CN116143686A - Preparation method of haloperidol impurity D - Google Patents

Preparation method of haloperidol impurity D Download PDF

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CN116143686A
CN116143686A CN202211743582.3A CN202211743582A CN116143686A CN 116143686 A CN116143686 A CN 116143686A CN 202211743582 A CN202211743582 A CN 202211743582A CN 116143686 A CN116143686 A CN 116143686A
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impurity
haloperidol
chlorophenyl
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mass ratio
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刘智君
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Shenzhen Jiangchuan Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of haloperidol impurity D, which comprises the following steps: stirring and reacting 1- (4-chlorophenyl) -4-hydroxybutan-1-one, 4- (4-chlorophenyl) -4-hydroxypiperidine and alkali I in an organic solvent I to obtain an intermediate 1 (1- {4- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl ] phenyl } -4-hydroxybutan-1-one); reacting the intermediate 1 with p-toluenesulfonyl chloride and a base II in a solvent II to obtain an intermediate 2 (4-methylbenzenesulfonic acid-4- {4- [4- (4-chlorophenyl) -4-hydroxyhexahydropyridin-1-yl ] phenyl } -4-oxybutylene butyl ester); stirring and reacting the intermediate 2, 4- (4-chlorophenyl) -4-hydroxy piperidine and alkali III in a solvent III to prepare haloperidol impurity D; the preparation method can obviously improve the yield, efficiently and quickly prepare the haloperidol impurity D in large quantity, and provides convenience for impurity analysis and research of haloperidol bulk drugs and preparations thereof.

