CN112898268A - Preparation method of desloratadine impurity - Google Patents
Preparation method of desloratadine impurity Download PDFInfo
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- CN112898268A CN112898268A CN202110372114.9A CN202110372114A CN112898268A CN 112898268 A CN112898268 A CN 112898268A CN 202110372114 A CN202110372114 A CN 202110372114A CN 112898268 A CN112898268 A CN 112898268A
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- desloratadine
- impurity
- grignard reagent
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- chloropiperidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a preparation method of desloratadine impurities, which comprises the following steps: reacting N-methyl-4-chloropiperidine with magnesium in a solvent to prepare a Grignard reagent; adding the bromo-impurities into the Grignard reagent, and reacting for 2-16 hours at the temperature of 0-60 ℃; quenching with aqueous ammonium chloride solution or dilute hydrochloric acid; extracting, drying and concentrating to obtain a crude product; and purifying the crude product by column chromatography. The invention can be prepared by utilizing the processing conditions, solvents, reagents and other raw materials in the synthesis of the loratadine, and only needs to be extracted after the preparation is finished, thereby saving the synthesis raw materials, simplifying the synthesis process and being beneficial to reducing the production cost of the desloratadine impurity.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of desloratadine impurities.
Background
Allergic diseases are a common disease of human beings, and include allergic dermatitis, allergic rhinitis, allergic asthma and the like. The onset symptoms mainly comprise sneezing, rhinorrhea, nasal obstruction, skin pruritus and the like, and the allergic diseases bring inconvenience to the work and life of people. In recent years, the number of allergic rhinitis diseases accounts for about 20-25% of the global number, and the allergic rhinitis diseases tend to rise year by year, and with the prevalence of the allergic rhinitis diseases, more people suffer from the allergic rhinitis diseases in the future. The pathogenesis of the disease is greatly related to Histamine (Histamine), an active substance in the body. Histamine is an auto-active substance with a small molecular weight, is obtained from L-histidine under the action of histamine decarboxylase, is present in all animals as an important neurotransmitter, and is widely distributed in various tissues of human bodies. When a human body is subjected to external stimuli such as antigen-antibody reaction or trauma, it is released outside the cells in an activated form, causing allergic reactions. It has been found that histamine is released in mg levels per million cells, with very small amounts being able to elicit a wide range and powerful physiological activity, and thus, histamine is a major mediator of immune and inflammatory responses. Desloratadine is an active metabolite of the loratadine obtained by removing ethyl acetate in vivo, has the effects of histamine resistance, allergy resistance and inflammation resistance, and clinical tests show that the desloratadine has better curative effects on chronic idiopathic urticaria, seasonal allergic rhinitis and perennial allergic rhinitis. The desloratadine can be specifically combined with H1 receptor with high selectivity, and among currently known antihistamine drugs, the desloratadine has strong binding capacity with H1 receptor and has remarkable effect of resisting H1 receptor. Desloratadine was 4-fold stronger than loratadine in known histamine-induced paw swelling in mice. In addition, the desloratadine is well absorbed, the onset time is less than 30min, the maximum blood concentration is reached within about 3h after the desloratadine is orally taken, the half-life period is about 24h, and the effect is durable. In the aspect of toxicity, desloratadine does not block cardiac potassium channels, does not trigger cardiac reaction, and has no cardiotoxicity. A series of experiments on the heart safety of desloratadine by Kreutner and the like are carried out, and the desloratadine is taken by mice, guinea pigs and monkeys at 12mg/kg, 25mg/kg and 12mg/kg respectively, so that the blood pressure, the heart rate and the electrocardiogram are not obviously changed. Banfield et al tested healthy volunteers with 9 times of the conventional oral dose of desloratadine and found that there was no abnormal change in various electrocardiogram indexes. In conclusion, desloratadine as a third-generation H1 receptor antagonist has the advantages of stronger H1 receptor binding capacity, quick response, long drug half-life, no obvious cardiotoxicity and the like.
