CN114539134A - Synthetic method of prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine - Google Patents

Synthetic method of prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine Download PDF

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CN114539134A
CN114539134A CN202011334979.8A CN202011334979A CN114539134A CN 114539134 A CN114539134 A CN 114539134A CN 202011334979 A CN202011334979 A CN 202011334979A CN 114539134 A CN114539134 A CN 114539134A
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张乃华
朱安国
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Lunan Pharmaceutical Group Corp
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    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine. The method takes cheap and easily-obtained 4-hydroxypiperidine as a reaction raw material, and reacts with urotropine after chlorination to construct amino to prepare the compound 1- (3-methoxypropyl) -4-piperidinamine.

Description

Synthetic method of prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine.
Background
Praparipril Succinate with chemical name of 4-amino-5-chloro-2, 3-dihydro-N- [1- (3-methoxypropyl) -4-piperidinyl]-7-benzofuran carboxamide succinate, a new generation of highly selective, high affinity 5-hydroxytryptamine 4 (5-HT) developed by Movetis, Belgium4) Receptor agonists, which restore impaired intestinal motility through direct action on the intestinal wall. The European Union of 10 months in 2009 approved for treating chronic constipation, 1 month in 2010 on Germany, 3 months in the same year on British and 10 months in 2012 on FDA approval, clinical studies show that the drug has constant and safe curative effect on patients with severe chronic constipation. The chemical structural formula is as follows:
Figure BDA0002796741610000011
currently, many methods are disclosed for preparing prucalopride, such as the synthesis of patents CN1164233A (CN1071332C), CN103664912B and prucalopride, pharmaceutical and clinical research, 2011, Aug; 19(4) 306-307, and the like, by amidation reaction of 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid as a starting material or a key intermediate with 1- (3-methoxypropyl) -4-piperidinamine.
Figure BDA0002796741610000012
In the patent CN108976216A, 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-formaldehyde is prepared through multi-step reaction, and then is coupled with 1- (3-methoxy propyl) -4-piperidine amine through oxidative dehydrogenation to prepare a target product.
Figure BDA0002796741610000013
Similarly, patent CN109232544A prepares (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-yl) methanol through multi-step reaction, and then the methanol and 1- (3-methoxy propyl) -4-piperidine amine are coupled through oxidative dehydrogenation to prepare the target product.
Figure BDA0002796741610000021
From the above, 1- (3-methoxypropyl) -4-piperidinamine is used as a key intermediate for preparing prucalopride in various synthetic strategies, so that 1- (3-methoxypropyl) -4-piperidinamine directly affects the production, market supply and quality problems of the medicine. The specific structural formula is as follows:
Figure BDA0002796741610000022
the current synthesis method of 1- (3-methoxypropyl) -4-piperidinamine mainly comprises the following steps according to the difference of amino construction:
the construction is carried out by substituting aminopiperidine.
In patent CN102295594B, N-protected aminopiperidine is used as a starting material, and after the N-protected aminopiperidine reacts with 1-substituted-3-methoxypropane under alkaline conditions, deprotection conditions of carbobenzoxy (Cbz) are generally hydrogenolysis or acidolysis (HBt or TMSI); acetyl and propionyl are usually removed by alkaline hydrolysis or acid hydrolysis ] to obtain the target product. However, the method has high price of the starting raw materials and basically has no market competitiveness.
Figure BDA0002796741610000023
② N-substituted-4-piperidone compounds are used as starting materials, and the compound is constructed by a reductive amination strategy.
Patent CN102898356B uses 4-piperidone hydrochloride monohydrate as starting material, and reacts with 1-substituted-3-methoxypropane under alkaline condition to prepare 1- (3-methoxypropyl) -4-piperidone, and then reacts in organic solution of ammonia gas under the action of hydrogen and catalyst (Raney Ni and/or Pd/C) to prepare the target product. The reaction time of the first step reaction of the route is longer (>15 hours), the second step reaction adopts high-pressure hydrogenation, the conditions are difficult to control, and a high-cost heavy metal catalyst palladium-carbon or inflammable highly-toxic Raney Ni is needed, so that the risk of heavy metal residue is brought to the bulk drug prucalopride.
