CN113135899B - Benzocycloheptapyridine compounds, process for their preparation and their use - Google Patents

Benzocycloheptapyridine compounds, process for their preparation and their use Download PDF

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CN113135899B
CN113135899B CN202110683082.4A CN202110683082A CN113135899B CN 113135899 B CN113135899 B CN 113135899B CN 202110683082 A CN202110683082 A CN 202110683082A CN 113135899 B CN113135899 B CN 113135899B
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benzocycloheptapyridine
grignard reagent
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loratadine
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CN113135899A (en
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孙学涛
黄晓俊
杨水凤
王永广
苏小庭
戴信敏
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Nalanga Shanghai Biomedical Technology Co ltd
Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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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
    • C07D401/14—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 three or more hetero rings
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
    • G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed

Abstract

The invention belongs to the field of medicines, and particularly relates to a benzocycloheptapyridine compound, a preparation method and an application thereof, wherein the benzocycloheptapyridine compound has a structure shown in a formula I or a formula IV:
Figure 264569DEST_PATH_IMAGE001
. The preparation method comprises the following steps: heating magnesium and N-methyl-4-chloropiperidine in a first reaction solvent to react under the action of an initiator to obtain a Grignard reagent; 8-chloro-5, 6-dihydro-11H-benzo [5,6]]Cycloheptane [1,2-b ]]And (3) reacting pyridine-11-ketone with the Grignard reagent in a second reaction solvent to obtain a compound I and a compound IV. The benzocycloheptapyridine compound prepared by the preparation method has high purity, can realize detection and monitoring of the compound I and the compound IV in the synthesis process of the loratadine, and has important significance for improving the quality of loratadine bulk drugs or preparations thereof.

Description

Benzocycloheptapyridine compounds, process for their preparation and their use
Technical Field
The invention belongs to the field of medicines, and particularly relates to a benzocycloheptapyridine compound, a preparation method and application thereof.
Background
The chemical name of Loratadine (Loratadine) is 4- (8-chloro-5, 6-dihydro-11H-benzo [5,6]]-cyclohepta [1,2-b ]]Pyridine-11-alkenyl) -1-piperidinecarboxylic acid ethyl ester, developed by Schering-Plough, USA, was first marketed in Belgium in 1988 under the trade name of Clarityne (Keratan), and is used for the treatment of allergic rhinitis, acute or chronic urticaria, allergic conjunctivitis, pollinosis and other allergic skin diseases, 2 nd generation H1The receptor blocker has the characteristics of long acting, no central inhibition or choline resistance.
Currently, the mainstream synthetic route of loratadine is as follows:
Figure DEST_PATH_IMAGE001
。
in the above synthesis process, in addition to the intermediate a, at least one of an impurity compound i (having a structure shown in formula i below) and an impurity compound iv (having a structure shown in formula iv below) may be generated in the reaction process of the compound ii and the Grignard reagent, and the generation of the impurity compound may reduce the yield of the intermediate a, affect the purity of the intermediate a, and may also ultimately exist as an impurity in the final product loratadine due to incomplete separation, so that the purity of the loratadine may be affected, and therefore, the impurity compound needs to be detected and monitored during the synthesis of the intermediate a, so as to control the quality of the intermediate a.
Figure DEST_PATH_IMAGE002
However, the content of the impurity compound in the synthesis process of loratadine is very low, the impurity compound is difficult to separate, and the prior art has no synthesis method aiming at the impurity compound, is difficult to obtain a large amount of high-purity impurity compound, lacks a corresponding reference substance, and greatly influences the detection and monitoring of the impurity compound in the synthesis process of loratadine. Therefore, it is urgently required to provide a method for preparing the impurity compound with high yield and good purity.
Disclosure of Invention
Aiming at the defects in the prior art, particularly lacking a preparation method of a compound I and a compound IV and lacking a high-purity compound I and a high-purity compound IV reference substance, the invention aims to provide a benzocycloheptapyridine compound, a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a process for the preparation of a benzocycloheptapyridine compound, comprising the steps of:
Figure DEST_PATH_IMAGE003
synthesis of the Grignard reagent:
heating magnesium and N-methyl-4-chloropiperidine in a first reaction solvent to react under the action of an initiator to obtain a Grignard reagent;
synthesis of Compounds I and IV:
8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (formula II) and the Grignard reagent react in a second reaction solvent to obtain a compound I and a compound IV, wherein the reaction temperature is 0-70 ℃.
Preferably, in the step of synthesizing the Grignard reagent, the initiator comprises at least one of 1, 2-dibromoethane and iodine, the first reaction solvent comprises at least one of tetrahydrofuran and diethyl ether, the reaction temperature is 40 ℃ to 100 ℃, and the molar ratio of the initiator to the magnesium is 0.01 to 1.
