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Synthetic method of 3-(2-chloroethyl)-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one
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A 2-a, chloroethyl technology, applied in the field of risperidone, can solve problems such as unfavorable industrialized production, high environmental protection pressure, and complicated post-processing operations, and achieve excellent yield and purity, high safety, and easy operation. Effect
Active Publication Date: 2022-05-31
CHONGQING MEDICAL UNIVERSITY
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[0011] This process uses a large amount of phosphorus oxychloride and toluene as the reaction solvent, which produces a large amount of waste gas and waste liquid, which has great pressure on environmental protection, and the post-processing operation is cumbersome, which is not conducive to industrial production.
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Embodiment 1
[0038] Preparation of 2-acetyl-4-chlorobutyric acid ethyl ester
[0039] 10ml of dried DMF was added to a 100ml there-necked flask under nitrogen protection, the reaction flask was cooled to -20°C, (0.92g, 23mmmol) sodiumhydride (60%) was added to the reaction flask in batches, and then 2 times (v / v) DMF diluted ethyl acetoacetate (3g, 23mmmol) solution was added dropwise, dripped in 20min, and the temperature was controlled to continue stirring and reacting for 30min, then the reaction flask was moved to room temperature and stirred until the reaction solution recovered After reaching room temperature, 1-bromo-2-chloro-ethane (3.1 g, 27.7 mmol) was added at one time, and the temperature of the reaction solution was increased to 100 °C. The reaction solution was extracted, and the ethyl acetatelayers were combined and concentrated to obtain 4.3 g of a colorless liquid with a yield of 97%.
[0042] Preparation of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
[0043] 2-Acetyl-4-chlorobutyric acid ethyl ester (1.92g, 10mmmol), 2-aminopyridine (0.75g, 8mmol) and imidazolehydrochloride (0.52g, 5mmol) were added to a 10ml reaction flask, in The temperature was controlled by stirring the reaction under the condition of 100-110°C. After 6 hours, the reaction was complete, cooled to room temperature, the reaction solution was dissolved in methanol, decolorized with activated carbon, filtered, and the filtrate was decompressed to remove the solvent to obtain the crude product, which was recrystallized from ethyl acetate to obtain the crude product. , the yield was 2.12 g, and the yield was 95%.
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Abstract
The present invention provides a kind of synthetic method of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, the method uses ethyl acetoacetate and 1- Bromo-2-chloroethane undergoes a substitution reaction under alkaline conditions to obtain 2-acetyl-4-chlorobutyric acid ethyl ester, and 2-acetyl-4-chloro-butyric acidethyl ester reacts with 2-aminopyridine to obtain Peridone intermediate 3‑(2‑chloroethyl)‑2‑methyl‑4H‑pyrido[1,2‑a]pyrimidin‑4‑one. The method of the invention is simple to operate and is suitable for industrial production. The compound 2-acetyl-4-chlorobutyrate ethyl ester provided by the invention can be used as a raw material or intermediate to synthesize 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a ] pyrimidin-4-one, and then synthesize risperidone. The present invention also provides the compound 2-acetyl-4-chlorobutyric acid ethyl ester as 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine-4- Use in the impurity reference substance of ketone.
Description
technical field [0001] The invention relates to risperidone, in particular to a method for synthesizing risperidone intermediate 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, belonging to field of medicinal chemistry. Background technique [0002] The chemical name of risperidone is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6, 7,8,9-Tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is a novel atypical antipsychoticdrug developed by Janssen Pharmaceuticals, Belgium in 1984. it with 5-HT 2 receptors and dopamine D 2 The receptor has a strong affinity and can also interact with α 1 -Adrenergic receptors bind, and with lower affinity to H-receptors and alpha 2 -Adrenergic receptors bind, but not cholinergic receptors. Risperidone is now widely used in the treatment of various types of schizophrenia, and its efficacy is better than that of traditional antipsychotics, effective for both positive and negative symptoms, and the incidence o...
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