Figure BDA0002796741610000024
CN103193699B patent uses 4-piperidone as starting material, at K2CO3The reaction with 1-bromo-3-methoxypropane under the alkaline condition to prepare 1- (3-methoxypropyl) -4-piperidone, and then the reflux reaction is carried out for 8 hours at 110 ℃ in a formic acid/ammonium formate system to prepare the target product. The process has long high-temperature reaction time and high energy consumption, and simultaneously, because the polarity of a target product is very high, the reaction of the last step of the method is incomplete, an intermediate and a byproduct are difficult to remove, and the purification difficulty is high.
Figure BDA0002796741610000031
Another literature, Tetrahedron Lett,2001,42(25):4257-4259 directly reduces carbonyl to amino group using Pd/C as catalyst and ammonium formate as nitrogen and hydrogen source. The synthesis of prucalopride succinate, China journal of medical industry, 2012,43(1):5-8, directly converts carbonyl into amino by catalytic hydrogenation of 10% Pd/C with methanol solution of saturated ammonia gas as solvent to obtain the target product.
The patent CN103508939A uses the key intermediate 1- (3-methoxy propyl) -4-piperidone in the above process as a starting material, and the starting material and hydroxylamine hydrochloride are heated, refluxed and dehydrated to prepare the key intermediate 1- (3-methoxy propyl) -4-piperidine oxime, and then the target product is prepared by catalytic (Raney Ni) hydrogenation. The process has expensive starting materials, uses Raney Ni catalyst with strong toxicity, and is not suitable for industrial production.
Figure BDA0002796741610000032
In addition, Chinese patent CN1143858(US6479487) also adopts the above strategy to prepare the key intermediate 1- (3-methoxypropyl) -4-piperidine oxime, and then adopts lithium aluminum hydride to reduce to obtain the corresponding product. The lithium aluminum hydride needs strict oxygen-free and water-free environment during experimental operation, the post-treatment is complex, and the filtering is not easy, so the method has larger industrialization difficulty.
In patent CN103351329A, 1- (3-methoxypropyl) -4-piperidone is also used as a starting material, and the target product is prepared by using sodium triacetoxyborohydride as a reducing agent under the condition of a methanol solution of ammonia or ammonium formate.
Figure BDA0002796741610000033
Patent CN103804281A also uses 1- (3-methoxy propyl) -4-piperidone as starting material, the carbonyl is firstly processed by NaBH4Reducing to obtain 1- (3-methoxy propyl) -4-piperidinol, esterifying with p-toluenesulfonyl chloride to obtain 1- (3-methoxy propyl) -4-p-methyl benzene sulfonic acid ester piperidine, and reacting with phthalimide to obtain alkaline solutionAnd performing hydrazinolysis under the condition to obtain a target product. However, the process applies genotoxic substances to activate hydroxyl on tosyl chloride, and simultaneously adopts Gabriel reaction to prepare primary amine, so that the atom economy is poor, the polarity of phthalhydrazide generated by a hydrazinolysis method is large, the post-treatment is difficult, and in addition, the operation safety is poor by applying hypertoxic substances hydrazine hydrate.
Figure BDA0002796741610000034
Patent CN103848777A (WO2015139332) also uses 1- (3-methoxypropyl) -4-piperidone as starting material, and reacts with substituted or unsubstituted benzylamine under the action of reducing agent to produce N- (3-methoxypropyl) -4-benzylaminopiperidine, and finally the target product is obtained by catalytic reduction with palladium on carbon.
Figure BDA0002796741610000041
And thirdly, constructing by using 4-formamide piperidine as a starting material or a key intermediate through Hofmann rearrangement reaction.
CN1143858(US6479487) uses 4-formamide piperidine as raw material, and after alkylation reaction with 1-methoxy-3-bromopropane, the 4-formamide piperidine is reacted with high valence iodine compound bis (trifluoroacetyloxy) iodobenzene [ PhI (O)2CCF3)2]Under the action, a target product is generated through Hofmann rearrangement. In the process, the raw materials and the high-valence iodine compounds are high in price, and the problems of stability and safety of the high-valence iodine compounds always restrict the large-scale application of the high-valence iodine compounds in industrial production.