In any of the above embodiments, preferably, in the step of reacting the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one with the Grignard reagent in a second reaction solvent to obtain the compound I and the compound IV, the second reaction solvent comprises at least one of tetrahydrofuran and diethyl ether, and after the reaction is finished, water or an aqueous reagent is added to obtain the compound I and the compound IV.
In any of the above embodiments, preferably, in the step of synthesizing the grignard reagent, a ligand is added to the grignard reagent, the ligand includes at least one of anhydrous lithium chloride, N, -tetramethylethylenediamine, and a molar ratio of the ligand to the magnesium is 1 to 5.
In any of the above embodiments, it is preferable that the molar ratio of the N-methyl-4-chloropiperidine to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1 to 8, and the molar ratio of the magnesium to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1 to 8.
In any of the above schemes, preferably, after the step of reacting the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one with the Grignard reagent in the second reaction solvent to obtain the compound I and the compound IV, the method further comprises purifying and separating the compound I and the compound IV.
In any of the above schemes, preferably, the purifying and separating of the compound i and the compound iv comprises the following steps:
and (3) extracting, concentrating under reduced pressure and carrying out column chromatography separation on reaction liquid containing the compound I and the compound IV to obtain a pure product of the compound I and a pure product of the compound IV.
The preparation method of the benzocycloheptapyridine compound comprises the steps of firstly taking N-methyl-4-chloropiperidine and magnesium as raw materials, heating the raw materials in a first reaction solvent under the action of an initiator to react to obtain a Grignard reagent, then reacting 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone with the Grignard reagent in a second reaction solvent to obtain a compound I and a compound IV, and finally purifying and separating the compound I and the compound IV to obtain the pure products of the compound I and the compound IV. The preparation method synthesizes a new substance for the first time: the compound I and the compound IV have the advantages of simple route, convenient operation, low requirement on equipment conditions, easy realization and simple post-treatment, and meanwhile, the benzocycloheptapyridine compound prepared by the preparation method has high yield and good purity, can be used for detecting and monitoring the compound in the production of loratadine raw material medicines, thereby controlling the quality of an intermediate A and having important significance for improving the synthesis route of loratadine and improving the quality of the loratadine raw material medicines or preparations thereof.
In a second aspect, the present invention provides a benzocycloheptapyridine compound obtained by the method for producing a benzocycloheptapyridine compound according to the first aspect, the benzocycloheptapyridine compound having a structure of formula i:
Figure DEST_PATH_IMAGE004
Ⅰ。
the chemical name of the benzocycloheptapyridine compound is 8-chloro-3- (1-methylpiperidin-4-yl) -5, 6-dihydro-11H-benzo [5,6]Cycloheptane [1,2-b ]]Pyridine compound-11-ketone of formula C20H21ClN2The new compound shown in the formula (I) is an impurity generated in the existing loratadine production process, and the content of the impurity directly influences the yield and purity of the loratadine intermediate A, so that the accurate structure of the impurity is determined for the first time, the benzocycloheptapyridine compound can be used as an impurity reference substance in the detection and monitoring of the loratadine bulk drug or the preparation production process thereof, the control on the benzocycloheptane pyridine compound is facilitated, the quality of the intermediate A is controlled, and the new compound has important significance in improving the quality of the loratadine bulk drug or the preparation thereof.
In a third aspect, the present invention provides a benzocycloheptapyridine compound obtained by the method for producing a benzocycloheptapyridine compound according to the first aspect, wherein the benzocycloheptapyridine compound has a structure of formula iv:
Figure DEST_PATH_IMAGE005
Ⅳ。
the chemical name of the benzocycloheptapyridine compound is 8-chloro-3, 11-bis (1-methylpiperidin-4-yl) -6, 11-dihydro-5H-benzo [5, 6-]Cycloheptane [1,2-b ]]Pyridine-11-ol, molecular formula C26H34ClN3The new compound shown in the formula (IV) is an impurity generated in the existing loratadine production process, and the content of the impurity directly influences the yield and purity of the loratadine intermediate A, so that the accurate structure of the impurity is determined for the first time, the benzocycloheptapyridine compound can be used as an impurity reference substance in the detection and monitoring of the production process of a loratadine bulk drug or a preparation thereof, the control on the benzocycloheptane pyridine compound is facilitated, the quality of the intermediate A is controlled, and the new compound has important significance in improving the quality of the loratadine bulk drug or the preparation thereof.
