CN112979643B - 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one - Google Patents
3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one Download PDFInfo
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Abstract
The invention provides 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, which is prepared by performing substitution reaction on ethyl acetoacetate and 1-bromo-2-chloroethane under an alkaline condition to obtain 2-acetyl-4-chlorobutyric acid ethyl ester, and then reacting the 2-acetyl-4-chlorobutyric acid ethyl ester with 3-hydroxy-2-aminopyridine. Compared with the existing preparation method of paliperidone, the preparation method of the intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone can avoid the use of highly polluting chlorinating agents, such as: thionyl chloride, phosphorus oxychloride and the like, does not generate waste gas and waste liquid, has cheap and easily obtained raw materials, does not need harsh reaction conditions, has excellent yield and purity, high safety, simple and convenient operation and high process economy, and is suitable for industrial production.
Description
Technical Field
The invention relates to paliperidone, in particular to a synthetic method of a paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, and belongs to the technical field of pharmaceutical chemistry.
Background
Paliperidone (paliperidone) with chemical name of 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidyl]-ethyl radical]-6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]Pyrimidin-4-one, Johnson, USA&Dopamine D developed by Johnson corporation2Receptors and 5-HT2A dual antagonist of the a receptor, a sustained release tablet (trade name invaga) was approved by the FDA in the united states for 12 months 2006 and marketed. Studies show that paliperidone can effectively delay the recurrence of schizophrenia, is used for acute short-term and long-term maintenance treatment of schizophrenia, can also be used for single treatment of schizoaffective disorder and auxiliary treatment of mood stabilizer or antidepressant, and can effectively stabilize the condition of patients after long-term use.
Paliperidone has the following structural formula:
patent WO2008024415 a2 discloses a synthetic route for paliperidone, which is condensation synthesized from 2-amino-3-hydroxypyridine and 3-acetyldihydrofuran-2 (3H) -ketone in the presence of phosphorus oxychloride into 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-a ] pyrimidin-4-one; the route is as follows:
as above, (2-chloroethyl) -9-hydroxy-2-methyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidin-4-one is an important intermediate of paliperidone, the yield is low when the (2-chloroethyl) -9-hydroxy-2-methyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidin-4-one is synthesized by the above route, and the phosphorus oxychloride which is a seriously polluted chemical is used, so that the environmental protection pressure is high, and the industrial production is not facilitated. (2-chloroethyl) -9-hydroxy-2-methyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidin-4-one (formula II) can be prepared by reduction of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one (formula III); the route is as follows:
therefore, the 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone can also be used as a raw material or an intermediate for synthesizing paliperidone.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for synthesizing 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone (formula III).
Except for special description, the parts are parts by weight, and the percentages are mass percentages.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one (formula III), comprising the following steps:
(i) performing substitution reaction on ethyl acetoacetate and 1-bromo-2-chloroethane serving as raw materials under an alkaline condition to obtain ethyl 2-acetyl-4-chlorobutyrate;
(ii) the paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is prepared by the reaction of 2-acetyl-4-ethyl chlorobutyrate and 3-hydroxy-2-aminopyridine.
The reaction route is as follows:
in the method, the base used in the step (i) is selected from one or a combination of more of potassium hydroxide, sodium hydride, potassium carbonate, potassium tert-butoxide, sodium ethoxide and magnesium ethoxide; the catalyst used in step (ii) is selected from LiCl, BiCl2And imidazole hydrochloride or a combination of a plurality of imidazole hydrochlorides.
Preferably, the base used in step (i) is sodium hydride; further, the amount of sodium hydride used was 1.2 eq.
Preferably, the catalyst used in step (ii) is imidazole hydrochloride; further, imidazole hydrochloride was used in an amount of 0.5 eq.
In the above method, the solvent used in step (i) is selected from one or more of DMF, THF, DCM, toluene, ethanol, and petroleum ether, preferably DMF.
In order to improve the yield and purity of the ethyl 2-acetyl-4-chlorobutyrate prepared in the step (i), the reaction is carried out in two steps, activation is carried out firstly, the temperature during activation is-70-0 ℃ (preferably-20 ℃), then the temperature is increased for reaction, the reaction temperature is 25-120 ℃ (preferably 100 ℃), and the reaction time is 10-16h (preferably 10-12 h).
In order to improve the yield and purity of the final product, the reaction temperature of the step (ii) is 70-150 ℃ (preferably 100-110 ℃), and the reaction time is 6-10h (preferably 6 h).