Figure BDA0002796741610000042
The patent CN106146386A and the literature of the synthesis of prucalopride succinate, the journal of the Chinese medical industry 2015,46(11):1158-1160 takes 4-piperidinecarboxylic acid which is cheap and easy to obtain as a raw material, and esterifies the raw material in thionyl chloride-methanol to obtain 4-piperidinecarboxylic acid methyl ester hydrochloride; then carrying out alkylation reaction on the obtained product and 1-methoxy-3-bromopropane to obtain 1- (3-methoxypropyl) piperidine-4-methyl formate; then carrying out ammonolysis in ammonia water to obtain 1- (3-methoxypropyl) piperidine-4-formamide; finally, carrying out Hofmann rearrangement with dibromohydantoin under an alkaline condition to obtain a crude product, and then rectifying to obtain a target product with the purity of more than 99.5%. However, the total yield of the process is only 56%, and the process needs rectification and purification and is complex to operate.
Figure BDA0002796741610000043
In conclusion, the current process for preparing 1- (3-methoxypropyl) -4-piperidinamine mainly has the following problems:
1. the price of the adopted starting materials and various reagents is higher, so that the production cost is increased, and the problem of market competitiveness is basically solved.
2. The target product is prepared by catalytic hydrogenation, the related high-pressure reaction condition is difficult to control, a high-cost heavy metal catalyst palladium carbon or a flammable high-toxicity catalyst Raney Ni is needed, and the risk of heavy metal residue is brought to the bulk drug prucalopride.
3. High temperature and long time reaction are needed, which causes high energy consumption.
4. The reaction needs no water and oxygen or the target product needs rectification and purification, so that the operation is complicated.
5. The reaction needs p-toluenesulfonyl chloride to activate hydroxyl, and Gabriel reaction is adopted to prepare primary amino, so that the atom economy is poor.
6. Hydrazine hydrate and catalytic hydrogenation or hydride are adopted for reduction, so that the operation safety is low.
In view of the defects existing in the prior preparation of the 1- (3-methoxypropyl) -4-piperidinamine, the research and search for a preparation process which is simple and safe to operate, mild in reaction conditions, high in product yield and high in purity and is suitable for industrial production of the 1- (3-methoxypropyl) -4-piperidinamine still needs to solve at present.
Disclosure of Invention
Aiming at the problems existing in the synthesis of the prucalopride related intermediate 1- (3-methoxypropyl) -4-piperidylamine at present, the invention provides a novel synthesis method of 1- (3-methoxypropyl) -4-piperidylamine. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The invention is realized by the following technical scheme:
a synthetic method of a prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine is characterized in that 4-hydroxypiperidine is used as a reaction raw material to perform substitution reaction with 3-substituted propyl methyl ether to obtain an intermediate I-1, and then the intermediate I-1 and SOCl are subjected to substitution reaction2The intermediate I-2 is prepared by chlorination reaction under the action of alkali, the intermediate I-2 reacts with urotropine under the action of a catalyst to prepare the compound 1- (3-methoxy propyl) -4-piperidine amine, and the reaction formula is as follows:
Figure BDA0002796741610000051
wherein 3-substituted propyl methyl ether
Figure BDA0002796741610000052
Wherein X is selected from one of Cl, Br, I, MsO and TsO, and Br is preferred.
A method for synthesizing prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine as shown in formula I comprises the following steps:
step 1, adding 4-hydroxypiperidine, 3-substituted propyl methyl ether and alkali into an organic solvent A, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain an intermediate I-1;
step 2, dissolving the intermediate I-1 in an anhydrous organic solvent B, stirring, and reacting benzotriazole and SOCl2Diluting the mixture to 1.5M by using an anhydrous organic solvent B, adding the diluted mixture into a reaction solution, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain an intermediate I-2;
and 3, adding the intermediate I-2, urotropine and a catalyst into the organic solvent C, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the compound I.
Preferably, the base in step 1 is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, piperidine or a combination thereof, preferably potassium carbonate.
Preferably, the organic solvent A in the step 1 is selected from one of acetonitrile, butanone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide or a combination thereof, and is preferably acetonitrile.
Preferably, the feeding molar ratio of the 4-hydroxypiperidine to the 3-substituted propyl methyl ether in the step 1 is 1:1.1 to 1.5, preferably 1: 1.3.
