CN112694437A - Preparation method of chlorpheniramine maleate impurity - Google Patents

Preparation method of chlorpheniramine maleate impurity Download PDF

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CN112694437A
CN112694437A CN202011615902.8A CN202011615902A CN112694437A CN 112694437 A CN112694437 A CN 112694437A CN 202011615902 A CN202011615902 A CN 202011615902A CN 112694437 A CN112694437 A CN 112694437A
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compound
sodium
preparation
tert
chlorpheniramine maleate
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宋更申
刘立杰
姚鹏
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Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
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Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
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Abstract

The invention relates to the technical field of pharmaceutical chemical quality control, in particular to a preparation method of chlorpheniramine maleate impurities. The preparation method of the chlorpheniramine maleate impurity provided by the invention comprises the following steps: (1) under the action of an alkaline condition and a phase transfer catalyst, reacting the compound 1 with N- (tert-butyloxycarbonyl) -2-chloroethyl amine to obtain a compound 2; (2) and reacting the compound 2 with a reducing agent to obtain the chlorpheniramine maleate impurity. The preparation method provided by the invention can directionally synthesize the EP impurity C in the European pharmacopoeia in chlorphenamine maleate, has the advantages of simple and feasible process operation, high yield, high purity, short reaction time and the like, solves the problem of shortage of an impurity reference substance, and is more favorable for quality control of a chlorphenamine maleate raw material product.