In a fourth aspect, the present invention provides a use of the benzocycloheptapyridine compound according to the second or third aspect as a control in the examination of loratadine-related substances.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a benzocycloheptapyridine compound obtained in example 1 of the present invention;
FIG. 2 is a mass spectrum of a benzocycloheptapyridine compound obtained in example 1 of the present invention;
FIG. 3 is a high performance liquid chromatography spectrum of a benzocycloheptapyridine compound obtained in example 1 of the present invention;
FIG. 4 is a table showing peaks of a HPLC chromatogram of the benzocycloheptapyridine compound obtained in example 1 of the present invention;
FIG. 5 is a NMR spectrum of a benzocycloheptapyridine compound obtained in example 4 of the present invention;
FIG. 6 is a mass spectrum of a benzocycloheptapyridine compound obtained in example 4 of the present invention;
FIG. 7 is a high performance liquid chromatography chromatogram of a benzocycloheptapyridine compound obtained in example 4 of the present invention;
FIG. 8 is a table showing peaks of a HPLC chromatogram of a benzocycloheptapyridine compound obtained in example 4 of the present invention;
FIG. 9 is a high performance liquid chromatogram of loratadine intermediate A;
fig. 10 is a table of peaks of a high performance liquid chromatogram of loratadine intermediate a.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, embodiments of the present invention provide a method for preparing a benzocycloheptapyridine compound, comprising the steps of:
Figure DEST_PATH_IMAGE006
(1) synthesis of the Grignard reagent:
heating magnesium and N-methyl-4-chloropiperidine in a first reaction solvent to react under the action of an initiator to obtain a Grignard reagent;
(2) synthesis of Compounds I and IV:
8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone and the Grignard reagent react in a second reaction solvent to obtain a compound I and a compound IV, wherein the reaction temperature is 0-70 ℃.
The preparation method of the benzocycloheptapyridine compound comprises the steps of firstly taking N-methyl-4-chloropiperidine and magnesium as raw materials, heating the raw materials in a first reaction solvent under the action of an initiator to react to obtain a Grignard reagent, then reacting 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone with the Grignard reagent in a second reaction solvent to obtain a compound I and a compound IV, and finally purifying and separating the compound I and the compound IV to obtain the pure products of the compound I and the compound IV. The preparation method synthesizes a new substance for the first time: the compound I and the compound IV have the advantages of simple route, convenient operation, low requirement on equipment conditions, easy realization and simple post-treatment, and meanwhile, the benzocycloheptapyridine compound prepared by the preparation method has high yield and good purity, can be used for detecting and monitoring the compound in the production of loratadine raw material medicines, and reduces the synthesis cost of loratadine, thereby controlling the quality of an intermediate A, having important guiding significance for improving the synthesis route of loratadine, and having important significance for improving the quality of loratadine raw material medicines or preparations thereof.
The invention provides a method for synthesizing the compound I and the compound IV for the first time, so that the technical personnel in the field have clear knowledge on the reaction process for generating the compound I and the compound IV and provide a basis for improving the synthesis process of the loratadine. In the process of preparing loratadine, a compound I and a compound IV can be obtained according to the method provided by the embodiment of the invention and are used as reference substances for detecting and monitoring the compound I and the compound IV in the production of loratadine raw material medicines, when the content of the compound I or the compound IV is increased, effective control measures can be taken in time, the reaction conditions or the proportion or the types of materials in the reaction process are changed to reduce the generation of the compound I and the compound IV, the yield of a loratadine intermediate A is increased, the purity of the loratadine intermediate A is improved, the production cost of loratadine is reduced, the generation of impurities in the production process of loratadine is reduced, and the method has important significance for improving the synthesis route of loratadine and improving the quality of loratadine.
Further, in the step (1), the initiator comprises at least one of 1, 2-dibromoethane and iodine.
Further, in the step (1), the first reaction solvent includes at least one of tetrahydrofuran and diethyl ether.
Further, in the step (1), the reaction temperature is 40 ℃ to 100 ℃, for example, the reaction temperature may be 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃, and the like, preferably, the reaction temperature is 60 ℃ to 70 ℃, for example, the reaction temperature may be 60 ℃, 65 ℃ or 70 ℃, and the like.
Further, in the step (1), the molar ratio of the initiator to the magnesium is 0.01 to 1, for example, the molar ratio of the initiator to the magnesium may be 0.01, 0.02, 0.1, 0.2, 0.4, 0.6, 0.8, 1, or the like, and preferably the molar ratio of the initiator to the magnesium is 0.1 to 0.3.
Further, in the step (2), the second reaction solvent includes at least one of tetrahydrofuran and diethyl ether.
Further, in the step (2), after the reaction is completed, water or an aqueous reagent is added to obtain the compound I and the compound IV.
Further, the aqueous reagent is an ammonium chloride aqueous solution, and if water is directly added, magnesium hydroxide precipitate can be generated in the reaction solution, and the precipitate wraps the product, so that the extraction efficiency of the reaction solution in the later period is influenced, and the yield of the product is reduced.
