CN115260087A - Nicardipine hydrochloride impurity and synthesis method and application thereof - Google Patents
Nicardipine hydrochloride impurity and synthesis method and application thereof Download PDFInfo
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- CN115260087A CN115260087A CN202211210225.0A CN202211210225A CN115260087A CN 115260087 A CN115260087 A CN 115260087A CN 202211210225 A CN202211210225 A CN 202211210225A CN 115260087 A CN115260087 A CN 115260087A
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- 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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to an impurity of nicardipine hydrochloride, a synthesis method and application thereof. The nicardipine hydrochloride impurity has a structure shown in a formula (I), and is TPJ for short; the invention takes 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid as a raw material, oxalyl chloride and N-methyldiethanolamine are sequentially dropwise added into the raw material to synthesize nicardipine hydrochloride impurities which are easy to generate in the production process of nicardipine hydrochloride so as to facilitate the research on the structure and the property of the impurities.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an impurity of nicardipine hydrochloride, a synthesis method and application thereof.
Background
Nicardipine hydrochloride is used as calcium ion antagonist of dihydropyridines, is mainly used for treating cardiovascular and cerebrovascular diseases clinically, and has the effects of dilating coronary artery, improving myocardial ischemia, dilating peripheral blood vessels, reducing blood pressure and the like.
Currently, nicardipine hydrochloride is mostly produced by adopting a synthesis route of an esterification method, but the applicant finds in research that when nicardipine hydrochloride is produced in a workshop by adopting the synthesis route of the esterification method, polymer-like nicardipine hydrochloride impurities (TPJ for short) are generated in liquid phase detection of a product, and the impurities are easy to remain in the product (generally, the content is about 0.5%) in the subsequent refining process of a crude product of nicardipine hydrochloride, so that the purity of the product is influenced. The inventor further discovers that after trace N-methyldiethanolamine, 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid and oxalyl chloride form an intermediate TM3, the TM3 and the N-methyldiethanolamine form TPJ as an impurity after the N-benzyl-N-methylaminoethanol used as a raw material for synthesizing the nicardipine hydrochloride contains the trace N-methyldiethanolamine.
The generation of the impurity TPJ reduces the quality of the nicardipine hydrochloride, and in order to effectively detect and control the content of the impurity in the nicardipine hydrochloride, a reference substance of the impurity TPJ needs to be obtained for quantitative and qualitative analysis. However, the purity of the commonly-occurring impurities is low, the research conditions on the structure and the properties of the impurities cannot be met, the single preparation yield is low, and the research technology on the impurities is hindered. Therefore, it is necessary to carry out a more intensive study on the synthesis method of the impurity TPJ to make up for the defects in the prior art, provide a qualified and easily-obtained reference substance for the quality control of nicardipine hydrochloride, and provide an important guiding significance for safe medication.
Disclosure of Invention
Aiming at the problems in the prior art and aiming at monitoring and optimizing the quality of nicardipine hydrochloride, the invention deeply researches impurities of nicardipine hydrochloride (TPJ for short) and provides a synthesis method and application thereof.
The impurity TPJ has the following structure:
the synthetic route is as follows:
the method comprises the following specific steps:
(1) Adding a solvent into a reaction bottle, cooling to-5-5 ℃, adding 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, slowly dropwise adding oxalyl chloride, and keeping the temperature at-5-5 ℃ for reaction after dropwise adding;
(2) After the reaction is finished, dropwise adding N-methyldiethanolamine into the reaction bottle, and then carrying out heat preservation reaction;
(3) After the reaction is finished, dropwise adding water into the system for quenching, separating liquid, drying and carrying out rotary evaporation to obtain the product.
In the step (1), the solvent is a mixed solvent of dichloromethane and DMF, and the volume ratio of dichloromethane: DMF =100-200:1.
in step (1), 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid: oxalyl chloride =1:1-1.5.
In the step (1), the reaction is carried out for 2-3h under the condition of heat preservation.
5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, by mole ratio: n-methyldiethanolamine =1:0.5-1.1.
In the step (2), the reaction is carried out for 1-2h under the condition of heat preservation.
