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Preparation method for paliperidone palmitate

A technology of paliperidone and palmitic acid is applied in the field of preparation of paliperidone palmitate and achieves the effects of simple method, low toxicity and high product purity

Inactive Publication Date: 2016-12-14
广州仁恒医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] No matter the preparation method of paliperidone palmitate abroad or the preparation method of paliperidone palmitate in China, there are deficiencies and need to be improved in technology

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation method of the paliperidone palmitate of the present embodiment is as follows:

[0044] Step 1, 0.5g 3-(2-hydroxyethyl)-9-hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one plus 10mL tetrahydrofuran, add 0.05g wet palladium carbon ( 50%), add trifluoroacetic acid to adjust pH to 3, vacuumize, H 2 After replacing the air 3 times, it was heated to 65°C and reacted. After 6h, the reaction was complete. Filter, spin the filtrate to dry, add water to dissolve, extract with chloroform, retain the water phase to adjust the pH to 10, then extract with chloroform, dry the chloroform phase and spin dry.

[0045] Step 2: Take 0.50 g of the solid obtained in the first step, add 2.5 mL of DCM, stir to dissolve, and cool to 5 ° C; another 0.46 g of PCl 5 Add 2.5mL DCM to dissolve, keep the internal temperature not exceeding 10°C, add PCl drop by drop 5 DCM solution, dropwise to consume PCl 5 After half of the DCM solution, the reaction solution was warmed up...

Embodiment 2

[0049] The preparation method of the paliperidone palmitate of the present embodiment is as follows:

[0050] Step 1, 10.6g 3-(2-hydroxyethyl)-9-hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one plus 106mL dioxane, add 0.53g wet Palladium carbon (10%), add 1M HCl to adjust pH to 3, vacuumize, H 2 After replacing the air 3 times, it was heated to 65°C and reacted. After 6h, the reaction was complete. Filter, spin the filtrate to dryness, add water to dissolve, extract with ethyl acetate, keep the water phase to adjust the pH to 10, then extract with ethyl acetate, dry the ethyl acetate phase and spin dry.

[0051] Step 2, take 7.6g of the solid obtained in the first step, add 50mL of chloroform and stir to dissolve, cool to 5°C; take another 7.06g of PCl 5 Add 50mL chloroform to dissolve, keep the internal temperature not exceeding 10°C, slowly add PCl dropwise 5 Chloroform solution, added dropwise to consume PCl 5 After half of the chloroform solution, the reaction...

Embodiment 3

[0055] The preparation method of the paliperidone palmitate of the present embodiment is as follows:

[0056] Step 1, 10.6g 3-(2-hydroxyethyl)-9-hydroxy-2-methyltetrahydro-pyridin[1,2-α]pyrimidin-4-one plus 106mL methanol, add 1.06g wet palladium carbon ( 10%), add 1M HCl to adjust the pH to 3, vacuumize, H 2 After replacing the air 3 times, it was heated to 65°C and reacted. After 6h, the reaction was complete. Filter, spin the filtrate to dry, add water to dissolve, extract with DCM, keep the water phase to adjust the pH to 10, add DCM for extraction, dry the DCM phase and spin dry.

[0057] Step 2, take 7.6g of the solid obtained in the first step, add 50mL of DCM to stir and dissolve, cool to 5°C; take another 7.06g of PCl 5 Add 50mL DCM to dissolve, keep the internal temperature not exceeding 10°C, slowly add PCl dropwise 5 DCM solution, dropwise to consume PCl 5 After half of the DCM solution, the reaction solution was warmed up to 10 degrees Celsius, and then conti...

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Abstract

The invention discloses a preparation method for paliperidone palmitate. The preparation method comprises the following steps: step 1, synthesis of 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyltetrahydro-pyridino[1,2-alpha]pyrimidin-4-one; step 2, synthesis of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyltetrahydro-pyridino[1,2-alpha]pyrimidin-4-one; step 3, synthesis of paliperidone; and step 4, synthesis of paliperidone palmitate. Compared with the prior art, the preparation method provided by the invention has the advantages of short reaction time, low cost, controllability of impurities, easiness in purification, high product purity and high yield.

Description

technical field [0001] The invention relates to the field of pharmaceutical compositions, in particular to a preparation method of paliperidone palmitate. Background technique [0002] Schizophrenia is a group of severe psychiatric diseases of unknown etiology. Clinically, it is often manifested as a syndrome with different symptoms, involving various obstacles in perception, thinking, emotion, and behavior, as well as incoordination of mental activities. Drugs for the treatment of schizophrenia are divided into classic antipsychotics and atypical antipsychotics. Paliperidone is an atypical antipsychotic. [0003] Paliperidone palmitate is a long-acting injection of the second-generation antipsychotic drug paliperidone. It is mainly used for the treatment of schizophrenia. The active ingredient is paliperidone. Paliperidone is also known as 9-hydroxyrisperidone, and its chemical name is 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidinyl]ethyl ]-7-Hydroxy-4-methyl-1,5-d...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 田元周胜安
Owner 广州仁恒医药科技股份有限公司
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