Preferably, the feeding molar ratio of the 4-hydroxypiperidine to the base in the step 1 is 1: 1.2-2.0, preferably 1: 1.6.
Preferably, the reaction temperature in the step 1 is 60-90 ℃, preferably 75-80 ℃.
In a preferred embodiment, the post-treatment step described in step 1 is as follows: and after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to dryness, adding dichloromethane, washing for 1-2 times by using 0.5-2M dilute hydrochloric acid, collecting an organic layer, drying, and concentrating under reduced pressure to obtain an intermediate I-1.
Preferably, the benzotriazole and SOCl described in step 22The feeding molar ratio of (A) to (B) is 1:1.
Preferably, I-1 and SOCl are as described in step 22The feeding molar ratio of (3) is 1: 1.1-1.5, preferably 1: 1.2.
Preferably, the organic solvent B in the step 2 is selected from one or a combination of dichloromethane and chloroform, preferably dichloromethane.
Preferably, the reaction temperature in the step 2 is 10-30 ℃, preferably 20-25 ℃.
In a preferred embodiment, the post-treatment step in step 2 is as follows: and after the reaction is finished, filtering, washing the filtrate by using a saturated sodium bicarbonate solution, washing the filtrate by using purified water, drying, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain an intermediate I-2.
Preferably, the organic solvent C in step 3 is selected from one or a combination of methanol, ethanol, isopropanol, n-butanol and tert-butanol, preferably ethanol.
Preferably, the catalyst in step 3 is selected from one or a combination of sodium iodide and potassium iodide, preferably potassium iodide.
Preferably, the feeding molar ratio of the intermediate I-2 in the step 3 to the urotropine is 1: 1.05-1.5, preferably 1: 1.2.
Preferably, the feeding molar ratio of the intermediate I-2 to the catalyst in the step 3 is 1: 0.05-0.1, preferably 1: 0.08.
Preferably, the reaction temperature in the step 3 is 30-60 ℃, preferably 45-50 ℃.
In a preferred embodiment, the post-treatment step in step 3 is as follows: after the reaction is finished, cooling the reaction liquid to room temperature, dropwise adding concentrated hydrochloric acid until the pH value is 1-2, stirring until a large amount of solid is precipitated, filtering, washing a filter cake with a small amount of organic solvent C, and drying to obtain a target product I, namely hydrochloride; stirring the mixture for 1 to 2 hours at room temperature under the action of alkali by using methanol or ethanol as a solvent, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain a target product I; preferably, the base is selected from one or a combination of potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate; preferably, the charging amount of the alkali is 1.5-3 times of the molar amount of the intermediate I-2.
The invention has the beneficial effects that:
the invention provides a simple, convenient and efficient method for synthesizing prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine. The method takes cheap and easily-obtained 4-hydroxypiperidine as a starting raw material, and the chloro-substituted 4-hydroxypiperidine reacts with urotropine to directly construct amino to prepare the compound I. Compared with the prior art, the method can effectively avoid the catalytic hydrogenation technology with dangerous operation, has safe operation and high atom utilization rate, and reduces the production cost. The whole synthesis process is simple and convenient to operate, mild in condition, environment-friendly and suitable for industrial production, and the target product prepared by the process has high yield and purity.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Synthesis of I-1:
example 1
Adding 4-hydroxypiperidine (40.46g, 0.40mol), 3-bromopropylmethyl ether (X ═ Br, 79.57g, 0.52mol) and potassium carbonate (88.45g, 0.64mol) into acetonitrile (400ml), controlling the temperature to be 75-80 ℃ for reaction, after the detection reaction is finished, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, adding dichloromethane (500ml), washing 1-2 times with 1M diluted hydrochloric acid (150ml), drying the organic layer, and concentrating under reduced pressure to obtain an intermediate I-1, wherein the yield is 96.4% and the purity is 99.3%.