The invention has the following beneficial effects:
1. the invention provides a method for synthesizing nicardipine hydrochloride impurities (TPJ for short), provides a new substance and a synthesis and purification mode of the new substance, and fills the blank of the prior art;
2. the method for synthesizing and purifying nicardipine hydrochloride impurities (TPJ for short) provided by the invention is simple and convenient to operate, easy to control and simple in post-treatment, and the single preparation yield reaches gram level, so that the impurity quality control requirement is met;
3. the synthesized nicardipine hydrochloride impurity (TPJ for short) has stable property and high purity (96-99 percent), can be directly used as a high-quality standard product for monitoring the content detection of the impurity in the nicardipine hydrochloride product, has high application value, and can meet the research requirements of the industry on the structure and the property of the nicardipine hydrochloride and the nicardipine hydrochloride impurity.
Drawings
FIG. 1 is a mass spectrum of impurities of nicardipine hydrochloride (TPJ for short);
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of nicardipine hydrochloride impurity (TPJ for short);
FIG. 3 is a nuclear magnetic resonance carbon spectrum of nicardipine hydrochloride impurity (TPJ for short) of the present invention;
FIG. 4 is a liquid chromatogram of nicardipine hydrochloride impurity (TPJ for short) of the invention;
FIG. 5 is a liquid chromatogram of impurities (TPJ for short) of nicardipine hydrochloride and nicardipine hydrochloride.
Detailed Description
Example 1
A method for synthesizing nicardipine hydrochloride impurities comprises the following steps:
(1) Adding 200ml DCM and 2ml DMF into a reaction bottle, cooling to-5 ℃, adding 10.0g 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, slowly dropwise adding 4.20g oxalyl chloride, and preserving the temperature at-5 ℃ for reacting for 2 hours after dropwise adding;
(2) After the reaction is finished, 1.80g of N-methyldiethanolamine is dripped into the reaction bottle, and the reaction is carried out for 2 hours after the dripping is finished;
(3) After the reaction is finished, 100ml of water is dripped into the system for quenching, liquid separation, drying and rotary evaporation are carried out, and 4.5g of the product, namely TPJ, is obtained, the yield is 40 percent, and the purity is 99.4 percent.
Example 2
A method for synthesizing nicardipine hydrochloride impurities comprises the following steps:
(4) 150ml DCM and 1ml DMF are added into a reaction bottle, the temperature is reduced to 5 ℃, 10.0g 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid is added, 5.60g of oxalyl chloride is slowly dripped, and the temperature is kept at 5 ℃ for reaction for 2.5 hours after the dripping is finished;
(5) After the reaction is finished, 3.9g of N-methyldiethanolamine are dripped into the reaction bottle, and the reaction is carried out for 1 hour after the dripping is finished;
(3) After the reaction is finished, 100ml of water is dripped into the system for quenching, liquid separation, drying and rotary evaporation are carried out, and 3.94g of the product, namely TPJ, is obtained, the yield is 35 percent, and the purity is 99.2 percent.
Example 3
A method for synthesizing nicardipine hydrochloride impurities comprises the following steps:
(6) Adding 200ml DCM and 1ml DMF into a reaction bottle, cooling to 0 ℃, adding 10.0g 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, slowly dropwise adding 4.80g oxalyl chloride, and preserving the temperature at 0 ℃ for reacting for 3 hours after dropwise adding;
(7) After the reaction is finished, 2.8g of N-methyldiethanolamine are dripped into the reaction bottle, and the reaction is carried out for 1.5h after the dripping is finished;
(3) After the reaction is finished, 100ml of water is dripped into the system for quenching, liquid separation, drying and rotary evaporation are carried out, and 5.0g of the product, namely TPJ, is obtained, the yield is 44.4 percent, and the purity is 99.5 percent.
The mass spectrum, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum of the nicardipine hydrochloride impurity (abbreviated as TPJ) obtained in example 3 are respectively shown in fig. 1-3.