The impurities of the medicine refer to substances which have no treatment effect or influence the stability and the curative effect of the medicine and are even harmful to the health of human bodies. In the aspects of research, production, storage, clinical application and the like of the medicine, the purity of the medicine must be maintained, and the impurities of the medicine are reduced, so that the effectiveness and the safety of the medicine can be ensured. The purity of a drug can be generally evaluated by integrating the structure, appearance, physicochemical constants, impurity inspection, content measurement, and the like of the drug into a whole. Impurities contained in the medicine are main factors influencing the purity of the medicine, and if the medicine contains more than limited amount of impurities, the physicochemical constants can be changed, the appearance character can be changed, and the stability of the medicine can be influenced; the increase of impurities also inevitably causes the content of the medicine to be lower or the activity to be reduced, and the toxic and side effects are obviously increased. Therefore, the impurity inspection of the medicine is a very important link for controlling the purity of the medicine and improving the quality of the medicine.
Disclosure of Invention
Based on the above, the invention aims to provide a preparation method of desloratadine impurities, so as to obtain a new desloratadine impurity reference substance for checking and researching drug impurities.
In order to achieve the above purpose, the invention adopts the following technical scheme.
The invention provides a preparation method of desloratadine impurities, which is characterized in that when the desloratadine is synthesized by using tricyclic ketone and Grignard reagent, the brominated impurities of the tricyclic ketone, namely 8-bromo-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone, are used as raw materials to prepare the desloratadine impurities, and the method comprises the following steps:
reacting N-methyl-4-chloropiperidine with magnesium in a solvent to prepare a Grignard reagent;
adding the bromo-impurity 8-bromo-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone into the Grignard reagent, and reacting for 2-16 hours at the temperature of 0-60 ℃;
quenching with aqueous ammonium chloride solution or dilute hydrochloric acid;
extracting, drying and concentrating to obtain a crude product;
and purifying the crude product by column chromatography.
Preferably, the step of reacting N-methyl-4-chloropiperidine with magnesium in a solvent to prepare the grignard reagent specifically comprises:
mixing N-methyl-4-chloropiperidine and magnesium strips according to the proportion of 5: adding the mixture ratio of 1 (mass ratio) into tetrahydrofuran solvent with the mass volume of 5-10 times, and reacting for 2-6 hours at room temperature to prepare the Grignard reagent.
Preferably, the mass ratio of the N-methyl-4-chloropiperidine to the brominated impurities is 1: 1.
Preferably, the crude product is obtained by extraction with an organic phase and concentration by drying.
In the process of synthesizing loratadine by using tricyclic ketone, bromo-impurity C is probably mixed in the raw material14H10BrNO, the invention directly utilizes the bromo-impurity as the raw material to synthesize the desloratadine impurity, on one hand, the cost of the raw material can be reduced, the bromo-impurity or a substitute is not required to be purchased additionally, on the other hand, the raw materials such as processing conditions, a solvent, a reagent and the like during the synthesis of the desloratadine can be utilized to prepare the desloratadine, and the desloratadine impurity can be extracted only after the preparation is completed, so that the synthesis raw material is saved, the synthesis process is simplified, and the reduction of the production cost of the desloratadine impurity is.
Drawings
FIG. 1 is a diagram of the synthetic route to loratadine;
FIG. 2 is a synthesis scheme of desloratadine impurity in an embodiment of the present invention.
The implementation of the objects of the present invention and their functions and principles will be further explained in the detailed description with reference to the attached drawings.
Detailed Description
The following further description is made with reference to the drawings and specific embodiments.
Loratadine is one of the best antihistamine drugs sold at present, and the synthesis method thereof is a research hotspot of chemists. The synthesis scheme shown in figure 1 is that after tricyclic ketone and Grignard reagent are eliminated, the tricyclic ketone and ethyl chloroformate react to obtain loratadine. Because the raw material containing chlorine, namely the tricyclic ketone inevitably contains bromide impurities (namely 8-bromo-5, 6-dihydro-11H-benzo [5,6]]Cycloheptane [1,2-b ]]Pyridin-11-one, C14H10BrNO), the bromide impurity will also react similarly, so this example provides a preparation method of desloratadine impurity, which can be directly used to synthesize the desloratadine impurity target C20H23BrN2And O, so that the utilization rate of raw materials can be improved, chemical raw materials can be saved, and the synthesis process can be simplified, thereby effectively reducing the production cost of the desloratadine impurities.
