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One-step process for the preparation of paliperidone and its oxalate

A kind of technology of paliperidone and trialkyl phosphite, applied in the one-step field of preparing paliperidone and its oxalate

Inactive Publication Date: 2011-11-30
QUIMICA SINTETICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Paliperidone prepared by currently known methods can only be obtained in satisfactory quality after several steps using expensive enzymes and requiring enzyme isolation and purification

Method used

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  • One-step process for the preparation of paliperidone and its oxalate
  • One-step process for the preparation of paliperidone and its oxalate
  • One-step process for the preparation of paliperidone and its oxalate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Preparation of LiHMDS

[0056] Place a small amount of 2,2'-bipyridine crystals in a 25mL round bottom flask, and place the system under an argon atmosphere. Anhydrous toluene (2 mL) was added, the solution was cooled to -10°C, freshly distilled hexamethyldisilazane (735 μL, 3.52 mmol) was added, followed by n-butyllithium (1.6M n-hexane solution, 2.0 mL, 3.2 mmol). The mixture was stirred at -10°C for 30 minutes to obtain an approximately 0.68M LiHMDS red solution.

Embodiment 2

[0058] oxidation reaction

[0059] Connect the 50 mL two-neck round bottom flask to a compressed air pump (GC grade, H 2 O2 SO 4 Dry and remove solvent under reduced pressure. The residue was purified by flash chromatography on silica gel (20 g) eluting with a gradient of dichloromethane / methanol (90:10 to 86:14) to give the ketone by-product (43 mg, 8%) as a yellow oil in the initial fraction, Paliperidone (342 mg, 66%) was subsequently obtained as a white foam. The product was further purified by crystallization from ethyl acetate / n-hexane to obtain a product with a melting point of 162.2-162.4°C.

[0060] 1 H NMR (300MHz, CDCl 3 , 298K) δ1.77 (1H, m center); 1.89-2.04 (1H, m); 2.07-2.21 (6H, m); 2.25-2.42 (2H, m); 2.36 (3H, s); 2.55 and 2.79 (4H, A and X are part of an AA'XX' system); 3.10 (1H, m center); 3.18 (2H, width d, J 11.4Hz); 3.87-4-03 (2H, m); 4. .12 (1H, wide s); 4.51 (1H, dd, J6.3 and 10.2Hz); 7.07 (1H, dt, J2.1 and 15.3Hz); 7.25 (1H, dd, J2.4 and 9.0Hz...

Embodiment 3

[0063] Purification of paliperidone by salt formation

[0064] The crude product paliperidone (theoretical yield 24.4 mmol) obtained from the oxidation reaction of 10 g risperidone was dissolved in methanol (100 mL) after the above-mentioned aqueous treatment, and oxalic acid (1.3 g, 14.4 mmol).

[0065] The crystalline material was filtered and washed with methanol to obtain paliperidone oxalate (7.2 g, 60% yield) as a colorless solid, mp 135-140° C., shown as figure 1 XRPD pattern.

[0066] Paliperidone was obtained quantitatively from the oxalate salt (7.2 g, 13.9 mmol), treated with 20% ammonium hydroxide, extracted with dichloromethane (50 mL), washed with brine, dried the organic extract over sodium sulfate, and concentrated to solid residue. Paliperidone can optionally be recrystallized from acetonitrile.

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Abstract

The invention relates to a one-step method for preparing antipsychotic drug paliperidone by oxidizing risperidone, and to paliperidone oxalate or its hydrate, solvate or polymorph.

Description

field of invention [0001] The present invention relates to a one-step method for preparing antipsychotic drug paliperidone (paliperidone) by oxidizing risperidone (Risperidone), and relates to paliperidone oxalate or its hydrate, solvate or polymorph. Background of the invention [0002] Paliperidone is a potent antagonist of the neurotransmitters serotonin and dopamine, and antagonism of said mediators will inhibit or alleviate a variety of symptoms caused by the excessive release of these mediators. [0003] Serotonin antagonists have been reported to be effective against psychosis, aggression, anxiety, depression, and migraine. Centrally acting serotonin antagonists can improve the negative symptoms of schizophrenia, such as lack of resilience, apathy, social withdrawal and depressed mood, and can also reduce extrapyramidal symptoms while providing treatment with classic antipsychotic drugs such as dopamine antagonists Incidence of side effects (EPS). [0004] Dopamine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/517A61P25/00
CPCC07D471/04A61P25/00A61P25/18A61K31/519C07D413/14
Inventor G·卡斯塔尔迪M·拉斯帕里尼G·马拉斯L·班菲F·德莫利内尔F·穆苏梅奇R·里瓦
Owner QUIMICA SINTETICA
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