Example 4
Application of the product obtained in example 3 as a Standard
A chromatographic column GL C18.6X 250mm,5μm; the detection wavelength is 236nm; the column temperature is 35 ℃; the sample injection amount is 20 mu l; the flow rate is 1.0ml/min; mobile phase A, 2.8g/L sodium perchlorate solution (perchloric acid adjusted pH to 2.5); mobile phase B acetonitrile-methanol (70; gradient program:
and (3) testing results: as shown in fig. 4 and 5. FIG. 4 shows a liquid chromatogram of nicardipine hydrochloride impurity (TPJ for short); fig. 5 shows a liquid chromatogram of nicardipine hydrochloride impurity (abbreviated as TPJ) and nicardipine hydrochloride.
As can be seen from FIG. 5, impurities of nicardipine hydrochloride (TPJ for short) and nicardipine hydrochloride can be simultaneously detected by a liquid chromatography detection method, and the impurities and the nicardipine hydrochloride have good separation degree. The content of impurities (TPJ for short) of the nicardipine hydrochloride and the content of other impurities in the preparation process of the nicardipine hydrochloride can be detected by a liquid chromatography detection method, so that qualitative and quantitative analysis of the nicardipine hydrochloride can be facilitated, and the quality of the nicardipine hydrochloride can be better improved.
Claims (8)
1. An impurity of nicardipine hydrochloride having the structure of formula (I):
2. a method for synthesizing the nicardipine hydrochloride impurity of claim 1, comprising the steps of:
(1) Adding a solvent into a reaction bottle, cooling to-5-5 ℃, adding 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid, slowly dripping oxalyl chloride, and keeping the temperature to react at-5-5 ℃;
(2) After the reaction is finished, dropwise adding N-methyldiethanolamine into the reaction bottle, and then carrying out heat preservation reaction;
(3) After the reaction is finished, dropwise adding water into the system for quenching, separating liquid, drying and carrying out rotary evaporation to obtain the product.
3. The method for synthesizing nicardipine hydrochloride impurity of claim 2, wherein in step (1), the solvent is a mixed solvent of dichloromethane and DMF, and the volume ratio of dichloromethane: DMF =100-200:1.
4. the method for synthesizing the nicardipine hydrochloride impurity of claim 2 wherein in step (1), 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid: oxalyl chloride =1:1-1.5.
5. The method for synthesizing nicardipine hydrochloride impurity as claimed in claim 2, characterized in that in step (1), the reaction is carried out for 2-3h under the condition of heat preservation.
6. The method for synthesizing nicardipine hydrochloride impurity of claim 2 wherein 5- (methoxycarbonyl) -2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid: n-methyldiethanolamine =1:0.5-1.1.
7. The method for synthesizing nicardipine hydrochloride impurity according to claim 2, characterized in that in step (2), the reaction is carried out for 1-2h under the condition of heat preservation.
8. The use of the impurity of nicardipine hydrochloride of claim 1 as a standard in monitoring the quality of nicardipine hydrochloride products.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397245A (en) * | 2011-11-05 | 2012-04-04 | 辽宁海神联盛制药有限公司 | Nicardipine hydrochloride glucose injection |
| CN111289653A (en) * | 2020-03-19 | 2020-06-16 | 陕西省食品药品监督检验研究院 | Method for detecting 5-hydroxymethylfurfural impurity and impurity I in nicardipine hydrochloride glucose injection |
| CN113072483A (en) * | 2021-03-30 | 2021-07-06 | 济南良福精合医药科技有限公司 | Refining method of nicardipine hydrochloride |
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- 2022-09-30 CN CN202211210225.0A patent/CN115260087A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397245A (en) * | 2011-11-05 | 2012-04-04 | 辽宁海神联盛制药有限公司 | Nicardipine hydrochloride glucose injection |
| CN111289653A (en) * | 2020-03-19 | 2020-06-16 | 陕西省食品药品监督检验研究院 | Method for detecting 5-hydroxymethylfurfural impurity and impurity I in nicardipine hydrochloride glucose injection |
| CN113072483A (en) * | 2021-03-30 | 2021-07-06 | 济南良福精合医药科技有限公司 | Refining method of nicardipine hydrochloride |
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