Further, in the step (2), the reaction temperature is 0 ℃ to 70 ℃, for example, the reaction temperature may be 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃ or 70 ℃, and the like, the reaction temperature is too high, side reactions are likely to occur, black oily by-products are generated in the reaction system, the oily by-products can wrap the products, the later extraction of the products is difficult, the yield of the products is reduced, the reaction temperature is too low, the activity of the format reagent is reduced, and the yield of the products is low, preferably, the reaction temperature is 10 ℃ to 35 ℃, and in this temperature range, the yield of the compound i and the compound iv is the highest.
Further, in the step (1), a ligand is added into the Grignard reagent, wherein the ligand comprises at least one of anhydrous lithium chloride, N, N, -tetramethylethylenediamine, and the ligand plays a role in coordination passivation, and the ligand and the Grignard reagent form a complex, so that the activity of the Grignard reagent is reduced, organic anions are activated, the conversion rate of the compound I and the compound IV can be improved, and the generation of byproducts is reduced. The different ligands have different binding capacities to the Grignard reagent and different activation energies, resulting in different yields of Compound I and Compound IV, which are significantly increased when the ligands comprise at least one of anhydrous lithium chloride, N, N, -tetramethylethylenediamine, preferably N, N, N, N, -tetramethylethylenediamine, as compared to the case in which no ligand is present.
Further, in the step (1), a ligand is added to the Grignard reagent, and the molar ratio of the ligand to the magnesium is 1 to 5, for example, the molar ratio of the ligand to the magnesium may be 1,2, 3, 4, or 5.
Further, the molar ratio of the N-methyl-4-chloropiperidine to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1 to 8, for example, the molar ratio of the N-methyl-4-chloropiperidine to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one may be 1,2, 3, 4, 5,6, 7, or 8, etc., preferably, the molar ratio of the N-methyl-4-chloropiperidine to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 3 to 5, within this molar ratio range, the yields of compound I and compound IV are highest.
Further, the molar ratio of the magnesium to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1 to 8, for example, the molar ratio of magnesium to 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one may be 1,2, 3, 4, 5,6, 7, or 8, and the like, and preferably the molar ratio of magnesium to 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 3 to 6, and the yields of compound I and compound IV are highest within the molar ratio range.
Further, in the step (2), the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is dissolved in the second reaction solvent to obtain a second mixed solution, and the second mixed solution is dropwise added into the Grignard reagent to carry out a reaction, so as to obtain a compound I and a compound IV. The yield of the compound I and the compound IV can be improved by dropwise adding the mixed solution into a Grignard reagent for reaction, the Grignard reagent reacts with 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-ketone to form an exothermic reaction, and the temperature of a reaction system is controlled by dropwise adding operation to prevent the reaction temperature from rising too fast to cause material splashing.
Further, after the step (2), the method further comprises the following steps: and purifying and separating the compound I and the compound IV.
Further, the purification and separation of the compound I and the compound IV comprise the following steps:
and (3) extracting, concentrating under reduced pressure and carrying out column chromatography separation on reaction liquid containing the compound I and the compound IV to obtain a pure product of the compound I and a pure product of the compound IV.
Further, the purification and separation of the compound I and the compound IV comprise the following steps:
and extracting the reaction liquid containing the compound I and the compound IV by using ethyl acetate, and then carrying out reduced pressure concentration and column chromatography separation to obtain a pure product of the compound I and a pure product of the compound IV.
The purity of the compound I and the purity of the compound IV are determined according to a high performance liquid chromatography method in 'Chinese pharmacopoeia' 2020 edition, and the purity of the compound I and the compound IV is 97 percent and 95 percent according to an HPLC (high performance liquid chromatography) area normalization method, so that the compound I and the compound IV obtained by the preparation method can be used as reference substances, can be applied to qualitative and quantitative research and detection of benzocycloheptapyridine compounds, and has important significance for effectively controlling the quality of loratadine and preparations thereof.
In a second aspect, embodiments of the present invention provide a benzocycloheptapyridine compound obtained according to the method for producing a benzocycloheptapyridine compound of the first aspect, the benzocycloheptapyridine compound having the structure of formula i:
Figure DEST_PATH_IMAGE007
Ⅰ。
the chemical name of the benzocycloheptapyridine compound is 8-chloro-3- (1-methylpiperidin-4-yl) -5, 6-dihydro-11H-benzo [5,6]Cycloheptane [1,2-b ]]Pyridin-11-one of formula C20H21ClN2O, molecular weight is 340.85, test results show that the novel compound shown in formula (I) is an impurity generated in the existing production process of loratadine, the content of the impurity directly influences the yield and purity of loratadine intermediate A, no related report on the impurity exists in the prior art, and an impurity reference substance cannot be purchased from the marketThe benzocycloheptapyridine compound can be used as an impurity reference substance in the detection and monitoring of the production process of the loratadine bulk drug or the preparation thereof, is favorable for enhancing the control of the benzocycloheptapyridine compound, reduces the synthesis cost of the loratadine, and further improves the quality of the loratadine bulk drug or the preparation thereof.
