% cyanopropylphenyl-36% dimethyl polysiloxane or similar polarity (DB-1701, 30m × 0.53mm, 1.5μm);

[0072] Inlet temperature: 210℃;

[0073] Detection temperature: 250℃;

[0074] Flow rate: 4.0 ml / min;

[0075] Flow split ratio: 15:1;

[0076] 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.

[0077] The retention time of 1-(3-methoxypropyl)-4-piperidineamine is approximately 14.3 min.

[0078] The structural confirmation data of compound I-1-1 obtained in this invention are as follows:

[0079]

[0080] 1 H NMR (600MHz, DMSO-d6) δ: 5.04~5.08(m,1H),3.47(t,J=7.4Hz,2H),3.37~3.42(m,5H),2.82~2.86(m,2H),2.60(t,J=7.6Hz,2H) ,2.43~2.48(m,2H),2.30~2.34(m,2H),1.82~1.86(m,2H),1.62~1.66(m,2H),1.49(s,9H),1.19(t,J=7.4Hz,2H),0.18(s,9H); 13 C NMR (151MHz, DMSO-d6) δ: 150.63, 81.94, 70.47, 58.89, 52.83, 51.76, 50.23, 46.68, 30.27, 28.36, 27.84, 8.54, -2.55.

[0081] The structural confirmation data of compound I-1-2 obtained in this invention are as follows:

[0082]

[0083] 1 H NMR (600MHz, DMSO-d6) δ: 7.68 (d, J=7.8Hz, 2H), 7.35 (d, J=7.8Hz, 2H), 3.40 (s, 3H), 3.32 (t, J=7.4Hz, 2H), 2.90~2.96 (m, 1H), 2.71~2.77(m,4H),2.50(s,3H),2.43(t,J=7.4Hz,2H),2.25~2.30(m,2H),1.65~1.71(m,2H),1.52~1.60(m,2H),1.46(s,9H); 13C NMR (151MHz, DMSO-d6) δ: 151.68, 141.74, 138.46, 120.76, 128.10, 81.23, 70.30, 56.93, 52.46, 50.25, 48.01, 31.35, 28.78, 27.47, 21.15.

[0084] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0085] Synthesis of I-1:

[0086]

[0087] Example 1

[0088] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (73.17 g, 0.26 mol), and triphenylphosphine (TPP, 104.92 g, 0.40 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, diethyl azodicarbonate (DEAD, 73.15 g, 0.42 mol) was added dropwise at 0–5 °C. After the addition was complete, the reaction was carried out at 20–30 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 94.3% and a GC purity of 98.7%.

[0089] Example 2

[0090] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (61.91 g, 0.22 mol), and triphenylphosphine (TPP, 104.92 g, 0.40 mol) were added to anhydrous N,N-dimethylacetamide (600 ml). After all the materials were dissolved, diisopropyl azodicarbonate (DIAD, 80.88 g, 0.40 mol) was added dropwise at 5–10 °C. After the addition was complete, the reaction was carried out at 25–30 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 92.4% and a GC purity of 98.7%.

[0091] Example 3

[0092] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (59.10 g, 0.21 mol), and tri-n-butylphosphine (TBP, 80.93 g, 0.40 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, di-tert-butyl azodicarbonate (DBAD, 92.11 g, 0.40 mol) was added dropwise at 5–10 °C. After the addition was complete, the reaction was carried out at 25–30 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 91.8% and a GC purity of 98.1%.

[0093] Example 4

[0094] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (90.06 g, 0.32 mol), and 1,2-bis(diphenylphosphine)ethane (DPPE, 159.25 g, 0.40 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, di-p-chlorobenzyl azodicarbonate (DCAD, 146.41 g, 0.40 mol) was added dropwise at 0–5 °C. After the addition was complete, the reaction was carried out at 15–20 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 89.3% and a GC purity of 97.6%.

