CN115108981A - Synthesis method of brexpiprazole impurity - Google Patents
Synthesis method of brexpiprazole impurity Download PDFInfo
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- CN115108981A CN115108981A CN202211036450.7A CN202211036450A CN115108981A CN 115108981 A CN115108981 A CN 115108981A CN 202211036450 A CN202211036450 A CN 202211036450A CN 115108981 A CN115108981 A CN 115108981A
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- impurity
- brexpiprazole
- piperazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Abstract
The invention discloses a synthesis method of an brexpiprazole impurity, belonging to the technical field of medicines. The method comprises the step of carrying out substitution reaction on a compound D and piperazine under the conditions of alkali and an organic solvent to obtain piperazine butoxy double-bond impurities, wherein the equivalent number of the compound D is 1.2eq-4.0 eq. The method successfully synthesizes the piperazine butoxy double-grafting impurity of the ipiprazole in a targeted mode, has high purity of the synthesized piperazine butoxy double-grafting impurity, can be used as a reference substance of related substances of the ipiprazole, is used for content determination of the ipiprazole and detection of the impurity and the related substances, and is an essential product for quality control of the ipiprazole.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of an brexpiprazole impurity.
Background
Ipiprazole was developed by tsukamur pharmaceutical companies together with the north medicine of denmark ling. The Food and Drug Administration (FDA) approved it for marketing at 7 months of 2015. The ipiprazole is effective in adjuvant therapy of schizophrenia and depressive disorder and has good safety and tolerance. The original patent WO2006112464A1 and the same family of Chinese patent CN101155804A report the following synthetic routes.
The research on related substances is an important content in the research and development process of the medicine, is directly related to the quality control and the medication safety of the medicine, and can ensure the quality and the safety of the product by controlling impurities in the medicine product. The related substances of the brexpiprazole refer to starting materials, intermediates, side reaction products, raw material residual derived impurities, degradation products and the like brought in the production process of the brexpiprazole.
In step 1 of the above synthetic scheme, the equivalent weight of piperazine will generally be much greater than 1.0 equivalent, typically 3.0 equivalents of piperazine. The purpose of the piperazine excess is to reduce the content of piperazine thiophene double-linked impurity E. However, if the excess piperazine is not removed completely after the post-treatment, the piperazine butoxy double-bond impurity F is generated by the continuous reaction with the compound C in the next step.
The precondition for researching the types and sources of impurities in the bulk drugs and controlling the generation of process impurities is to obtain related substances, so the directional synthesis of the piperazine butoxy double-junction impurity has important significance for effectively controlling the quality of the bulk drugs of the brexpiprazole and the preparations of the brexpiprazole. However, no literature is reported on the preparation of piperazine butoxy double-ligated impurities.
Disclosure of Invention
The invention provides a synthesis method of an brexpiprazole impurity to solve the technical problem.
The invention is realized by adopting the following technical scheme.
A synthetic method of an brexpiprazole impurity comprises the following steps: carrying out substitution reaction on a compound D and piperazine under the conditions of alkali and organic solvent to obtain piperazine butoxy double-bonded impurity F, wherein the structural formula of the compound D is shown in the specification
In the compound D, X is chlorine, bromine or iodine;
the structural formula of the piperazine butoxy double-bonded impurity F is shown in the specification
Further, the alkali is one or a mixture of more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, sodium hydride, triethylamine, DBU and DIPEA.
Furthermore, the organic solvent is selected from a protic solvent and/or an aprotic solvent.
Furthermore, the protic solvent is one or more of N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1, 4-dioxane, tetrahydrofuran, N, N-dimethylacetamide and 2-methyltetrahydrofuran.
Furthermore, the aprotic solvent is one or a mixture of methanol, ethanol, isopropanol and water.
Further, the number of equivalents of the compound D is 1.2eq to 4.0 eq. Preferably, the number of equivalents of compound D is 2.2 eq.
Further, the molar ratio of piperazine, compound D and base is 1: (1.5-3.0): (1.5 to 4.0), preferably 1: 2.2: 3.0.
further, the amount of the organic solvent is 5 to 15 times by volume, preferably 8 times by volume, of the compound D.
Further, the reaction temperature is 60-140 ℃, and the reaction time is 10-30 h.
The present application has the following advantageous effects.
The method successfully synthesizes the piperazine butoxy double-grafting impurity of the ipiprazole in a targeted mode, has high purity of the synthesized piperazine butoxy double-grafting impurity, can be used as a reference substance of related substances of the ipiprazole, is used for content determination of the ipiprazole and detection of the impurity and the related substances, and is an essential product for quality control of the ipiprazole. The whole preparation method is simple and convenient, lays a foundation for quality research and process development work of the brexpiprazole, and has wide application prospect.
Drawings
FIG. 1 shows the butoxy-bridged impurity compound F of piperazine prepared in example 1 of the present invention 1 H-NMR spectrum;
FIG. 2 is a low resolution mass spectrum of piperazine butoxy double-grafted impurity compound F prepared in example 1 of the present invention;
FIG. 3 is a high performance liquid chromatogram of piperazine butoxy-bis-grafted impurity compound F prepared in example 1 of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The preparation of piperazine butoxy double-grafting impurity comprises the following synthetic route:
to a 250 mL three-necked flask was added piperazine (0.73 g, 8.43mmol, 1.0 eq), potassium carbonate (3.0 eq, 25.29mmol, 3.49 g) and DMF (40 mL), was added compound D (2.2eq, 18.55mmol, 4.67g) and potassium iodide (MW: 166, 1.0eq, 8.43mmol, 1.4 g). Stirring at 50 deg.C for half an hour, and reacting at 80 deg.C for 12 h. And (3) cooling, adding purified water (100 mL) into the system, and carrying out crystallization and filtration.