Example 2
Adding 4-hydroxypiperidine (40.45g, 0.40mol), 3-iodopropyl methyl ether (X ═ I, 88.01g, 0.44mol) and triethylamine (64.76g, 0.64mol) into N, N-dimethylformamide (400ml), controlling the temperature to be 80-85 ℃ for reaction, filtering after detection reaction is finished, concentrating the filtrate under reduced pressure to dryness, adding dichloromethane (500ml), washing 1-2 times with 2M diluted hydrochloric acid (150ml), drying the organic layer, and concentrating under reduced pressure to obtain an intermediate I-1, wherein the yield is 93.7% and the purity is 99.4%.
Example 3
Adding 4-hydroxypiperidine (40.43g, 0.40mol), 3-chloropropylmethyl ether (X ═ Cl, 64.82g, 0.60mol) and sodium bicarbonate (53.76g, 0.64mol) into butanone (400ml), controlling the temperature to 75-80 ℃ for reaction, after the detection reaction is finished, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, adding dichloromethane (500ml), washing 1-2 times with 0.5M dilute hydrochloric acid (150ml), drying the organic layer, and concentrating under reduced pressure to obtain an intermediate I-1, wherein the yield is 95.9%, and the purity is 98.1%.
Example 4
Adding 4-hydroxypiperidine (40.46g, 0.40mol), methanesulfonic acid 3-methoxypropyl ester (X MsO, 87.47g, 0.52mol) and potassium bicarbonate (48.05g, 0.48mol) into dimethyl sulfoxide (400ml), controlling the temperature to be 85-90 ℃ for reaction, after the reaction is detected to be finished, filtering, concentrating the filtrate under reduced pressure to be dry, adding dichloromethane (500ml), washing 1-2 times by using 1M diluted hydrochloric acid (150ml), drying the organic layer, and concentrating under reduced pressure to obtain an intermediate I-1, wherein the yield is 94.0%, and the purity is 99.2%.
Example 5
Adding 4-hydroxypiperidine (40.45g, 0.40mol), 3-methoxypropyl p-toluenesulfonate (X ═ TsO, 127.04g, 0.52mol) and sodium carbonate (84.79g, 0.80mol) into acetonitrile (400ml), controlling the temperature to 70-75 ℃ for reaction, after the detection reaction is finished, filtering, concentrating the filtrate under reduced pressure to dryness, adding dichloromethane (500ml), washing 1-2 times with 1M dilute hydrochloric acid (150ml), drying the organic layer, and concentrating under reduced pressure to obtain an intermediate I-1, wherein the yield is 94.3%, and the purity is 98.5%.
I synthesis:
example 6
Intermediate I-1(51.98g, 0.30mol) was dissolved in anhydrous dichloromethane (200ml) and stirred, benzotriazole (42.89g, 0.36mol) was reacted with SOCl2Diluting the mixture (42.83g, 0.36mol) to 1.5M by using anhydrous dichloromethane, adding the diluted mixture into the reaction solution, controlling the temperature to be 20-25 ℃ for reaction, filtering after detection reaction, washing the filtrate by using a saturated sodium bicarbonate solution (150ml multiplied by 2), washing by using purified water (150ml multiplied by 2), drying, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain an intermediate I-2 which is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (50.47g, 0.36mol) and potassium iodide (3.99g, 0.024mol) into ethanol (250ml), controlling the temperature to 45-50 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in ethanol (200ml), adding potassium carbonate (82.92g, 0.60mol), stirring at room temperature for 1.5 h, filtering, concentrating the filtrate under reduced pressure to dryness to obtain compound I, with the total yield of the two steps 95.2% and the purity 99.6%.
Example 7
Intermediate I-1(51.96g, 0.30mol) was dissolved in anhydrous chloroform (200ml) and stirred, benzotriazole (39.31g, 0.33mol) was reacted with SOCl2(39.26g, 0.33mol) of the mixture was diluted to 1.5M with anhydrous dichloromethane, added to the reaction mixture,controlling the temperature to be 25-30 ℃ for reaction, after the reaction is detected, filtering, washing filtrate with saturated sodium bicarbonate solution (150ml multiplied by 2), washing with purified water (150ml multiplied by 2), drying, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain an intermediate I-2 which is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (41.39g, 0.31mol) and potassium iodide (3.97g, 0.024mol) into methanol (250ml), controlling the temperature to 40-45 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in ethanol (200ml), adding potassium carbonate (82.94g, 0.60mol), stirring at room temperature for 1.5 h, filtering, concentrating the filtrate under reduced pressure to dryness to obtain compound I, the total yield of the two steps is 93.2%, and the purity is 99.3%.