Description

Preparation method of chlorpheniramine maleate impurity
Technical Field
The invention belongs to the technical field of pharmaceutical chemical quality control, and particularly relates to a preparation method of chlorpheniramine maleate impurities.
Background
Chlorpheniramine maleate, also known as chlorpheniramine maleate, is an antihistamine drug and has the following structure. Chlorpheniramine maleate has an antiallergic effect through antagonism to H1 receptors, is mainly used for relieving cold symptoms such as lacrimation, sneezing, watery nasal discharge and the like, and has great market demand.
The existence of impurities in the raw material drug product of chlorpheniramine maleate can influence the pharmacological activity of the drug per se and even generate adverse reactions, so the research on the impurities is carried out standardly, the impurities are controlled within a safe and reasonable limit range, and the quality and the safety of the chlorpheniramine maleate are directly related. In the prior art, researches on a method for synthesizing impurities in a chlorpheniramine maleate raw material medicine finished product exist, and for example, CN111100067A discloses a novel chlorpheniramine impurity and a preparation process thereof.
However, monomethyl impurities (i.e. impurity C in european pharmacopoeia EP, structure shown below) generally exist in the finished chlorpheniramine maleate bulk drug product, and no reports related to the preparation process are found.
Figure BDA0002876669590000011
The method has great significance for synthesizing the impurity C in EP, and can be used for qualitative and quantitative analysis of impurities in chlorphenamine maleate production, thereby improving the quality standard of chlorphenamine maleate.
Therefore, the invention is especially provided.
Disclosure of Invention
The invention provides a preparation method of chlorpheniramine maleate impurities, which has the advantages of simplicity, easiness, high yield, high purity, short reaction time and the like, solves the problem of shortage of reference substances, and is more favorable for quality control of chlorpheniramine maleate raw material medicine finished products.
The preparation method of the chlorpheniramine maleate impurity comprises the following steps:
(1) under the action of an alkaline condition and a phase transfer catalyst, reacting the compound 1 with N- (tert-butyloxycarbonyl) -2-chloroethyl amine to obtain a compound 2;
the compound 1 is
Figure BDA0002876669590000021
Compound 2 is
Figure BDA0002876669590000022
(2) Reacting the compound 2 with a reducing agent to obtain chlorpheniramine maleate impurities
Figure BDA0002876669590000023
The invention takes the compound 1 as a raw material, and not only obtains the monomethyl impurity C through the route design of reaction with N- (tert-butyloxycarbonyl) -2-chloroethyl amine and further reduction, but also has the advantages of simple and easy synthetic route, high yield and high purity; compared with other conventional reagents containing-NH groups, the method selects N- (tert-butyloxycarbonyl) -2-chloroethylamine to react with the compound 1, and has the advantages of more complete reaction and higher reaction system purity.
The specific synthetic route is as follows:
Figure BDA0002876669590000024
the invention also optimizes the synthesis conditions, which are as follows:
further, in the step (1), the base used in the alkaline condition is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydrogen, sodium amide, pyridine, DBU (1, 8-diazabicycloundecen-7-ene), sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium amide; compared with other alkalis, the sodium amide has the advantages of mild reaction conditions and simple and convenient post-treatment.
Further, in the step (1), the Phase Transfer Catalyst (PTC) is one or more of tetrabutylammonium fluoride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate or tetrabutylammonium hydrogen sulfate, preferably tetramethylammonium chloride and/or tetrabutylammonium bromide, and more preferably tetrabutylammonium bromide. Compared with other catalysts, the tetrabutylammonium bromide is more favorable for accelerating the reaction process and shortening the reaction time.
Further, in the step (1), the molar ratio of the compound 1 to the N- (tert-butyloxycarbonyl) -2-halogenated ethylamine is 1 (0.8-1.5), preferably 1 (1.05-1.1). Research shows that reasonable addition ratio of N- (tert-butyloxycarbonyl) -2-halogenated ethylamine helps to improve reaction yield.
Further, in the step (1), the reaction temperature is 35-90 ℃, preferably 65-75 ℃. The reaction yield and the system purity are improved by controlling the reaction temperature.
As one embodiment of the present invention, in the step (1), the base used in the alkaline condition is sodium amide; the phase transfer catalyst is tetrabutylammonium bromide; the molar ratio of the compound 1 to the N- (tert-butyloxycarbonyl) -2-halogenated ethylamine is 1 (1.05-1.1); the temperature of the reaction is 65-75 ℃. By specific selection of alkali and catalyst and control of material molar ratio and reaction conditions, the reaction yield and efficiency can be obviously improved.
In the step (2), the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, red aluminum or lithium aluminum hydride, preferably sodium borohydride and/or lithium aluminum hydride, and more preferably lithium aluminum hydride. Compared with other reducing agents, the lithium aluminum hydride is more beneficial to improving the reaction yield.
Further, in the step (2), the solvent used in the reaction is one or more of tetrahydrofuran, toluene, DMSO (dimethyl sulfoxide), 1, 4-dioxane or diethyl ether, and is preferably toluene. Compared with other solvents, the toluene is more beneficial to improving the purity of the reaction system.
Furthermore, in the step (2), the reaction temperature is 35-100 ℃, preferably 75-85 ℃, which is more beneficial to improving the reaction yield and the system purity.
Further, in the step (2), the molar ratio of the compound 2 to the reducing agent is 1 (1.5-3.5), preferably 1 (2.0-2.5). The addition proportion of the reducing agent is reasonably controlled, so that the purity of the system is improved.
The invention has the following beneficial effects:
the preparation method provided by the invention can directionally synthesize the EP impurity C in the European pharmacopoeia in chlorphenamine maleate, has the advantages of simple and feasible process operation, high yield, high purity, short reaction time and the like, solves the problem of shortage of an impurity reference substance, and is more favorable for quality control of a chlorphenamine maleate raw material product.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Each of the components in the following examples is commercially available.
Example 1
The embodiment provides a preparation method of chlorpheniramine maleate impurities, which comprises the following steps:
(1) adding compound 1(2.04g, 10mmol) into 30mL of toluene, weighing sodium amide (0.98g, 25mmol) into the toluene solution, adding N- (tert-butoxycarbonyl) -2-chloroethylamine solid (1.97g, 11mmol) and tetrabutylammonium chloride (140mg, 0.5mmol), reacting at 65-70 ℃ for 5-6h, cooling, adding 10mL of water for quenching reaction, extracting, separating liquid, and concentrating the organic phase to remove the solvent to obtain 3.11g of compound 2 with the yield of 89.7%.
(2) Adding the oily compound 2 obtained in the step (1) into 25mL of toluene, weighing sodium borohydride (750mg, 20mmol), adding the sodium borohydride into the toluene solution, reacting at 75-85 ℃ for 4-5h, cooling, adding 10mL of water to quench the reaction, extracting and separating liquid, and concentrating an organic phase to remove the solvent to obtain 1.88g of a target compound, wherein the yield is 72.3% and the purity is 90.07% according to the compound 1.
Example 2
The embodiment provides a preparation method of chlorpheniramine maleate impurities, which comprises the following steps:
(1) the compound 1(2.04g, 10mmol) was added to 30mL of toluene, sodium amide (0.98g, 25mmol) was weighed and added to the above toluene solution, N- (tert-butoxycarbonyl) -2-chloroethylamine solid (1.97g, 11mmol) and tetramethylammonium chloride (55mg, 0.5mmol) were added, reacted at 65-70 ℃ for 4-5h, after cooling, 10mL of water was added to quench the reaction, extraction and separation were carried out, and the organic phase was concentrated to remove the solvent, whereby 3.16g of the compound 2 was obtained, with a yield of 91.3%.
(2) Adding the oily compound 2 obtained in the step (1) into 25mL of toluene, weighing lithium aluminum hydride (0.72g, 20mmol), adding the lithium aluminum hydride into the toluene solution, reacting at 75-85 ℃ for 4-5h, cooling, adding 10mL of water for quenching reaction, extracting, separating liquid, and concentrating an organic phase to remove a solvent to obtain 2.10g of a target compound, wherein the yield is 80.5% and the purity is 89.66% according to the compound 1.
Example 3
The embodiment provides a preparation method of chlorpheniramine maleate impurities, which comprises the following steps:
(1) adding compound 1(2.04g, 10mmol) into 30mL of toluene, weighing sodium amide (0.98g, 25mmol) into the toluene solution, adding N- (tert-butoxycarbonyl) -2-chloroethylamine solid (1.97g, 11mmol) and tetrabutylammonium bromide (0.16g, 0.5mmol), reacting at 65-70 ℃ for 2-3h, cooling, adding 10mL of water for quenching reaction, extracting, separating liquid, concentrating the organic phase, and removing the solvent to obtain 3.32g of compound 2, wherein the yield is 95.3%.
(2) Adding the oily compound 2 obtained in the step (1) into 25mL of toluene, weighing lithium aluminum hydride (0.72g, 20mmol), adding the lithium aluminum hydride into the toluene solution, reacting at 75-85 ℃ for 4-5h, cooling, adding 10mL of water for quenching reaction, extracting, separating liquid, and concentrating an organic phase to remove a solvent to obtain 2.25g of a target compound, wherein the yield is 86.53 percent and the purity is 92.46 percent based on the compound 1.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims (10)