Adding ethanol (160 mL), acetic acid (16 mL) and concentrated hydrochloric acid (5 mL) into the obtained filter cake, heating to 80 ℃, dissolving, cooling, crystallizing and filtering.
Adding ethanol (200 mL) into the obtained filter cake, heating to 70-80 ℃, and adding an aqueous solution of NaOH (0.72 g of NaOH is dissolved in 5mL of water for preparation). After the addition, cooling, crystallizing and filtering.
The obtained filter cake was subjected to normal phase silica gel column chromatography to obtain piperazine butoxy double-ligated impurity compound F (0.54g, white powder).
HPLC purity: 99.27 percent;
1 H-NMR（600Mhz，DMSO-d 6 ）δppm：11.566（2H，br），7.80（2H，d，J= 12.0Hz）,7.55（2H，m），6.78（4H，m），6.29（2H，d，J= 12.0Hz），4.02（4H，t，J= 6.0Hz），2.39（8H，m），1.77~1.57（4H，m），1.58（4H，m）
mass spectrum (ES +): m/z 517.64[ M + H ]] +
Mass Spectrometry (ES-): m/z 515.87[ M-H] - Theoretical value: 516.27.
the hplc results of piperazine butoxy double-ligated impurity compound F are shown in table 1 and fig. 3.
TABLE 1
Example 2
The preparation of piperazine butoxy double-grafting impurity comprises the following synthetic route:
piperazine (0.50 g, 5.81mmol, 1.0 eq), potassium hydroxide (3.0 eq, 17.43mmol, 0.98 g) and methanol (40 mL) were added to a 250 mL three-necked flask, compound D (2.2eq, 12.78mmol, 3.21g) was added, and reaction was carried out at 64 ℃ for 12 h. Cooling, crystallizing and filtering. The obtained filter cake was subjected to normal phase silica gel column chromatography to give piperazine butoxy double-bonded impurity compound F (0.61g, purity 97.17%, white powder).
The embodiments of the present invention are preferred embodiments of the present invention, and the scope of the present invention is not limited by these embodiments, so: all equivalent changes made according to the structure, shape and principle of the invention are covered by the protection scope of the invention.
Claims (9)
1. A synthesis method of an brexpiprazole impurity is characterized by comprising the following steps: the compound D and piperazine are subjected to substitution reaction under the conditions of alkali and organic solvent to obtainTo piperazine butoxy double-grafting impurity F, the structural formula of compound D is
In the compound D, X is chlorine, bromine or iodine;
the structural formula of the piperazine butoxy double-bonded impurity F is shown in the specification
2. The synthesis method of brexpiprazole impurity according to claim 1, wherein the base is selected from one or a mixture of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, sodium hydride, triethylamine, DBU, DIPEA.
3. The method for synthesizing brexpiprazole impurity according to claim 1, wherein the organic solvent is selected from protic solvent and/or aprotic solvent.
4. The method for synthesizing brexpiprazole impurity according to claim 3, wherein the protic solvent is one or more selected from N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1, 4-dioxane, tetrahydrofuran, N, N-dimethylacetamide and 2-methyltetrahydrofuran.
5. The method for synthesizing brexpiprazole impurity according to claim 3, wherein the aprotic solvent is selected from one or more of methanol, ethanol, isopropanol and water.
6. The method for synthesizing brexpiprazole impurity according to claim 1, wherein the number of equivalents of said compound D is 1.2eq-4.0 eq.
7. The method for synthesizing brexpiprazole impurity according to claim 1, wherein the molar ratio of piperazine, compound D and base is 1: (1.5-3.0): (1.5-4.0).
8. The process for synthesizing brexpiprazole as an impurity according to claim 1, wherein the amount of the organic solvent is 5 to 15 times the volume of the compound D.
9. The synthesis method of the brexpiprazole impurity according to claim 1, wherein the reaction temperature is 60-140 ℃ and the reaction time is 10-30 h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892909A (en) * | 2015-12-18 | 2017-06-27 | 重庆医药工业研究院有限责任公司 | One kind is according to piperazine azoles impurity compound and preparation method thereof |
| WO2018060916A1 (en) * | 2016-09-28 | 2018-04-05 | Alembic Pharmaceuticals Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN111393423A (en) * | 2019-01-03 | 2020-07-10 | 上海科胜药物研发有限公司 | Epipiprazole impurity compound and preparation method thereof |
| CN114166960A (en) * | 2021-11-10 | 2022-03-11 | 西安远大科创医药科技有限公司 | Detection method of brexpiprazole related substance |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892909A (en) * | 2015-12-18 | 2017-06-27 | 重庆医药工业研究院有限责任公司 | One kind is according to piperazine azoles impurity compound and preparation method thereof |
| WO2018060916A1 (en) * | 2016-09-28 | 2018-04-05 | Alembic Pharmaceuticals Limited | Process for the preparation of brexpiprazole and intermediates thereof |
| CN111393423A (en) * | 2019-01-03 | 2020-07-10 | 上海科胜药物研发有限公司 | Epipiprazole impurity compound and preparation method thereof |
| CN114166960A (en) * | 2021-11-10 | 2022-03-11 | 西安远大科创医药科技有限公司 | Detection method of brexpiprazole related substance |
Non-Patent Citations (1)
| Title |
|---|
| 甄汉深，等: "《药物分析学》", 31 August 2017, 中国中医药出版社 * |
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Application publication date: 20220927 |