[0095] Example 5

[0096] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (95.69 g, 0.34 mol), and diphenyl-(2-pyridyl)phosphine (105.31 g, 0.40 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, 1,1'-(azodicarbonyl)piperidine (ADDP, 100.93 g, 0.40 mol) was added dropwise at 0–5 °C. After the addition was complete, the reaction was carried out at 15–20 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 90.1% and a GC purity of 98.4%.

[0097] Example 6

[0098] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (73.17 g, 0.26 mol), and triphenylphosphine (68.20 g, 0.26 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, N,N,N',N'-tetramethylazodicarboxamide (TMAD, 44.77 g, 0.26 mol) was added dropwise at 5–10 °C. After the addition was complete, the reaction was carried out at 25–30 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 88.5% and a GC purity of 97.3%.

[0099] Example 7

[0100] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-1 (73.17 g, 0.26 mol), and tris[4-(dimethylamino)phenyl]phosphine (219.24 g, 0.56 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, diethyl azodicarbonate (DEAD, 97.53 g, 0.56 mol) was added dropwise at -5 to 0 °C. After the addition was complete, the reaction was carried out at 15 to 20 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-1, with a yield of 88.9% and a GC purity of 97.5%.

[0101] Example 8

[0102] Under argon protection and in the dark, dry SM-1 (34.65 g, 0.2 mol), SM-2-1 (73.17 g, 0.26 mol), and triphenylphosphine (152.13 g, 0.58 mol) were added to anhydrous N,N-dimethylformamide (600 ml). After all the materials were dissolved, 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazaoctyl was added at a controlled temperature of -10 to -5 °C. Because 3,8-dione (DHTD, 98.70 g, 0.58 mol) was added dropwise, the reaction was carried out at a controlled temperature of 15–20 °C. After the reaction was completed, the mixture was filtered, and the filtrate was added to purified water (1500 ml). Ethyl acetate (500 ml × 3) was used for extraction, followed by washing with purified water (400 ml × 2), drying with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to dryness to obtain intermediate I-1-1, with a yield of 91.3% and a GC purity of 97.3%.

[0103] Example 9

[0104]

[0105] Under argon protection and in the dark, dried SM-1 (34.65 g, 0.2 mol), SM-2-2 (70.55 g, 0.26 mol), and 4-(dimethylamino)phenylbisphenylphosphine (85.50 g, 0.28 mol) were added to anhydrous N-methylpyrrolidone (600 ml). After all the materials were dissolved, N,N,N',N'-tetraisopropylazodicarboxamide (TIPA, 79.63 g, 0.28 mol) was added dropwise at 5–10 °C. After the addition was complete, the reaction was carried out at 25–30 °C. After the reaction was detected to be complete, the mixture was filtered. The filtrate was added to purified water (1500 ml), extracted with dichloromethane (500 ml × 3), washed with purified water (400 ml × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I-1-2, with a yield of 92.4% and an HPLC purity of 97.5%.

[0106] Synthesis of I

[0107]

[0108] Example 10

[0109] At room temperature, compound I-1-1 (43.67 g, 0.10 mol) and hydrochloric acid (6 mol / L, 150 ml) were added to methanol (300 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 13-14 with sodium hydroxide or potassium hydroxide. The solution was extracted with dichloromethane (150 ml × 3), 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 I. The yield was 95.6%, and the GC purity was 99.5%.

[0110] Example 11

[0111] At room temperature, compound I-1-1 (43.67 g, 0.10 mol) and hydrochloric acid (4 mol / L, 150 ml) were added to ethanol (300 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 13-14 with sodium hydroxide or potassium hydroxide. The solution was extracted with dichloromethane (150 ml × 3), 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 I. The yield was 93.2%, and the GC purity was 99.3%.