In addition, the benzocycloheptapyridine compound can also be used as an impurity reference substance in the detection and analysis of the loratadine bulk drug or the preparation thereof, so that the accurate positioning and the qualitative determination of the benzocycloheptapyridine compound during the detection and analysis of the loratadine bulk drug or the preparation thereof are improved. The benzocycloheptapyridine compound can also be used as a standard substance, so that the later research on the pharmacological toxicity of the benzocycloheptapyridine compound becomes possible, and the benzocycloheptapyridine compound has important guiding significance on the safe medication of loratadine.
In a third aspect, embodiments of the present invention provide a benzocycloheptapyridine compound obtained according to the method for producing a benzocycloheptapyridine compound of the first aspect, the benzocycloheptapyridine compound having a structure of formula iv:
Figure DEST_PATH_IMAGE008
Ⅳ。
the chemical name of the benzocycloheptapyridine compound is 8-chloro-3, 11-bis (1-methylpiperidin-4-yl) -6, 11-dihydro-5H-benzo [5, 6-]Cycloheptane [1,2-b ]]Pyridine-11-ol, molecular formula C26H34ClN3O, molecular weight is 440.03, test results show that the new compound shown in formula (IV) is an impurity generated in the existing production process of loratadine, the content of the impurity directly influences the yield and purity of loratadine intermediate A, no related report on the impurity exists in the prior art, and an impurity reference substance cannot be purchased from the marketThe impurity reference substance is beneficial to enhancing the control of the benzocycloheptapyridine compound, reducing the synthesis cost of the loratadine and further improving the quality of the loratadine bulk drug or the preparation thereof.
In addition, the benzocycloheptapyridine compound can also be used as an impurity reference substance in the detection and analysis of the loratadine bulk drug or the preparation thereof, so that the accurate positioning and the qualitative determination of the benzocycloheptapyridine compound during the detection and analysis of the loratadine bulk drug or the preparation thereof are improved. The benzocycloheptapyridine compound can also be used as a standard substance, so that the later research on the pharmacological toxicity of the benzocycloheptapyridine compound becomes possible, and the benzocycloheptapyridine compound has important guiding significance on the safe medication of loratadine.
In a fourth aspect, embodiments of the present invention provide the use of a benzocycloheptapyridine compound according to the second or third aspect, as a control in the examination of loratadine-related substances.
The benzocycloheptapyridine compound is used as a reference substance, so that qualitative and quantitative analysis can be performed on impurities in loratadine, and the qualitative and quantitative analysis method is a High Performance Liquid Chromatography (HPLC) method.
The invention is described in further detail with reference to a number of tests performed in sequence, and a part of the test results are used as reference, and the following detailed description is given with reference to specific examples.
And (3) column chromatography separation and purification: the column chromatography separation and purification method disclosed by the invention adopts silica gel columns, the mesh number of the silica gel columns is 100-200 meshes, the eluent is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 10: 1.
firstly, preparing a small amount of crude products of a compound I and a compound IV according to the preparation method of the benzocycloheptapyridine compound, separating and purifying the crude products of the compound I and the compound IV by column chromatography, collecting eluents at different time points, confirming substance structures in eluents flowing out at different time points by a nuclear magnetic resonance hydrogen spectrogram, a mass spectrogram and a high performance liquid chromatogram, and confirming the time points of the compound I and the compound IV respectively flowing out from a silica gel column.
The synthetic routes of the compound I and the compound IV are as follows:
Figure DEST_PATH_IMAGE009
EXAMPLE 1 Synthesis of Compound I
(1) Synthesis of the Grignard reagent:
adding magnesium chips (5.72 g, 0.24 mol) into 220mL tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (6 mL, 0.07 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (32.01 g, 0.24 mol), after the reaction is initiated, reacting at 65 ℃ until the magnesium chips completely disappear to obtain a Grignard reagent, cooling to room temperature, adding N, N, N, N-tetramethylethylenediamine (27.90 g, 0.24 mol) into the Grignard reagent, uniformly stirring, and cooling to room temperature to obtain a first mixed solution.
(2) Synthesis of Compound I:
adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (30.06 g, 0.12 mol) into 250mL tetrahydrofuran, stirring and dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 10 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding a saturated ammonium chloride aqueous solution after the reaction is finished, then adding ethyl acetate, stirring and layering, extracting an organic phase on an upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 18.04g of a compound I, wherein the compound I is a yellow solid, the yield is 44.0%, and the HPLC purity is 97%.
