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Paliperidone amino-acid ester and preparation method thereof

A technology of paliperidone amino acid ester and diperidone amino acid ester, which is applied in the field of paliperidone ester and its preparation, can solve the problem of amino acid combination that has not been seen, and achieve the purpose of increasing oral bioavailability and reducing toxic and side effects , the effect of promoting absorption

Active Publication Date: 2013-03-27
温州医科大学慈溪生物医药研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There is no report on the binding of amino acids to paliperidone

Method used

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  • Paliperidone amino-acid ester and preparation method thereof
  • Paliperidone amino-acid ester and preparation method thereof
  • Paliperidone amino-acid ester and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Embodiment 1: the synthesis of paliperidone glycinate (compound 1)

[0015] a. Protection of amino groups

[0016] Add 0.75g (10mmol) of L-glycine into the flask, add 10ml of water, 20ml of acetone, and add 2.08ml of triethylamine (Et 3 N), control the temperature and add di-tert-butyl dicarbonate (Boc) under stirring at 25°C 2 O 4.27ml (20mmol), and continue to stir for 4.5h, distill the acetone off under reduced pressure, extract the water layer 3 times with diethyl ether, 10ml each time, adjust the pH value of the water layer to 2-3 with dilute HCl, then dilute the water layer with ethyl acetate Extract 3 times, 15ml each time, combine the ethyl acetate layers, wash 2 times with saturated brine, 10ml each time, dry over anhydrous sodium sulfate, filter and evaporate to dryness, the product obtained is washed with ethyl acetate and petroleum ether (1:2 , volume ratio) to crystallize to obtain Boc-L-glycine with a yield of 90%. (Yield rate: the ratio of the actual p...

Embodiment 2

[0021] Embodiment 2: the synthesis of paliperidone DL-alanine ester (compound 2)

[0022] a. Protection reaction of amino group:

[0023] Add DL-alanine 0.89g (10mmol) into the flask, dissolve in 3.5ml of water and 7ml of 1,4-dioxane, cool with ice water, add dropwise 2.2ml of di-tert-butyl dicarbonate ( 11mmol) in 1,4-dioxane (7ml) and sodium hydroxide (0.5g) in water (7ml), after the dropwise addition was completed, the mixture was stirred in ice bath for 2h and at room temperature overnight. Add 1 mol / l hydrochloric acid to adjust the pH to 2, extract 3 times with ethyl acetate, combine, wash with 1 mol / l hydrochloric acid and water three times, dry over anhydrous sodium sulfate, evaporate the solvent, and recrystallize petroleum ether to obtain a white solid , the yield was 70%.

[0024] b. Synthesis of esters:

[0025] Dissolve 3mmol of protected alanine in 20ml of anhydrous dichloromethane, add catalyst DMAP, add 3mmol of paliperidone under stirring, add 10mmol of DCC...

Embodiment 3

[0028] Embodiment 3: the synthesis of paliperidone D-valine ester (compound 3)

[0029] a. Protection of amino groups

[0030] Add D-valine (10mmol) into the flask, add 10ml of water, 20ml of acetone, and add 2.08ml of Et 3 N, control the temperature and add (Boc) under stirring at 25°C 2 O (10mmol, 2.2ml), and continued to stir for 4.5h, distilled off the acetone under reduced pressure, extracted the water layer with diethyl ether 3 times, 10ml each time, adjusted the pH value of the water layer to 2-3 with dilute HCl, and then Esters were extracted 3 times, 15ml each time, the organic layers were combined, washed 2 times with saturated brine, 10ml each time, anhydrous Na 2 SO 4 After drying, it was filtered and evaporated to dryness, and the obtained product was crystallized with ethyl acetate and petroleum ether (1:2, volume ratio) to obtain Boc-D-valine with a yield of 70%.

[0031] b. Synthesis of esters:

[0032] The D-valine after the protection of 2.6mmol and the ...

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Abstract

The invention discloses a preparation method of a paliperidone amino-acid ester compound or medicinal salt thereof used for treating mental disease, wherein the structural formula of the compound is shown as a formula (I) (described in the specification). The compound can be an optical isomer and also can be a racemic mixture. The paliperidone amino-acid ester can be metabolized and converted into paliperidone (II) with pharmacological activity in vivo after being ingested in a human body, the paliperidone (II) is taken as an antagonist for neurotransmission substance to play a pesticide effect, and the paliperidone (II) is used for treating related mental diseases such as schizophrenia.

Description

【Field of Invention】 [0001] The invention relates to a paliperidone compound for treating schizophrenia and a preparation method thereof, in particular to a paliperidone ester and a preparation method thereof. [Background of the invention] [0002] Paliperidone (chemical formula II) is a derivative of benzisoxazole, which is a new generation of antipsychotic drugs. It is a selective monoaminergic antagonist with unique properties, which can interact with 5-HT2. Body and dopamine D2 receptors have a high affinity. Therefore, the U.S. FDA approved the listing of oral controlled-release tablets (Invega) developed by Johnson & Johnson in December 2006, but because the hydroxyl group of the compound causes its hydrophilicity to increase, thereby reducing its oral absorption rate, its absolute bioavailability Only 28%, resulting in an increase in its daily dosage, thereby increasing its possible side effects of unabsorbed drugs. The long-chain fatty acid ester of paliperidone ha...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P25/18
CPCY02P20/55
Inventor 鲁翠涛苏正兴吕海峰赵应征
Owner 温州医科大学慈溪生物医药研究院
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