1. A preparation method of chlorpheniramine maleate impurities is characterized by comprising the following steps:
(1) under the action of an alkaline condition and a phase transfer catalyst, reacting the compound 1 with N- (tert-butyloxycarbonyl) -2-chloroethyl amine to obtain a compound 2;
the compound 1 is
Figure FDA0002876669580000011
Compound 2 is
Figure FDA0002876669580000012
(2) Reacting the compound 2 with a reducing agent to obtain chlorpheniramine maleate impurities
Figure FDA0002876669580000013
2. The preparation method according to claim 1, wherein in the step (1), the base used in the basic condition is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydrogen, sodium amide, pyridine, DBU, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium amide.
3. The method according to claim 1, wherein in the step (1), the phase transfer catalyst is one or more of tetrabutylammonium fluoride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, or tetrabutylammonium hydrogen sulfate, and preferably tetrabutylammonium bromide.
4. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the compound 1 to the N- (tert-butoxycarbonyl) -2-haloethylamine is 1 (0.8-1.5), preferably 1 (1.05-1.1).
5. The method according to claim 1, wherein the reaction temperature in the step (1) is 35 to 90 ℃, preferably 65 to 75 ℃.
6. The process according to claim 1, wherein in the step (1), the base used in the basic condition is sodium amide; the phase transfer catalyst is tetrabutylammonium bromide; the molar ratio of the compound 1 to the N- (tert-butyloxycarbonyl) -2-halogenated ethylamine is 1 (1.05-1.1); the temperature of the reaction is 65-75 ℃.
7. The method according to any one of claims 1 to 6, wherein in the step (2), the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, red aluminum, or lithium aluminum hydride, preferably sodium borohydride and/or lithium aluminum hydride, and more preferably lithium aluminum hydride.
8. The method according to any one of claims 1 to 6, wherein in step (2), the solvent used in the reaction is one or more of tetrahydrofuran, toluene, DMSO, 1, 4-dioxane, or diethyl ether, preferably toluene.
9. The process according to any one of claims 1 to 6, wherein the reaction temperature in the step (2) is 35 to 100 ℃, preferably 75 to 85 ℃.
10. The method according to any one of claims 1 to 6, wherein in the step (2), the molar ratio of the compound 2 to the reducing agent is 1 (1.5-3.5), preferably 1 (2.0-2.5).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113956197A (en) * 2021-09-29 2022-01-21 艾希尔(深圳)药物研发有限公司 Preparation method of chlorpheniramine maleate impurity
CN114773176A (en) * 2022-05-12 2022-07-22 山西辅仁恒峰药业有限公司 Chlorpheniramine maleate impurity, and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015767A1 (en) * 2005-07-20 2007-02-08 Eli Lilly And Company Pyridine derivatives as dipeptedyl peptidase inhibitors
EP3339304A1 (en) * 2016-12-20 2018-06-27 Laboratorios del Dr. Esteve, S.A. Quinoline and isoquinoline derivatives for treating pain and pain related conditions
CN111039854A (en) * 2019-12-31 2020-04-21 四川迪菲特药业有限公司 Novel chlorpheniramine oxide impurity and preparation process thereof
CN111100067A (en) * 2019-12-31 2020-05-05 四川迪菲特药业有限公司 New chlorpheniramine maleate impurity and preparation process thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015767A1 (en) * 2005-07-20 2007-02-08 Eli Lilly And Company Pyridine derivatives as dipeptedyl peptidase inhibitors
EP3339304A1 (en) * 2016-12-20 2018-06-27 Laboratorios del Dr. Esteve, S.A. Quinoline and isoquinoline derivatives for treating pain and pain related conditions
CN111039854A (en) * 2019-12-31 2020-04-21 四川迪菲特药业有限公司 Novel chlorpheniramine oxide impurity and preparation process thereof
CN111100067A (en) * 2019-12-31 2020-05-05 四川迪菲特药业有限公司 New chlorpheniramine maleate impurity and preparation process thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113956197A (en) * 2021-09-29 2022-01-21 艾希尔(深圳)药物研发有限公司 Preparation method of chlorpheniramine maleate impurity
CN114773176A (en) * 2022-05-12 2022-07-22 山西辅仁恒峰药业有限公司 Chlorpheniramine maleate impurity, and preparation method and application thereof

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Application publication date: 20210423