The resulting yellow solid product was identified:
nuclear magnetic resonance hydrogen spectrum of yellow solid product (1H-NMR) spectrum is shown in FIG. 1, the detailed data of hydrogen spectrum is shown in Table 1, the testing instrument is Avance DRX500Bruker, the testing solvent is d6-DM SO。
The numbering of the hydrogen atoms in the structure is as follows (non-systematic nomenclature, used only for1H-NMR analysis):
Figure DEST_PATH_IMAGE010
。
table 1 details of nmr hydrogen spectra of yellow solid product:1H-NMR（600MHz，DMSO-d6）
Figure DEST_PATH_IMAGE011
the mass spectrum of the yellow solid product is shown in fig. 2, the test solvent is methanol solvent, and ESI-MS (m/z) of the yellow solid product can be observed in the MS spectrum: 341.14114 of [ M + H]+Molecular ion peak, molecular weight 340.85, consistent with the molecular weight of this compound.
The above-mentioned yellow solid product was thus identified as 8-chloro-3- (1-methylpiperidin-4-yl) -5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one, the chemical formula of which is shown below:
Figure 471351DEST_PATH_IMAGE007
。
purity detection of the yellow solid product:
taking 5mg of a yellow solid product, namely 8-chloro-3- (1-methylpiperidine-4-yl) -5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one, to be dissolved in 10 mL of acetonitrile/water (the volume ratio of acetonitrile to water is 80: 20) mixed solvent to be used as a sample solution, wherein the sample concentration is 500ug/mL, the injection volume is 10uL, the sample solution is measured according to the high performance liquid chromatography in the method of 2020 edition Chinese pharmacopoeia, and the high performance liquid chromatogram and the peak chart of the 8-chloro-3- (1-methylpiperidine-4-yl) -5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one are shown in figures 3 and 4, the purity of the yellow solid product can be known to be 97 percent according to the detection result (2020 version Chinese pharmacopoeia method, according to HPLC peak area normalization method).
EXAMPLE 2 Synthesis of Compound I
(1) Synthesis of the Grignard reagent:
adding magnesium chips (8.68 g, 0.36 mol) into 250mL of tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (6 mL, 0.07 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (48.10 g, 0.36 mol), after the reaction is initiated, reacting at 65 ℃ until the magnesium chips completely disappear to obtain a Grignard reagent, cooling to room temperature, adding anhydrous lithium chloride (15.57 g, 0.36 mol) into the Grignard reagent, and uniformly stirring to obtain a first mixed solution.
(2) Synthesis of Compound I
Adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (30.06 g, 0.12 mol) into 250m L tetrahydrofuran, stirring and dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 20 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding a saturated ammonium chloride aqueous solution after the reaction is finished, then adding ethyl acetate, stirring and layering, extracting an organic phase on an upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 13.12g of a compound I which is a yellow solid, wherein the yield is 32.1% and the HPLC purity is 97.5%.
EXAMPLE 3 Synthesis of Compound I
(1) Synthesis of the Grignard reagent:
adding magnesium chips (3.02 g, 0.12 mol) into 150mL tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (3 mL, 0.035 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (16.03 g, 0.12 mol), after the reaction is initiated, reacting at 65 ℃ until the magnesium chips disappear, and cooling to room temperature to obtain a Grignard reagent, thus obtaining a first mixed solution.
(2) Synthesis of Compound I:
adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (10 g, 0.04 mol) into 150mL tetrahydrofuran, stirring and dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 30 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding a saturated ammonium chloride aqueous solution after the reaction is finished, then adding ethyl acetate, stirring and layering, extracting the organic phase on the upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 2.45g of a compound I, wherein the compound I is a yellow solid, the yield is 18.0%, and the HPLC purity is 96.8%.
EXAMPLE 4 Synthesis of Compound IV
(1) Synthesis of the Grignard reagent:
adding magnesium chips (2.97 g, 0.12 mol) into 100mL of tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (1.5 mL, 0.02 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (16.02 g, 0.12 mol), after the reaction is initiated, carrying out the reaction at 65 ℃ until the magnesium chips completely disappear to obtain a Grignard reagent, cooling to room temperature, adding N, N, N, -tetramethylethylenediamine (13.94 g, 0.12 mol) into the Grignard reagent, uniformly stirring, clarifying the solution, and cooling to room temperature to obtain a first mixed solution.
(2) Synthesis of Compound IV
Adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (7.31 g, 0.03 mol) into 100mL tetrahydrofuran, stirring for dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 20 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding 100mL saturated ammonium chloride aqueous solution after the reaction is finished, adding ethyl acetate after 30min, stirring for layering, extracting the organic phase on the upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 2.92g of a compound IV which is a yellow solid, wherein the yield is 22.2%, and the HPLC purity is 94.76%.