Example 8
Intermediate I-1(51.95g, 0.30mol) was dissolved in anhydrous dichloromethane (200ml) and stirred, benzotriazole (53.60g, 0.45mol) was reacted with SOCl2Diluting the mixture (53.53g, 0.45mol) to 1.5M with anhydrous dichloromethane, adding the diluted mixture into the reaction solution, controlling the temperature to be 15-20 ℃ for reaction, after the detection reaction is finished, filtering, washing filtrate with saturated sodium bicarbonate solution (150ml multiplied by 2), washing with purified water (150ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain an intermediate I-2 which is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (63.09g, 0.45mol) and sodium iodide (3.60g, 0.024mol) into isopropanol (250ml), controlling the temperature to 50-55 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving the compound I in ethanol (200ml), adding sodium carbonate (63.60g, 0.60mol), stirring at room temperature for 1.5 hours, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain the compound I, wherein the total yield of the two steps is 94.5 percent, and the purity is 98.4 percent.
Example 9
Intermediate I-1(52.00g, 0.30mol) was dissolved inAnhydrous dichloromethane (200ml) was stirred and benzotriazole (42.89g, 0.36mol) was reacted with SOCl2(42.83g, 0.36mol) of the mixture is diluted to 1.5M by using anhydrous dichloromethane, added into the reaction solution, the temperature is controlled to 20-25 ℃ for reaction, after the detection reaction is finished, the reaction solution is filtered, the filtrate is washed by saturated sodium bicarbonate solution (150ml multiplied by 2), purified water (150ml multiplied by 2) is washed, the intermediate I-2 is obtained after drying, filtering and decompression concentration of the filtrate to dryness, and the intermediate I-2 is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (44.16g, 0.30mol) and potassium iodide (4.00g, 0.024mol) into ethanol (250ml), controlling the temperature to 45-50 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in methanol (200ml), adding potassium bicarbonate (60.05g, 0.60mol), stirring at room temperature for 1.5 h, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain compound I, wherein the total yield of the two steps is 92.4%, and the purity is 99.0%.
Example 10
Intermediate I-1(51.99g, 0.30mol) was dissolved in anhydrous dichloromethane (200ml) and stirred, benzotriazole (42.90g, 0.36mol) was reacted with SOCl2Diluting the mixture (42.85g, 0.36mol) to 1.5M with anhydrous dichloromethane, adding the diluted mixture into the reaction solution, controlling the temperature to be 20-25 ℃ for reaction, after the detection reaction is finished, filtering, washing the filtrate with saturated sodium bicarbonate solution (150ml multiplied by 2), washing with purified water (150ml multiplied by 2), drying, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain an intermediate I-2 which is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (75.70g, 0.54mol) and sodium iodide (3.60g, 0.016mol) into isopropanol (250ml), controlling the temperature to 50-55 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in methanol (200ml), adding sodium bicarbonate (50.40g, 0.60mol), stirring at room temperature for 2.0 h, filtering, concentrating the filtrate under reduced pressure to dryness to obtain compound I, the total yield of the two steps is 92.9%, and the purity is 98.5%.
Example 11
Intermediate I-1(51.95g, 0.30mol) was dissolved in anhydrous dichloromethane (200ml) and stirred, benzotriazole (42.86g, 0.36mol) was reacted with SOCl2Diluting the mixture (42.80g, 0.36mol) to 1.5M by using anhydrous dichloromethane, adding the diluted mixture into the reaction solution, controlling the temperature to be 20-25 ℃ for reaction, filtering after the detection reaction is finished, washing the filtrate by using a saturated sodium bicarbonate solution (150ml multiplied by 2), washing by using purified water (150ml multiplied by 2), drying, filtering, and concentrating the filtrate under reduced pressure to be dry to obtain an intermediate I-2 which is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (50.45g, 0.36mol) and potassium iodide (2.50g, 0.015mol) into n-butanol (250ml), controlling the temperature to 35-40 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in ethanol (200ml), adding potassium carbonate (82.90g, 0.60mol), stirring at room temperature for 1.5 h, filtering, concentrating the filtrate under reduced pressure to dryness to obtain compound I, the total yield of the two steps is 94.3%, and the purity is 99.2%.
