CN116199618A - Method for synthesizing haloperidol impurity E with high yield and high purity - Google Patents

Abstract

The invention discloses a method for synthesizing haloperidol impurity E with high yield and high purity, comprising the following steps: dissolving compound 1, compound 2 and magnesium in a first organic solvent, stirring and reacting at the first temperature for 1-5 hours, After the reaction is complete, add water to quench, extract with an organic solvent, and obtain compound 3 through column chromatography; dissolve compound 3 in a second organic solvent, add acid, and stir at a second temperature for 0.5-3h. After the reaction is complete, spin Dry the reaction solution to obtain compound 4; dissolve compound 4 and haloperidol impurity E in the third organic solvent, add alkali, stir at the third temperature for 1‑20h, add water and organic solvent for extraction, and dry the organic phase , the haloperidol impurity E was obtained by column chromatography. The haloperidol impurity prepared by the invention has high impurity purity, meets the requirements of the impurity reference substance, and can be used as the haloperidol impurity standard substance in the qualitative and quantitative research and detection of the haloperidol impurity.

Description

A method for synthesizing haloperidol impurity E with high yield and high purity

technical field

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing haloperidol impurity E with high yield and high purity.

Background technique

Haloperidol (Haloperidol), the chemical name is 1-(4-fluorophenyl)-4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-butanone, The chemical formula is C ₂₁ H ₂₃ ClFNO ₂ , the molecular weight is 375.864, and its chemical structure is shown in formula I. It is a typical antipsychotic drug. Haloperidol is suitable for various acute and chronic schizophrenia and mania. Intramuscular injection of this product can quickly control agitation, hostility and aggressive behavior, and can also be used for brain organic mental disorders and senile mental disorders.

The quality of the drug is an important criterion for measuring the quality of the drug. Impurities are the main factors affecting the purity of the drug. If the drug contains impurities exceeding the limit, it may cause changes in physical and chemical constants, variation in appearance, and affect the stability of the drug. . The increase of impurities will inevitably make the content of the drug lower or the activity lower, and the toxic and side effects will increase significantly. Therefore, the impurity inspection of drugs is a very important link to control the purity of drugs and improve the quality of drugs. The quality standard of haloperidol is recorded in the European Pharmacopoeia, and the European Pharmacopoeia clearly points out that haloperidol contains the impurity E of haloperidol, namely 4-{3-[4-(4-chlorophenyl)benzene base]-3-hydroxyhexahydropyridin-1-yl}-1-(4-fluorophenyl)butan-1-one.

However, there is no relevant literature reporting on the preparation method of the impurity. The present invention prepares a haloperidol impurity (see formula II for its chemical structural formula), and the preparation and research of the impurity have very important significance for haloperidol bulk drug and preparation process research and quality control.

Contents of the invention

Aiming at the problems existing in the prior art, the present invention provides a method for synthesizing the haloperidol impurity E with high yield and high purity.

In order to achieve the above object, the technical scheme of the present invention is as follows:

A method for synthesizing haloperidol impurity E with high yield and high purity, comprising the steps of:

Step Ⅰ: Dissolving compound 1, compound 2 and magnesium in the first organic solvent, stirring and reacting at the first temperature for 1-5 hours, after the reaction is completed, adding water to quench, extracting with organic solvent, and separating by column chromatography to obtain compound 3 , the reaction equation is as follows:

Step II: Dissolving compound 3 in the second organic solvent, adding acid, stirring at the second temperature for 0.5-3h, after the reaction is completed, spinning the reaction solution to obtain compound 4, the reaction equation is as follows:

Step III: Dissolving compound 4 and compound 5 in the third organic solvent, adding base, stirring at the third temperature for 1-20 h, adding water and organic solvent for extraction, drying the organic phase, and separating by column chromatography to obtain haloperidol Impurity E, its reaction equation is as follows:

Preferably, the mass ratio of compound 1, compound 2 and magnesium in the step I is 1:0.5-3:1-4.

Preferably, the first organic solvent in the step I is selected from one or more of benzene, diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and other ether solvents, And the ratio of the weight (m) of the compound 1 to the volume (V) of the first organic solvent is 1:10-40.

Preferably, the first temperature in the step I is -10-20°C.

Preferably, the second organic solvent in the step II is selected from one or more of dichloromethane, 1,2 dichloroethane, tetrahydrofuran, methanol, ethanol isopropanol, tert-butanol, and compound 3 The ratio of the mass (m) of the second organic solvent to the volume (v) of the second organic solvent is 1:320.