As shown in fig. 2, the method of this embodiment specifically includes the following steps:
a. reacting N-methyl-4-chloropiperidine with magnesium in a solvent to prepare a Grignard reagent;
b. adding the bromo-impurity C into the Grignard reagent14H10BrNO, reacting for 2-16 hours at the temperature of 0-60 ℃;
c. quenching with aqueous ammonium chloride solution or dilute hydrochloric acid;
d. extracting, drying and concentrating to obtain a crude product;
e. and purifying the crude product by column chromatography.
The step a further comprises:
mixing N-methyl-4-chloropiperidine and magnesium strips according to the proportion of 5: adding the mixture of 1 (mass ratio) into a tetrahydrofuran solvent with the mass volume of 5-10 times, and reacting for 2-6 hours at room temperature (15-25 ℃) to prepare the Grignard reagent.
In the step b, N-methyl-4-chloropiperidine and bromo-impurity C14H10The mass ratio of BrNO is about 1: 1.
After the reaction was complete, the reaction was quenched with aqueous ammonium chloride or dilute hydrochloric acid.
Then, an organic phase (such as ethyl acetate) is used for extraction, and drying and concentration are carried out, so that a crude desloratadine impurity target product with higher purity is obtained.
Finally, purifying the crude product by column chromatography separation method to obtain the desloratadine impurity C with the purity of more than 96 percent20H23BrN2O。
It is understood that in other embodiments of the present invention, the solution used in step a is not limited to tetrahydrofuran, and an organic solvent having similar properties may be used instead.
In conclusion, the invention directly utilizes the bromo-impurity as the raw material to synthesize the desloratadine impurity, so that the raw material cost can be reduced, the bromo-impurity or a substitute is not required to be purchased additionally, and the raw materials such as processing conditions, a solvent, a reagent and the like in the synthesis of the desloratadine can be utilized to prepare the desloratadine impurity, and the desloratadine impurity can be extracted only after the preparation is finished, so that the synthesis raw material is saved, the synthesis process is simplified, and the reduction of the production cost of the desloratadine impurity is facilitated.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (4)
1. A method for preparing desloratadine impurity, which is characterized in that when the desloratadine is synthesized by using tricyclic ketone and Grignard reagent, the brominated impurity of the tricyclic ketone, namely 8-bromo-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one, is used as a raw material to prepare the desloratadine impurity, and the method comprises the following steps:
reacting N-methyl-4-chloropiperidine with magnesium in a solvent to prepare a Grignard reagent;
adding the bromo-impurities into the Grignard reagent, and reacting for 2-16 hours at the temperature of 0-60 ℃;
quenching with aqueous ammonium chloride solution or dilute hydrochloric acid;
extracting, drying and concentrating to obtain a crude product;
and purifying the crude product by column chromatography.
2. The method of claim 1, wherein the step of reacting N-methyl-4-chloropiperidine with magnesium in a solvent to form the grignard reagent comprises:
mixing N-methyl-4-chloropiperidine and magnesium strips according to the proportion of 5: adding the mixture ratio of 1 (mass ratio) into tetrahydrofuran solvent with the mass volume of 5-10 times, and reacting for 2-6 hours at room temperature to prepare the Grignard reagent.
3. The method of claim 1, wherein the mass ratio of N-methyl-4-chloropiperidine to brominated impurities is 1: 1.
4. The process of claim 1, wherein the crude product is obtained by extraction with an organic phase and concentration by drying.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3326924A (en) * | 1963-04-24 | 1967-06-20 | Schering Corp | Novel aza-dibenzo[a, d]-cycloheptene derivatives |
| US4659716A (en) * | 1984-02-15 | 1987-04-21 | Schering Corporation | Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines |
-
2021
- 2021-04-07 CN CN202110372114.9A patent/CN112898268A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3326924A (en) * | 1963-04-24 | 1967-06-20 | Schering Corp | Novel aza-dibenzo[a, d]-cycloheptene derivatives |
| US4659716A (en) * | 1984-02-15 | 1987-04-21 | Schering Corporation | Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines |
Non-Patent Citations (2)
| Title |
|---|
| FRANK J.VILLANI ET AL.: "Derivatives of 10,11-Dihydro-5H-dibenzo[a,d]cycloheptene and Related Compounds. 6. Aminoalkyl Derivatives of the Aza Isosteres", 《J. MED. CHEM.》 * |
| WUKUN LIU ET AL.: "Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antiumor and anti-inflammatory agents", 《BIOORG. MED. CHEM. LETT.》 * |
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