The resulting yellow solid product was identified:
nuclear magnetic resonance hydrogen spectrum of yellow solid product (1H-NMR) spectrum is shown in FIG. 5, the detailed data of hydrogen spectrum is shown in Table 2, the testing instrument is Avance DRX500Bruker, the testing solvent is d6-DM SO。
The numbering of the hydrogen atoms in the structure is as follows (non-systematic nomenclature, used only for1H-NMR analysis):
Figure DEST_PATH_IMAGE012
。
table 2 details of nmr hydrogen spectra of yellow solid product:1H-NMR（600MHz，DMSO-d6）
Figure DEST_PATH_IMAGE013
the mass spectrum of the yellow solid product is shown in fig. 6, the test solvent is methanol solvent, and ESI-MS (m/z) of the yellow solid product can be observed in the MS spectrum: 440.24 of [ M + H]+Molecular ion peak, molecular weight 440.03, consistent with the molecular weight of this compound.
The above-mentioned yellow solid product was thus determined to be 8-chloro-3, 11-bis (1-methylpiperidin-4-yl) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-ol, the chemical formula of which is shown below:
Figure DEST_PATH_IMAGE014
。
purity detection of the yellow solid product:
taking 5mg of a yellow solid product, namely 8-chloro-3, 11-bis (1-methylpiperidin-4-yl) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-ol, to be dissolved in 10 mL of acetonitrile/water (the volume ratio of acetonitrile to water is 80: 20) mixed solvent to be used as a sample solution, wherein the sample concentration is 500ug/mL, the injection volume is 10uL, the sample solution is measured according to the high performance liquid chromatography in the method of 2020 edition of Chinese pharmacopoeia, and the high performance liquid chromatogram and the peak table of 8-chloro-3, 11-bis (1-methylpiperidin-4-yl) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-ol are shown in FIGS. 7 and 8, according to the detection result, the purity of the yellow solid product is 94.76% (2020 version Chinese pharmacopoeia method, according to HPLC peak area normalization method).
EXAMPLE 5 Synthesis of Compound IV
(1) Synthesis of Grignard reagents
Adding magnesium chips (4.34 g, 0.18 mol) into 220mL tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (2 mL, 0.023 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (24.05 g, 0.18 mol), after the reaction is initiated, reacting at 65 ℃ until the magnesium chips are reacted to obtain a Grignard reagent, cooling to room temperature, adding anhydrous lithium chloride (7.63 g, 0.18 mol) into the Grignard reagent, and uniformly stirring to obtain a first mixed solution.
(2) Synthesis of Compound IV
Adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (9.75 g, 0.04 mol) into 220mL tetrahydrofuran, stirring for dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 25 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding 100mL saturated ammonium chloride aqueous solution after the reaction is finished, adding ethyl acetate after 30min, stirring for layering, extracting the organic phase on the upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 1.88g of a compound IV which is a yellow solid, wherein the yield is 10.7%, and the HPLC purity is 95.1%.
EXAMPLE 6 Synthesis of Compounds I and IV
(1) Synthesis of the Grignard reagent:
adding magnesium chips (2.97 g, 0.12 mol) into 100ml of tetrahydrofuran, starting stirring, adding iodine (3 g, 0.01 mol), reacting at 65 ℃, dropwise adding N-methyl-4-chloropiperidine (16.05 g, 0.12 mol), reacting at 65 ℃ after the reaction is initiated until the magnesium chips completely disappear to obtain a Grignard reagent, cooling to room temperature, adding N, N, N, N-tetramethylethylenediamine (13.94 g, 0.12 mol) into the Grignard reagent, and uniformly stirring to obtain a first mixed solution.
(2) Synthesis of Compounds I and IV
In the same manner as in the step (2) in example 4, the final separation by column chromatography gave 4.2g of compound I in 41.2% yield, 96.9% HPLC purity, 2.7g of compound IV in 20.5% yield, 94.84% HPLC purity.
EXAMPLE 7 Synthesis of Compound IV
(1) Synthesis of Grignard reagents
Adding magnesium chips (5.78 g, 0.24 mol) into 220mL tetrahydrofuran, starting stirring, adding 1, 2-dibromoethane (3 mL, 0.04 mol), heating to 65 ℃, dropwise adding N-methyl-4-chloropiperidine (32.06 g, 0.24 mol), after the reaction is initiated, reacting at 65 ℃ until the magnesium chips completely disappear to obtain a Grignard reagent, and cooling to room temperature to obtain a first mixed solution.