Preferably, the acid in step II is selected from one or more of sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, silica gel, and other acids of the same type.

Preferably, the second temperature in step II is -5-60°C.

Preferably, the mass ratio of compound 4, compound 5 and base described in step III is 1:1-2:1-5

Preferably, the third organic solvent in step III is selected from methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethyl One or more of the base acetamides, and the ratio of the weight of the compound 4 to the volume (v) of the third organic solvent is 1:5-20.

Preferably, the base in step III is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N, N-diisopropyl One or more of ethylamine, pyridine, other organic bases and inorganic bases.

Adopting the technical scheme of the present invention has the following beneficial effects: the scheme of the present invention has the advantages of simple operation, short preparation cycle, low cost and environmental protection, and the prepared haloperidol has high impurity purity and no obvious impurity points, which is in line with the impurity reference substance It can be used as a haloperidol impurity standard product in the qualitative and quantitative research and detection of haloperidol impurities, which has certain significance for the quality control of haloperidol raw materials and related preparations.

The present invention uses 4-bromo-4'-chloro-1,1'-biphenyl (raw material 1) and tert-butyl3-oxopiperidine-1-carboxylate (raw material 2), compound 5 as starting raw materials, raw material 1 reacts with magnesium powder Form a Grignard reagent to attack the carbon group in the structure of raw material 2 to obtain compound 3, compound 3 is obtained by simply removing the Boc protecting group to obtain compound 4, and finally compound 4 and compound 5 are condensed by halogen and amino under basic conditions to obtain haloperidol Pyridyl alcohol impurity E, the haloperidol impurity was synthesized with a total yield of 53.7%. In the synthesis process, the purification is simple, the yield is high, and no highly toxic and explosive dangerous goods are used, which conforms to the concept of modern environmental protection and sustainable development. convenient

Description of drawings

Fig. 1 is the synthetic schematic diagram of haloperidol impurity E of the present invention;

Fig. 2 is the hydrogen nuclear magnetic resonance spectrum schematic diagram of haloperidol impurity E of the present invention;

Fig. 3 is the mass spectrum schematic diagram 1 of haloperidol impurity E of the present invention;

Fig. 4 is the mass spectrum schematic diagram II of haloperidol impurity E of the present invention.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

Referring to Fig. 1 to Fig. 4, the present invention provides a kind of method of high yield and high purity synthetic haloperidol impurity E,

Step Ⅰ: Preparation of compound 3:

Take dry magnesium powder (2.0g, 0.083mol) and several iodine elemental substances in a dry 500mL round bottom flask, vacuumize and protect with nitrogen, add anhydrous 200MlTHF and dropwise add anhydrous THF dissolved raw material compound A (11.3 g, 0.041) and increase the temperature to 80°C, react for 2 hours to obtain the Grignard reagent of raw material 1, then dropwise add the THF solution of compound 2 (8.15g, 0.041mol), stir and dissolve at room temperature for 3 hours; then use The reaction was monitored by TLC chromatography, and the reaction was judged to be complete when the iodine cylinder developed color; then, after adding water to quench the reaction, dilute with ethyl acetate (500.0 mL) and transfer to a separatory funnel, followed by washing twice with water (100.0 mL) , then washed once with saturated brine (100.0mL), removed the water layer to collect the organic layer, then dried and filtered through anhydrous sodium sulfate, and the filtrate was distilled under reduced pressure to remove the organic solvent to obtain a crude product; then separated and purified by column chromatography (washing The removal agent was methanol:dichloromethane 1:20) to obtain (12.9g, yield 80%) white solid compound 3;

Step II: Preparation of Compound 4:

Take compound 3 (12.9 g, 0.033 mol) in 60.0 mL of MeOH, and add concentrated hydrochloric acid (0.70 mL, 0.087 mol). Stir at room temperature and react for 12 hours; monitor the reaction by mass spectrometry combined with TLC chromatography, and judge that the raw material has reacted completely after PMA color development; then add ethyl acetate (500.0mL) and add 200mL of water and adjust the pH to neutral and then extract. The organic layer was collected by removing the aqueous layer to obtain (8 g, 84%) white pure compound 4 by column chromatography.