Example 12
Intermediate I-1(51.98g, 0.30mol) was dissolved in anhydrous dichloromethane (200ml) and stirred, benzotriazole (42.89g, 0.36mol) was reacted with SOCl2(42.83g, 0.36mol) of the mixture is diluted to 1.5M by using anhydrous dichloromethane, added into the reaction solution, the temperature is controlled to 20-25 ℃ for reaction, after the detection reaction is finished, the reaction solution is filtered, the filtrate is washed by saturated sodium bicarbonate solution (150ml multiplied by 2), purified water (150ml multiplied by 2) is washed, the intermediate I-2 is obtained after drying, filtering and decompression concentration of the filtrate to dryness, and the intermediate I-2 is directly used for the next reaction.
Adding the obtained intermediate I-2(0.30mol), urotropine (50.47g, 0.36mol) and potassium iodide (4.98g, 0.030mol) into tert-butyl alcohol (250ml), controlling the temperature to 30-35 ℃ for reaction, cooling to room temperature after the reaction is detected, dropwise adding concentrated hydrochloric acid (12M) until the pH value is 1-2, stirring to separate out a large amount of solid, filtering, washing a filter cake with a small amount of ethanol, and drying to obtain the hydrochloride of the target product I. Dissolving it in ethanol (200ml), adding potassium carbonate (82.92g, 0.60mol), stirring at room temperature for 1.5 h, filtering, concentrating the filtrate under reduced pressure to dryness to obtain compound I, the total yield of the two steps is 94.7%, and the purity is 98.1%.

Claims (10)

1. A synthetic method of a prucalopride intermediate 1- (3-methoxypropyl) -4-piperidylamine is characterized in that 4-hydroxypiperidine is used as a reaction raw material to perform substitution reaction with 3-substituted propyl methyl ether to obtain an intermediate I-1, and then the intermediate I-1 is reacted with SOCl2The intermediate I-2 is prepared through chlorination reaction, the intermediate I-2 reacts with urotropine under the action of a catalyst to prepare the compound 1- (3-methoxy propyl) -4-piperidine amine, and the reaction formula is as follows:
Figure FDA0002796741600000011
wherein X in the 3-substituted propyl methyl ether is selected from one of Cl, Br, I, MsO and TsO.
2. The synthesis method according to claim 1, characterized by comprising the following steps:
step 1, adding 4-hydroxypiperidine, 3-substituted propyl methyl ether and alkali into an organic solvent A, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain an intermediate I-1;
step 2, dissolving the intermediate I-1 in an anhydrous organic solvent B, stirring, and mixing benzotriazole and SOCl2Diluting the mixture to 1.5M by using an anhydrous organic solvent B, adding the diluted mixture into a reaction solution, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain an intermediate I-2;
and 3, adding the intermediate I-2, urotropine and a catalyst into the organic solvent C, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the compound I.
3. The synthesis method according to claim 2, wherein the base in step 1 is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N-diisopropylethylamine, piperidine or their combination.
4. The synthesis method according to claim 2, wherein the organic solvent A in step 1 is selected from one of acetonitrile, butanone, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide, or a combination thereof.
5. The method of claim 2, wherein step 2 comprises reacting I-1 with SOCl2The feeding molar ratio of (A) to (B) is 1: 1.1-1.5.
6. The synthesis method according to claim 2, wherein the organic solvent B in step 2 is selected from one of dichloromethane, chloroform or their combination.
7. The synthesis method according to claim 2, wherein the organic solvent C in step 3 is selected from one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, or a combination thereof.
8. The synthesis method of claim 2, wherein the catalyst in step 3 is selected from one of sodium iodide and potassium iodide or a combination thereof.
9. The synthesis method of claim 2, wherein the feeding molar ratio of the intermediate I-2 to urotropin in the step 3 is 1: 1.05-1.5.
10. The synthesis method according to claim 2, wherein the feeding molar ratio of the intermediate I-2 to the catalyst in the step 3 is 1: 0.05-0.1.
CN202011334979.8A 2020-11-24 2020-11-24 Synthetic method of prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine Pending CN114539134A (en)

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