The method for preparing the 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is characterized by comprising the following steps:
(i) preparation of ethyl 2-acetyl-4-chlorobutyrate:
adding the dried solvent into a three-mouth reaction bottle under the nitrogen protection condition, adding alkali at-70-0 ℃ in batches (twice or three times), dropwise adding an ethyl acetoacetate solution diluted by 2 times by the solvent, controlling the temperature, continuously stirring for reaction for 30-60min, moving the reaction bottle to room temperature, stirring until the reaction solution is recovered to the room temperature, adding 1-bromo-2-chloro-ethane once, completely reacting at 25-120 ℃, separating and purifying to obtain 2-acetyl-4-chlorobutyric acid ethyl ester; the alkali is one of potassium hydroxide, sodium hydride, potassium carbonate, potassium tert-butoxide, sodium ethoxide and magnesium ethoxide; the solvent is one of DMF, THF, DCM, toluene, ethanol, and petroleum ether;
(ii) preparation of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Adding 2-acetyl-4-chlorobutyric acid ethyl ester, 3-hydroxy-2-aminopyridine and a catalyst into a reaction bottle, controlling the temperature to be 70-150 ℃ and reacting for 6-10H to prepare the 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]Pyrimidin-4-one; the catalyst is selected from LiCl and BiCl2And imidazole hydrochloride.
The invention provides application of a compound 2-acetyl-4-chlorobutyric acid ethyl ester serving as a raw material or an intermediate for synthesizing 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone.
The invention provides application of a compound 2-acetyl-4-chlorobutyric acid ethyl ester serving as an impurity reference substance of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone.
The compound 2-acetyl-4-chlorobutyric acid ethyl ester is used as a raw material or an intermediate to synthesize 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, and then paliperidone, wherein trace 2-acetyl-4-chlorobutyric acid ethyl ester may exist in the final product paliperidone. The invention provides application of a compound ethyl 2-acetyl-4-chlorobutyrate serving as an impurity reference substance of paliperidone.
Has the advantages that:
the invention provides a method for preparing a paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one, wherein ethyl acetoacetate and 1-bromo-2-chloroethane are subjected to substitution reaction under alkaline conditions to obtain ethyl 2-acetyl-4-chlorobutyrate, and the ethyl 2-acetyl-4-chlorobutyrate and 3-hydroxy-2-aminopyridine are reacted to obtain the paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one. Compared with the existing preparation method of paliperidone, the preparation method of the intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone can avoid the use of highly polluting chlorinating agents, such as: thionyl chloride, phosphorus oxychloride and the like, no waste gas or waste liquid is generated, the raw materials are cheap and easy to obtain, harsh reaction conditions are not needed, and the method has the advantages of excellent yield and purity, high safety, simplicity and convenience in operation, high process economy and suitability for industrial production.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure. The raw materials and reagents used in the invention are all commercial products.
Example 1
Preparation of ethyl 2-acetyl-4-chlorobutyrate
Adding 10ml of dried DMF into a 100ml three-necked bottle under the condition of nitrogen protection, cooling the reaction bottle to-20 ℃, adding (0.92g, 23mmmol) of sodium hydride (60%) into the reaction bottle in batches, dropwise adding an ethyl acetoacetate (3g, 23mmmol) solution diluted by 2 times (v/v) of DMF, dropwise adding the solution within 20min, controlling the temperature, continuously stirring for reaction for 30min, moving the reaction bottle to room temperature, stirring until the reaction solution returns to the room temperature, adding 1-bromo-2-chloro-ethane (3.1g, 27.7mmol) at one time, heating the reaction solution to 100 ℃, completely reacting after 10-12h, quenching the reaction solution with water, extracting the reaction solution with ethyl acetate/water, combining ethyl acetate layers, and concentrating to obtain a colorless liquid 4.3g, wherein the yield is 97%.
Ethyl 2-acetyl-4-chlorobutyrate, colorless liquid: 1H NMR (600MHz, DMSO) δ 4.37(t, J ═ 9.6Hz, 2H),4.08(q, J ═ 7.1Hz,2H),3.40(s,1H),2.78(m,2H),2.12(d, J ═ 1.5Hz,3H),1.20(t, J ═ 7.1Hz,3H), 13C NMR (151MHz, DMSO) δ 168.41,165.57,102.05,70.39,59.30,29.67, 14.68,14.01.