[0112] Example 12

[0113] At room temperature, compound I-1-1 (43.67 g, 0.10 mol) and hydrochloric acid (12 mol / L, 42 ml) were added to 1,4-dioxane (300 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 13-14 with sodium hydroxide or potassium hydroxide. The solution was extracted with dichloromethane (150 ml × 3), 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 I. The yield was 89.1%, and the GC purity was 98.3%.

[0114] Example 13

[0115] At room temperature, compound I-1-1 (43.67 g, 0.10 mol) and hydrochloric acid (6 mol / L, 300 ml) were added to isopropanol (300 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 13-14 with sodium hydroxide or potassium hydroxide. The solution was extracted with dichloromethane (150 ml × 3), 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 I. The yield was 92.1%, and the GC purity was 99.4%.

[0116] Example 14

[0117]

[0118] At room temperature, compound I-1-2 (42.66 g, 0.10 mol) and hydrochloric acid (6 mol / L, 316 ml) were added to methanol (300 ml). The mixture was refluxed under controlled temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 13-14 with sodium hydroxide or potassium hydroxide. The solution was extracted with ethyl acetate (150 ml × 3), 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 I. The yield was 94.5%, and the GC purity was 99.3%.

Claims

1. A method for preparing a prucalopride intermediate, characterized in that, Specifically, the following steps are included: Step A: Under inert gas protection and light-proof conditions, dry SM-1, SM-2, and reducing phosphine reagents are added to anhydrous solvent. After all materials are dissolved, oxidizing azo reagent is added dropwise under controlled temperature. After the addition is complete, the temperature is controlled until the reaction is finished. The mixture is filtered, purified water is added to the filtrate, and the extractant is used for extraction. The mixture is washed with purified water, the organic phase is dried, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain intermediate I-1. The reaction route is as follows: ； Step B: At room temperature, add compound I-1 and hydrochloric acid to the reaction solvent, control the temperature until the reaction is complete, adjust the pH of the reaction solution to 13-14 with sodium hydroxide or potassium hydroxide, add the extractant to extract, wash with purified water, dry the organic phase, filter, and concentrate the filtrate to dryness under reduced pressure to obtain I; The reaction route is as follows: ； In the substrate SM-2 and intermediate I-1, R is either SES or Tosyl. The reducing phosphine reagent mentioned in step A is one or a combination of tri-n-butylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane, diphenyl-(2-pyridyl)phosphine, 4-(dimethylamino)triphenylphosphine, and tris[4-(dimethylamino)phenyl]phosphine; The oxidizing azo reagent mentioned in step A is diethyl azodicarbonate, diisopropyl azodicarbonate, di-tert-butyl azodicarbonate, di-p-chlorobenzyl azodicarbonate, 1,1'-(azodicarbonyl)piperidine, N , N , N ', N '-Tetraisopropylazodicarboxamide, N , N , N ', N One or a combination of '-tetramethylazodicarboxamide, 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazaoctane-3,8-dione; The temperature at which the oxidizing azo reagent is added dropwise in step A is -10 to 10°C; the reaction temperature is 15 to 30°C.

2. The preparation method according to claim 1, characterized in that, The solvent mentioned in step A is N , N -Dimethylformamide, N , N -Dimethylacetamide, N One or a combination of methylpyrrolidones.

3. The preparation method according to claim 1, characterized in that, The molar ratio of SM-1 to SM-2, reducing phosphine reagent, and oxidizing azo reagent in step A is 1:1.1-1.6:1.4-2.8:1.4-2.

8.

4. The preparation method according to claim 1, characterized in that, The concentration of hydrochloric acid in step B is 4–12 mol / L; the molar ratio of compound I-1 to hydrochloric acid in step B is 1:6–18.

5. The preparation method according to claim 1, characterized in that, The extractant in steps A and B is one of dichloromethane, chloroform, and ethyl acetate; the reaction solvent in step B is one or a combination of methanol, ethanol, isopropanol, and 1,4-dioxane; and the reaction temperature in step B is the reflux temperature of the solvent used.

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