Description

Preparation method of haloperidol impurity D
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a novel haloperidol impurity D.
Background
Impurities contained in the medicine are main factors influencing the purity of the medicine, for example, if the medicine contains more than a limited amount of impurities, the physicochemical constant can be changed, the appearance characteristics can be changed, and the stability of the medicine can be influenced; the increase of impurities inevitably leads to lower content or lower activity of the medicine, and the toxic and side effects are obviously increased. Therefore, the impurity inspection of the medicine is an important link for controlling the purity of the medicine and improving the quality of the medicine.
The quality standard of haloperidol is described in the European pharmacopoeia, which explicitly states that haloperidol contains haloperidol impurity D, i.e
4- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl ] -1- [4- [4- (4-chlorophenyl) -4-hyd roxypiperidin-1-yl ] phenyl ] bunan 1-one. There are few reports of impurity D at present.
Chinese patent CN109970624a discloses a method for purifying haloperidol, comprising the steps of: dissolving the prepared haloperidol crude product in a hot DMSO solution, and filtering to remove dimeric impurities which are insoluble in DMSO, thus obtaining haloperidol with qualified dimeric impurity content; the reaction of haloperidol with 4- (4-chlorophenyl) -4-hydroxypiperidine under basic conditions is described as resulting in the presence of impurity D in the final drug substance, which is reported to be 0.57% and difficult to isolate, but this patent does not teach how to obtain impurity D.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method of haloperidol impurity D.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the invention provides a preparation method of haloperidol impurity D, which comprises the following steps:
step S1: stirring 1- (4-chlorophenyl) -4-hydroxybutan-1-one, 4- (4-chlorophenyl) -4-hydroxypiperidine and alkali I in an organic solvent I, filtering the reaction liquid after the reaction is finished, and separating and purifying by column chromatography to obtain an intermediate 1 (1- {4- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl ] phenyl } -4-hydroxybutan-1-one);
step S2: reacting the intermediate 1 with p-toluenesulfonyl chloride and alkali II in a solvent II, concentrating a reaction liquid after the reaction is finished, and separating and purifying by column chromatography to obtain an intermediate 2 (4-methylbenzenesulfonic acid-4- {4- [4- (4-chlorophenyl) -4-hydroxyhexahydropyridin-1-yl ] phenyl } -4-oxysubunit butyl ester);
step S3: stirring intermediate 2, 4- (4-chlorophenyl) -4-hydroxy piperidine and alkali III in a solvent III, reacting, adding water for quenching after the reaction is finished, extracting, drying and concentrating an organic phase, and separating and purifying by column chromatography to obtain haloperidol impurity D;
the reaction equation for the above steps is as follows:
Figure BDA0004029207470000021
preferably, the alkali one in the step S1 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine and pyridine, and the alkali one is 1- (4-chlorophenyl) -4-hydroxybutyl
-1-ketone with a mass ratio of 1.5:1.
preferably, the solvent one in the step S1 is selected from one or more of benzene, diethyl ether, tetrahydrofuran, 1, 4-dioxane and methyl tertiary butyl ether, and the mass ratio of the solvent one to 1- (4-chlorophenyl) -4-hydroxybut-1-one is 10:1.
preferably, in the step S1, the mass ratio of the 1- (4-chlorophenyl) -4-hydroxybut-1-one to the 4- (4-chlorophenyl) -4-hydroxypiperidine is 1:1.1.
preferably, the mass ratio of the intermediate 1 to the p-toluenesulfonyl chloride in the step S2 is 1:0.6.
preferably, the solvent II in the step S2 is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide, and the mass ratio of the solvent II to the intermediate 1 is 10:1.
preferably, the base two in the step S2 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine, pyridine, and the mass ratio of the base two to the intermediate 1 is 1:1.
preferably, the base three in the step S3 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine, pyridine, and the mass ratio of the base three to the intermediate 2 is 1.5:1.
preferably, the solvent three in the step S3 is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide, and the mass ratio of the solvent three to the intermediate 2 is 5:1.
preferably, the mass ratio of the intermediate 2 to the 4- (4-chlorophenyl) -4-hydroxypiperidine in the step S3 is 1:1.
the technical scheme of the invention has the following beneficial effects: advantage 1: the method can rapidly prepare a large amount of haloperidol impurity D by three-step conversion of the raw materials which are simple and easy to obtain. The main raw materials used in the method are as follows: 1- (4-chlorophenyl) -4-hydroxybutyrin-1-one can be prepared rapidly by literature methods (Chemistry-A EuropeanJournal,25 (15), 3950-3956; 2019); 4- (4-chlorphenyl) -4-hydroxy piperidine is an intermediate in the production of haloperidol bulk drug, and is cheap and available in large quantities.
Advantage 2: the method is efficient and rapid for preparing the haloperidol impurity D in large quantity, and provides convenience for impurity analysis and research of haloperidol bulk drugs and preparations thereof.
Drawings
FIG. 1 is a diagram of the reaction equation of the present invention;
FIG. 2 is a schematic diagram of the hydrogen nuclear magnetic resonance spectrum of haloperidol impurity D of the present invention;
FIG. 3 is a mass spectrum of haloperidol impurity D of the present invention.
Detailed Description
The invention will be further described with reference to the drawings and the specific examples.
Referring to fig. 1 to 3, the present invention provides a preparation method of haloperidol impurity D, which specifically comprises the following steps:
step S1: 5g of 1- (4-chlorophenyl) -4-hydroxybutan-1-one was dissolved in 10 times mass of 1, 4-dioxane, 1.1 mass ratio of 4- (4-chlorophenyl) -4-hydroxypiperidine was added, 1.5 mass ratio of sodium carbonate was heated to 50℃for 2 hours, and after the reaction was completed, the reaction solution was filtered, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate to give 7.2g of intermediate 1, yield 76% according to the following reaction equation:
Figure BDA0004029207470000041
step S2: 7.2g of intermediate 1 is dissolved in 10 times mass of N, N-dimethylformamide, 0.6 mass ratio of p-methylbenzoyl chloride and 1.0 mass ratio of cesium carbonate are added and heated to 40 ℃ for reaction for 6 hours, after the reaction is finished, filtration is carried out, the reaction solution is concentrated, and petroleum ether and ethyl acetate are used for column chromatography purification, so that 8.1g of intermediate 2 can be obtained, the yield is 80%, and the specific reaction equation is as follows:
Figure BDA0004029207470000042
step S3: dissolving 8.1g of intermediate 2 in dimethyl sulfoxide with the mass of 5 times, adding sodium hydride with the mass ratio of 1.5, reacting for 0.5 hour at room temperature, adding 4- (4-chlorophenyl) -4-hydroxy piperidine with the mass ratio of 1, reacting for 4 hours at room temperature, adding water for quenching after the reaction is finished, extracting with ethyl acetate, concentrating by organic phase drying, purifying by using petroleum ether and ethyl acetate column chromatography to obtain 6.6g of haloperidol impurity D, wherein the yield is 76%, and the specific reaction equation is as follows
Figure BDA0004029207470000051
The structure of the haloperidol impurity D product is confirmed by nuclear magnetic resonance hydrogen spectrum and mass spectrum, and the product is shown in the figures 2 to 3:
MS(Mm/z)：566(M+H)
1H NMR(400MHz，DMSO)δ7.54(d，J＝8.8Hz，2H)，7.40－7.55(m，4H)，7.20－7.38(m，4H)，7.04(d，J＝8.8Hz，2H)，5.26(s，1H)，4.50(s，1H)，3.85(d，J＝12Hz，2H)，3.28(t，J＝12Hz，2H)，2.87(t，J＝6.8Hz，2H)，2.50－2.68(m，2H)，2.24－2.41(m，4H)，1.85－2.01(m，2H)，1.54－1.85(m，6H)，1.48－1.54(m，2H)。
from the above embodiments, it can be seen that: the method can rapidly prepare a large amount of haloperidol impurity D by three-step conversion of the raw materials which are simple and easy to obtain. The main raw materials used in the method are as follows: 1- (4-chlorophenyl) -4-hydroxybutyrin-1-one can be prepared rapidly by literature methods (Chemistry-A European Journal,25 (15), 3950-3956; 2019); 4- (4-chlorphenyl) -4-hydroxy piperidine is an intermediate in the production of haloperidol bulk drug, and is cheap and available in large quantities.
The preparation method of the invention can efficiently and rapidly prepare a large amount of haloperidol impurity D, thereby providing convenience for impurity analysis and research of haloperidol bulk drugs and preparations thereof.
The foregoing description is only of the preferred embodiments of the present invention and is not intended to limit the scope of the invention, and all equivalent structural changes made by the description of the present invention and the accompanying drawings or direct/indirect application in other related technical fields are included in the scope of the invention.