Example 2
Preparation of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Adding 2-acetyl-4-chlorobutyric acid ethyl ester (1.92g, 10 mmol), 3-hydroxy-2-aminopyridine (0.88g, 8mmol) and imidazole hydrochloride (0.52g, 5mmol) into a 10ml reaction bottle, stirring at the temperature of 110 ℃ for reaction under the condition of 100 ℃, controlling the temperature, completely reacting after 6h, cooling to room temperature, dissolving the reaction solution with methanol, decoloring with activated carbon, filtering, removing the solvent from the filtrate under reduced pressure to obtain a crude product, and recrystallizing with ethyl acetate to obtain a white solid with the yield of 2.24g and the yield of 94%.
3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one. White solid: 1H NMR (600MHz, DMSO) δ 8.40(dd, J ═ 5.5,3.0Hz,1H),7.13(m,2H),3.56(t, J ═ 7.1Hz,2H),2.80(t, J ═ 7.1Hz,2H),2.50(s,3H).13C NMR (151MHz, DMSO) δ 160.45,157.75,149.90, 142.64,117.50,115.97,114.02,112.24,59.67,30.86,22.84.
The inventor of the invention finds that in the process of preparing the paliperidone intermediate 3- (2-chloroethyl) 9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, reaction media (solvent), alkali and catalyst and reaction temperature have large influence on reaction time and yield of final products, and the reaction media, the alkali and the catalyst and the reaction temperature have mutual influence relationship.
The inventors examined the effect of the reaction medium (solvent), base and reaction temperature on the reaction by operating according to the parameters of table 1 with reference to example 1.
In the initial experiments, the inventors conducted the exploration of the reaction conditions for the substitution reaction of ethyl acetoacetate with 1-bromo-2-chloroethane to produce ethyl 2-acetyl-4-chlorobutyrate, and the results are listed inIn table 1. The first reaction conditions we tried were EtONa as base and ethanol as solvent at 80 ℃ for 16h, unfortunately only trace amounts of product were formed and the desired reaction effect was not achieved (Table 1, entry 1). Followed by EtOMg, Na, K2CO3The desired reaction effect was not obtained with a reaction time of 12-16h for the base, also toluene, PE, THF were selected as solvent (Table 1, entries 2, 3, 4, 5). Where THF was used as the solvent, NaH was used as the base, and neither lowering the activation temperature nor raising the reaction temperature significantly changed the reaction effect (Table 1, entries 6,7,8, 9).
It is appreciated that when DMF is used as solvent, NaH is used as base, the activation temperature is-20 ℃ and the reaction temperature is 80 ℃ for 16h, the target product has a moderate yield (Table 1, entry 11). On the basis, the influence of the reaction temperature is considered, and the reaction at different temperatures from 25 ℃ to 120 ℃ is tried. The reaction temperature was lowered to 25 ℃ without changing the other conditions, and almost no target product was produced (Table 1, entry 10). The reaction temperature is shown to be an important factor influencing the reaction of the system. The reaction was completed in 12h by raising the reaction temperature to 100 deg.C (Table 1, entry 12), but the yield of the target product did not increase significantly by raising the reaction temperature to 120 deg.C (Table 1, entry 13). Therefore, the reaction temperature of 100 ℃ is the optimum reaction temperature of the reaction system. The activation temperature was increased to 0 ℃ and the effect of the reaction was significantly reduced (Table 1, entry 14). From the search results, it is preferable that the activation temperature be maintained at a temperature of-20 ℃ or lower.
Finally, the optimal conditions of the reaction system are determined, DMF is taken as a solvent, NaH is taken as an alkali, the reaction is carried out for 12 hours under the conditions that the activation temperature is-20 ℃ and the reaction temperature is 100 ℃, and the yield is highest and can reach 97 percent. The reaction route is as follows:
TABLE 1 reaction condition screening for the synthesis of ethyl 2-acetyl-4-chlorobutyratea
aThe reaction was carried out with ethyl acetoacetate (1eq), 1-bromo-2-chloroethane (1.2eq) and base (1 eq).
bIsolated in yield.
cTrace yield.
dNo reaction occurred.
The inventors examined the effect of catalyst and reaction temperature on the reaction by operating according to the parameters of table 2 with reference to example 2.