Step III: Preparation of Haloperidol Impurity E:

Take compound 4 (8.0g, 0.027mol), compound 5 (5.4g, 0.027mol), K ₂ CO ₃ (7.45g, 0.54mol) in 30.0mL DCE, stir and react at 60°C for 12 hours; through mass spectrometry combined with TLC The reaction was monitored by chromatography, and it was judged that the raw material had reacted completely by PMA color development; then added ethyl acetate (500.0mL) and 200mL water, extracted and removed the water layer to collect the organic layer, and obtained (9.7g, 80%) white pure Haloperidol impurity E, the structure of the final product obtained was confirmed by H NMR and mass spectrometry, and the purity of liquid chromatography was 98.5%, as shown in Figure 2, Figure 3 and Figure 4 below:

MS(m/z): 452.3(M+H)+

¹ H NMR (400MHz, DMSO) δ8.12(dd, J=3.5Hz, 2H), 7.77(d, J=5.1Hz, 2H), 7.65-7.67(m, 2H), 7.56(d, J=4.4 Hz, 2H), 7.46(d, J=4.5Hz, 2H), 7.38(t, J=3.2Hz, 2H), 3.10(t, J=2.4Hz, 2H), 2.41–2.60(m, 6H), 1.66–1.90 (m, 4H), 1.50 (t, J=2.4Hz, 2H).

It can be seen from the above examples that the present invention has the advantages of simple operation, short preparation cycle, low cost and environmental protection. The prepared haloperidol has high impurity purity and no obvious impurity points, which meets the requirements of the impurity reference substance and can be used as haloperidol Alcohol impurity standards are used in the qualitative and quantitative research and detection of haloperidol impurities, which has certain significance for the quality control of haloperidol raw materials and related preparations.

The above is only a preferred embodiment of the present invention, and does not therefore limit the patent scope of the present invention. Under the inventive concept of the present invention, the equivalent structural transformation made by using the description of the present invention and the contents of the accompanying drawings, or direct/indirect use All other relevant technical fields are included in the patent protection scope of the present invention.

Claims (10)

1. a method for high-yield and high-purity synthetic haloperidol impurity E, is characterized in that, comprises the steps: Step Ⅰ: Dissolving compound 1, compound 2 and magnesium in the first organic solvent, stirring and reacting at the first temperature for 1-5 hours, after the reaction is completed, adding water to quench, extracting with organic solvent, and separating by column chromatography to obtain compound 3 , the reaction equation is as follows:

Step II: Dissolving compound 3 in the second organic solvent, adding acid, stirring at the second temperature for 0.5-3h, after the reaction is completed, spinning the reaction solution to obtain compound 4, the reaction equation is as follows:

Step III: Dissolving compound 4 and compound 5 in the third organic solvent, adding base, stirring at the third temperature for 1-20 h, adding water and organic solvent for extraction, drying the organic phase, and separating by column chromatography to obtain haloperidol Impurity E, its reaction equation is as follows:

2. the method for high-yield and high-purity synthetic haloperidol impurity E according to claim 1, is characterized in that, the mass ratio of compound 1, compound 2 and magnesium in the step 1 is 1: (0.5- 3): (1-4). 3. the method for the high yield and high purity synthetic haloperidol impurity E according to claim 2, characterized in that, the first organic solvent in the step I is selected from benzene, ether, tetrahydrofuran, 1,4- One or more of dioxane and methyl tert-butyl ether, and the ratio of the weight of compound 1 to the volume of the first organic solvent is 1: (10-40). 4. The method for synthesizing haloperidol impurity E with high yield and high purity according to claim 3, characterized in that, the first temperature in the step I is -10°C-20°C. 5. the method for high-yield and high-purity synthetic haloperidol impurity E according to claim 1, is characterized in that, the second organic solvent in described step II is selected from dichloromethane, 1,2 dichloroethane , tetrahydrofuran, methanol, ethanol isopropanol, tert-butanol, and the ratio of the mass of compound 3 to the volume of the second organic solvent is 1:320. 6. the method for high-yield and high-purity synthetic haloperidol impurity E according to claim 5, is characterized in that, the acid in described step II is selected from sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, silica gel one or more of . 7. The method for synthesizing haloperidol impurity E with high yield and high purity according to claim 6, characterized in that, the second temperature in the step II is -5°C-60°C. 8. The method for synthesizing haloperidol impurity E with high yield and high purity according to claim 1, wherein the mass ratio of compound 4, compound 5 and alkali described in step III is 1:( 1-2): (1-5). 9. the method for high-yield and high-purity synthetic haloperidol impurity E according to claim 8, is characterized in that, the 3rd organic solvent in the described step III is selected from methanol, ethanol, THF, acetonitrile, N-formazol One or more of base pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and the weight of compound 4 and the volume (v) of the third organic solvent The ratio is 1:(5-20). 10. the method for high-yield and high-purity synthetic haloperidol impurity E according to claim 9, is characterized in that, in described step III, alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, One or more of lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, and pyridine.

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