Claims (10)

1. The preparation method of the haloperidol impurity D is characterized by comprising the following steps:
step S1: stirring 1- (4-chlorophenyl) -4-hydroxybutan-1-one, 4- (4-chlorophenyl) -4-hydroxypiperidine and alkali I in an organic solvent I, filtering the reaction liquid after the reaction is finished, and separating and purifying by column chromatography to obtain an intermediate 1 (1- {4- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl ] phenyl } -4-hydroxybutan-1-one);
step S2: reacting the intermediate 1 with p-toluenesulfonyl chloride and alkali II in a solvent II, concentrating a reaction liquid after the reaction is finished, and separating and purifying by column chromatography to obtain an intermediate 2 (4-methylbenzenesulfonic acid-4- {4- [4- (4-chlorophenyl) -4-hydroxyhexahydropyridin-1-yl ] phenyl } -4-oxysubunit butyl ester);
step S3: stirring intermediate 2, 4- (4-chlorophenyl) -4-hydroxy piperidine and alkali III in a solvent III, reacting, adding water for quenching after the reaction is finished, extracting, drying and concentrating an organic phase, and separating and purifying by column chromatography to obtain haloperidol impurity D;
the reaction equation for the above steps is as follows:
Figure QLYQS_1
2. the process for preparing haloperidol impurity D according to claim 1, wherein,
the first alkali in the step S1 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine and pyridine, and the mass ratio of 1- (4-chlorophenyl) -4-hydroxybut-1-one to the first alkali is 1:1.5.
3. the process for preparing haloperidol impurity D according to claim 2, wherein the solvent one in step S1 is selected from one or more of benzene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl t-butyl ether, and the mass ratio of 1- (4-chlorophenyl) -4-hydroxybutan-1-one to solvent one is 1:10.
4. the method for preparing haloperidol impurity D according to claim 3, wherein the mass ratio of 1- (4-chlorophenyl) -4-hydroxybut-1-one to 4- (4-chlorophenyl) -4-hydroxypiperidine in step S1 is 1:1.1.
5. the method for preparing haloperidol impurity D according to claim 1, wherein the mass ratio of intermediate 1 to p-toluenesulfonyl chloride in step S2 is 1:0.6.
6. the process for preparing the piperidinol impurity D as claimed in claim 5, wherein the solvent two in the step S2 is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N-dimethylformamide, and N, N-dimethylacetamide, and the mass ratio of the intermediate 1 to the solvent two is 1:10.
7. the process for preparing haloperidol impurity D according to claim 6, wherein the base in step S2 is one or more selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine, pyridine, and the mass ratio of the base two to the intermediate 1 is 1:1.
8. the method for preparing haloperidol impurity D according to claim 1, wherein the base three in step S3 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydride, lithium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine, pyridine, and the mass ratio of intermediate 2 to base three is 1:1.5.
9. the method for preparing haloperidol impurity D according to claim 8, wherein the solvent three in the step S3 is one or more selected from methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, and the mass ratio of the intermediate 2 to the solvent three is 1:5.
10. the method for preparing haloperidol impurity D according to claim 9, wherein the mass ratio of intermediate 2 to 4- (4-chlorophenyl) -4-hydroxypiperidine in step S3 is 1:1.
CN202211743582.3A 2022-12-30 2022-12-30 Preparation method of haloperidol impurity D Pending CN116143686A (en)

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