In the experiment, the inventors carried out the investigation of the reaction conditions for the reaction of ethyl 2-acetyl-4-chlorobutyrate with 3-hydroxy-2-aminopyridine to produce paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one, the results of which are shown in table 2. First, no reaction was attempted after 10 hours at 100-110 ℃ using bismuth chloride as a catalyst (Table 2, entry 1). It is desirable that when the catalyst is imidazole hydrochloride, the substrate can be reacted completely and the product yield can reach 94% under the conditions of 100 ℃ and 110 ℃ for 6h (Table 2, entry 2). The catalytic effect of imidazole hydrochloride was significantly better than that of lithium chloride and ferric chloride, so the best catalyst was imidazole hydrochloride (table 2, entries 3, 4). When the temperature was reduced to 70 ℃, the yield after 7h of reaction was reduced to 54%, and the reaction time was continued to be extended, which could reflect completion, but more impurities were produced (table 2, entry 5). When the temperature was increased to 120 ℃ there was no significant increase in the yield of the target product until the temperature was increased to 150 ℃ the yield of the target product decreased (table 2, entries 6, 7). The optimum reaction temperature for this reaction is therefore 100-110 ℃. Finally, the optimal condition of the reaction system is determined, imidazole hydrochloride is used as a catalyst, the reaction is carried out for 6 hours under the condition of 100-110 ℃, and the yield is the highest and can reach 94 percent. The reaction route is as follows:
TABLE 2 Synthesis of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a]Conditional screening of pyrimidin-4-onesa
a3-hydroxy-2-amino-pyridine (1eq), ethyl acetoacetate (1.2eq) and catalyst (0.5eq) were reacted.
bIsolated in yield.
cNo reaction occurred.
Claims (7)
1. A method for synthesizing 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one, which is characterized by comprising the following steps:
(i) performing substitution reaction on ethyl acetoacetate and 1-bromo-2-chloroethane serving as raw materials under an alkaline condition to obtain ethyl 2-acetyl-4-chlorobutyrate;
(ii) reacting ethyl 2-acetyl-4-chlorobutyrate with 3-hydroxy-2-aminopyridine to prepare a paliperidone intermediate 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone;
the reaction route is as follows:
the base used in step (i) is sodium hydride; the solvent used in step (i) is DMF; the reaction of the ethyl 2-acetyl-4-chlorobutyrate prepared in the step (i) is carried out in two steps, activation is carried out firstly, and the temperature during activation is-20 ℃; then raising the temperature for reaction, wherein the reaction temperature is 100 ℃; the catalyst used in step (ii) is imidazole hydrochloride.
2. The method of claim 1, wherein: the amount of alkaline sodium hydride used in step (i) was 1.2 eq.
3. The method of claim 1, wherein: the imidazole hydrochloride used as the catalyst in step (ii) was used in an amount of 0.5 eq.
4. The method of claim 1, wherein: the reaction time of the step (i) is 10-12 h.
5. The method of claim 1, wherein: the reaction temperature of the step (ii) is 70-150 ℃; the reaction time is 6-10 h.
6. The method of claim 1, wherein: the reaction temperature of the step (ii) is 100-110 ℃; the reaction time was 6 h.
7. The method of claim 1, wherein the steps are performed as follows:
(i) preparation of ethyl 2-acetyl-4-chlorobutyrate:
adding the dried solvent into a three-mouth reaction bottle under the protection of nitrogen, adding alkali at-20 ℃ for two or three times, dropwise adding an ethyl acetoacetate solution diluted by 2 times of the solvent, controlling the temperature, continuously stirring for reaction for 30-60min, moving the reaction bottle to room temperature, stirring until the reaction solution is recovered to the room temperature, adding 1-bromo-2-chloro-ethane once, completely reacting at 100 ℃, separating and purifying to obtain 2-acetyl-4-chlorobutyric acid ethyl ester; the base is sodium hydride; the solvent used was DMF;
(ii) preparation of 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Adding 2-acetyl-4-chlorobutyric acid ethyl ester, 3-hydroxy-2-aminopyridine and a catalyst into a reaction bottle, and controlling the temperature to be 70-150 ℃ to react for 6-10H to prepare 3- (2-chloroethyl) -9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone; the catalyst is imidazole hydrochloride.
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| Title |
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| Original SRN1 Reactions on New Non-Nitrated Heterocyclic System;Rémi Szabo et al.;《SYNLETT》;20081015(第18期);第2836–2840页 * |
| Solvent-Free Synthesis of 4H-Pyrido[ 1,2-a]p yrimidin-4 -ones Catalyze d by BiCl3: A Green Route to a Privileged Backbone;Irwan I. Roslan et al.;《European Journal of Organic Chemistry》;20150305;第2015卷(第11期);第2351-2355页 * |
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