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Improved synthesizing method of molindone

A synthetic method and technology of molindone, which is applied in the field of synthesis of antipsychotic drug molindone, can solve the problems of energy consumption and time-consuming in the post-treatment process of dilute acetic acid mother liquor, and achieve the effect of simplifying follow-up complexity, reducing waste water, and obvious comprehensive advantages

Active Publication Date: 2017-08-04
HEFEI LIFEON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The post-treatment process of a large amount of dilute acetic acid mother

Method used

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  • Improved synthesizing method of molindone
  • Improved synthesizing method of molindone
  • Improved synthesizing method of molindone

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0039] Example 1

[0040] 1) Condensation reaction

[0041] Put 715ml of methanol into a 1000ml reaction bottle, start stirring, slowly add concentrated hydrochloric acid into the bottle with a dropping funnel, and adjust the pH value of the solution to 3.5-3.8. After the addition, continue to stir for 5 minutes until the retest remains unchanged. Then add 89.5g (purity 0.5mol) of raw material 2-methyl-3-ethyl-4,5,6,7-tetrahydroindolin-4-one, 81.15g (purity 0.65mol) of hydrochloric acid Morpholine and 22.75g (in terms of formaldehyde, 0.75mol) paraformaldehyde), after the addition, the water bath was heated to 50°C, and kept stirring at 50-55°C for 5h, then heated to boiling, and refluxed for 1.25hr to reach Reaction endpoint (determined by HPLC method).

[0042] 2) Water analysis

[0043] After the reaction was completed, the reaction solution was poured into 2550 ml of normal temperature water while stirring. Continue to stir for 10min, and then let it stand for 2h. Th...

Example Embodiment

[0052] Embodiment 2 (pilot production example)

[0053] 1) Reaction: Put 115kg of methanol into a 200L glass-lined reactor equipped with a reflux condenser and a pH online detector at a time, and then slowly add reagent hydrochloric acid into the reactor through a dropping funnel until the pH value of the reaction solution reaches 3.65 Stop the dropwise addition and continue to stir for 10 minutes until the pH value of the retest remains unchanged. Then drop into the reactor 17.9kg (100.0mol.) 2-methyl-3-ethyl-4,5,6,7-tetrahydroindolin-4-one, 16.85kg (135.mol) hydrochloric acid morphine and 4.55 kg (151.5 mol) of paraformaldehyde. After the addition, the temperature of the water bath was raised to 50°-52°C and the reaction was stirred for 6 hours, then the temperature was raised to boiling, and the reaction was refluxed for 1.75 hours, and the end point was determined by HPLC.

[0054] 2) Water analysis and impurity removal: After the reaction is completed, drain the hot wat...

Example Embodiment

[0058] Embodiment 3 (reaction medium comparative example in embodiment 1)

[0059] Change the acidic methanol in Example 1 into equal volume, acidic anhydrous ethanol with the same pH value, and increase the heat preservation reaction temperature to 70 ° C ~ reflux temperature, and all other process conditions are exactly the same as Example 1, so Obtained unreacted raw material, alkalized crude product and ethanol primary recrystallization product yield and purity result are as follows:

[0060] 1) Recover 24.2 g of off-white powder unreacted raw material—2-methyl-3-ethyl-4,5,6,7-tetrahydroindolin-4-one, purity: 95.6%. The pure recovery rate: 26.1%.

[0061] 2) 87.9 g of white molindone crude product was obtained after alkalization of ammonia water, content: 96.1%, and condensation reaction yield: 82.7%.

[0062] 3) Take 84.5 g of the crude product, and recrystallize once with absolute ethanol according to the method of Example 1, to obtain 74.1 g of white needle-like molin...

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Abstract

The invention relates to the field of medicine synthesizing, and particularly relates to an improved synthesizing method of molindone. The improved synthesizing method of the molindone comprises the following steps of (1) under the condition of existence of an alcohol solvent and an ore acid catalyst, enabling 2-methyl-3-ethyl-4,5,6,7-tetrehydro indole-4-ketone, morpholine hydrochloride and paraformaldehyde to perform aminomethylation reaction at the temperature of 50 to 55 DEG C under the condition of refluxing reaction, so as to generate molindone hydrochloride; (2) separating out the unreacted raw material, namely 2-methyl-3-ethyl-4,5,6,7-tetrehydro indole ketone, and alkalifying a mother liquid, so as to directly obtain the molindone. The improved synthesizing method has the advantages that the usage amount of solvent in the Mannich reaction is reduced by times, the aminomethylation reaction time is greatly shortened, the subsequent impurity removal separation process is simplified, the yield rate is high, the cost is low, the production environment is obviously improved, the treatment cost of three wastes is low, and the comprehensive advantages are obvious.

Description

technical field [0001] The invention belongs to the field of organic and pharmaceutical synthesis, and in particular relates to a new method for synthesizing molindone, an antipsychotic drug. Background technique [0002] Malindone (Malindone) is a representative antipsychotic drug, which is clinically used in the form of hydrochloride (Malindone Hydrochloride), and its structural formula is as follows: [0003] [0004] At present about the synthetic method of morphindone, representative method has: US 3,491,093 discloses a kind of synthetic method of morphindone, this method is based on 2-methyl-3-ethyl-4,5,6,7-tetra Hydroindolin-4-one, morpholine hydrochloride, and paraformaldehyde are raw materials for Mannich reaction, which are refluxed in absolute ethanol for 40 hours, then concentrated in vacuo to dryness, and the crude residue is extracted with dilute hydrochloric acid. Unreacted raw materials 2- Methyl-3-ethyl-4,5,6,7-tetrahydroindolin-4-one is water-insoluble ...

Claims

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Application Information

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IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 季俊虬高美华李孝常陈军
Owner HEFEI LIFEON PHARMA
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