Preparation method of blonanserin intermediate

A technology for blonanserin and intermediates, which is applied in the field of preparation of key intermediates of blonanserin, can solve the problems of incomplete reaction, low yield, long reaction time and the like, so as to reduce solvent loss and improve product yield. , The effect of product purity is good

Inactive Publication Date: 2016-08-10
HEBEI GUOLONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using the extraction method, the process operation is cumbersome, resulting in a waste of solvents
[0006] Another literature uses phosphorus oxychloride or thionyl chloride as the chlorination reagent, but the reaction time is long and the reaction is incomplete; through experimental verification, it shows that phosphorus oxychloride is heated and refluxed for 2 hours, and the reaction cannot be completed;
[0007] In summary, most of the current preparation methods of blonanserin key intermediates have problems, or the process is cumbersome, or the reaction time is long and the reaction is incomplete, the yield is low, and they are not suitable for industrial production.

Method used

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  • Preparation method of blonanserin intermediate
  • Preparation method of blonanserin intermediate
  • Preparation method of blonanserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 4-(4-fluorophenyl)-3-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (120g) and phenylphosphonic dichloride (125mL ) into a 350mL thick-walled pressure-resistant bottle, heated at 120-130°C (external temperature) for 6 hours, and after the reaction was completed, phenylphosphonic dichloride was distilled under reduced pressure to obtain a black viscous liquid, which was poured into 2L of ice In the water mixture, add ammonia water to adjust the pH to 8.5, stir vigorously for 3-6 hours, an off-white solid precipitates, and filter to obtain a light gray or off-white solid (Compound I). Add compound I to ethanol (1.8 L), heat and stir to dissolve, add activated carbon (50 g), continue to stir at this temperature for 30 min, filter while hot, wash the filter cake with 400 mL of hot ethanol, the filtrate naturally crystallizes, and obtains white needles Crystals (110.8 g), yield 86.9%. HPLC purity 99.8%.

[0024] The proton nuclear magnetic resonance spectrum data of co...

Embodiment 2

[0027] 4-(4-fluorophenyl)-3-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (120g) and phenylphosphonic dichloride (187mL ) into a 350mL sealed tube, heated at 150°C (external temperature) for 4h, after the reaction was completed, phenylphosphonic dichloride was distilled under reduced pressure to obtain a black viscous liquid, which was poured into 2L of ice-water mixture, and ammonia water was added Adjust the pH to 9, stir vigorously for 3-6 hours, an off-white solid precipitates, filter or centrifuge to obtain a light gray or off-white solid. Then add ethanol (1.8L), heat and stir to dissolve, then add activated carbon (50g), continue stirring at this temperature for 30min, filter while it is hot, wash the filter cake with 400mL of hot ethanol, the filtrate crystallizes naturally to obtain white needle-shaped crystals (111.2 g), yield 87.2%. HPLC purity 99.8%.

[0028] The proton nuclear magnetic resonance spectrum data of compound I are as follows: δ6.99ppm (s, 1H); ...

Embodiment 3

[0031] 4-(4-fluorophenyl)-3-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one (120g) and phenylphosphonic dichloride (155mL ) into a 350mL thick-walled pressure-resistant bottle, heated at 180-190°C (external temperature) for 4 hours, and after the reaction was completed, phenylphosphonic dichloride was distilled under reduced pressure to obtain a black viscous liquid, which was poured into 2L of ice water Add ammonia water to the mixture to adjust the pH to 8, stir vigorously for 3 to 6 hours, an off-white solid precipitates, filter or centrifuge to obtain a light gray or off-white solid. Then add ethanol (1.8L), heat and stir to dissolve, then add activated carbon (50g), continue stirring at this temperature for 30min, filter while it is hot, wash the filter cake with 400mL of hot ethanol, the filtrate crystallizes naturally to obtain white needle-shaped crystals (109.5 g), yield 85.5%. HPLC purity 99.7%.

[0032] The proton nuclear magnetic resonance spectrum data of com...

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Abstract

The invention provides a preparation method of a blonanserin intermediate. The preparation method comprises the following steps: reacting 4-(4-fluorophenyl)-3-5,6,7,8,9,10-hexahydro cyclooctane pyridine-2(1H)-ketone with a chloro agent under a certain condition, pouring a reactant after the reaction into ice water, adjusting the pH value by using ammonia water, and performing stirring, filtration or centrifugation to obtain a crude product of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine (compound I); and dissolving, decoloring and recrystallizing the compound I by using hot ethanol to obtain a refined product of the compound I. Compared with the prior art, the method avoids multiple times of extraction during refining, reduces solvent loss in a middle process, is simple and easy to operate, improves the purity and yield of the product, and is suitable for process scaling and industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of a key intermediate of blonanserin. Background technique [0002] Blonanserin chemical name: 2-(4-ethyl-1-piperazine ring)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro ring Octacyclo[b]pyridine, molecular formula: C23H30FN3. Its structural formula is: [0003] [0004] Blonanserin is a new generation of atypical anti-schizophrenia drug, which belongs to 5-hydroxytryptamine receptor antagonist, and its main mechanism of action is strong blocking effect on dopamine D2 receptor and 5-hydroxytryptamine receptor. Treatment of schizophrenia. The drug was developed by Japan's Sumitomo Pharmaceutical Co., Ltd. and was launched in Japan in January 2008. The main dosage form is tablet, and the clinical application is 2mg and 4mg. At present, there is no listed variety of this drug in my country. [0005] The key intermediate in the synthetic route of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/04
CPCC07D221/04
Inventor 殷殿书孙立杰张伟吕金伟李彪赵晓雷马辉白雪张清江王春发
Owner HEBEI GUOLONG PHARMA CO LTD
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