(2) Synthesis of Compound IV
Adding 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one (9.75 g, 0.04 mol) into 220mL tetrahydrofuran, stirring for dissolving to obtain a second mixed solution, dropwise adding the second mixed solution into the first mixed solution, controlling the reaction temperature to be 30 ℃, continuing to react after dropwise adding, wherein the reaction time is 30min, adding 100mL saturated ammonium chloride aqueous solution after the reaction is finished, adding ethyl acetate after 30min, stirring for layering, extracting the organic phase on the upper layer for three times, combining the organic phases, concentrating the obtained organic phase under reduced pressure, and separating by column chromatography to obtain 1.51g of a compound IV which is a yellow solid, wherein the yield is 8.6%, and the HPLC purity is 94.92%.
EXAMPLE 8 Synthesis of Compound I
(1) Synthesis of the Grignard reagent: the procedure was exactly the same as in step (1) of example 1.
(2) Synthesis of Compound I: substantially the same as in the step (2) in example 1, except that the reaction temperature was controlled at 60 ℃ and the compound I7.38 g was finally obtained by column chromatography, the yield was 18.0% and the HPLC purity was 96%.
EXAMPLE 9 Synthesis of Compound IV
(1) Synthesis of the Grignard reagent: the procedure was exactly the same as in step (1) of example 4.
(2) Synthesis of Compound IV: substantially the same as in the step (2) in example 4, except that the reaction temperature was controlled to 60 ℃ and the compound IV was finally isolated by column chromatography to give 1.43g of the compound IV in a yield of 10.9% and a HPLC purity of 93.97%.
EXAMPLE 10 qualitative analysis of Compound I and Compound IV
(1) Preparation of loratadine intermediate a:
Figure DEST_PATH_IMAGE015
and (3) dropwise adding a Grignard reagent into a tetrahydrofuran solution containing a compound II to react at the temperature of minus 20 ℃ to minus 10 ℃, adding a saturated ammonium chloride aqueous solution into the reaction liquid system after the reaction is finished, maintaining the temperature in the reaction bottle at 10-30 ℃, and standing for layering after the addition is finished. Adding ethyl acetate into the water phase, stirring, standing for layering, combining organic phases, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain oily substance. Adding methanol into the oily matter, stirring at 60 ℃ until the solution becomes clear, preparing 10% sodium hydroxide aqueous solution, cooling to room temperature, slowly dropwise adding the aqueous solution into a methanol phase, cooling to 5-15 ℃ after dropwise adding is finished, crystallizing, and performing suction filtration to obtain a solid, namely an intermediate A, wherein the yield is 71.4%, the purity is 98.2%, and separating the product obtained by the preparation method, so that a compound I and a compound IV cannot be obtained.
The preparation method of the loratadine intermediate A is obtained by referring to the research progress [ J ] of the synthesis process of loratadine, namely Pachioguang, Zhangguang, Zhouyuan, Wang hongbo and the Chinese medical industry journal 2013 and 44 (12).
(2) The chromatogram of the loratadine intermediate A is measured by high performance liquid chromatography, the chromatogram and the peak table are shown in figures 9 and 10, and the detection conditions are completely the same as the detection conditions of the chromatogram of the compound I and the compound IV measured by high performance liquid chromatography.
As can be seen from comparison of fig. 9, 3 and 7, the compound i prepared in example 1 had a peak position of 10.679min and a peak time error of 2s with the impurity peak time at 10.708min in loratadine intermediate a, both of which were identical and contained in an amount of 0.38%, the compound iv prepared in example 4 had a peak position of 11.360min and a peak time error of 2s with the impurity peak time at 11.358min in loratadine intermediate a, both of which were identical and contained in an amount of 1.3%.
The preparation of the loratadine intermediate a is carried out according to the synthesis method of the loratadine intermediate a provided in this embodiment, in the preparation process, the compound i and the compound iv obtained by the preparation method of the compound i and the compound iv provided in the present invention are used as reference substances for detecting and monitoring the compound i and the compound iv in the production process for preparing the second and third batches of loratadine intermediate a, after a certain period of reaction, the contents of the compound i and the compound iv in the reaction solution are detected by using a high performance liquid chromatography, the contents of the compound i and the compound iv in the product are calculated according to a 2020 version chinese pharmacopoeia method, an HPLC peak area normalization method, and the detection result is: the content of the compound I in the reaction liquid in the second batch of production process is 2.1%, the content of the compound IV is 2.8%, the content of the compound I in the reaction liquid in the third batch of production process is 1.9%, and the content of the compound IV is 2.4%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (7)

1. A process for the preparation of a benzocycloheptapyridine compound, comprising the steps of:
Figure 346031DEST_PATH_IMAGE001
synthesis of the Grignard reagent:
heating magnesium and N-methyl-4-chloropiperidine in a first reaction solvent to react under the action of an initiator to obtain a Grignard reagent, adding a ligand into the Grignard reagent, wherein the ligand is N, N, N, N-tetramethylethylenediamine, and the initiator is at least one of 1, 2-dibromoethane and iodine;
synthesis of Compounds I and IV:
8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one reacts with the Grignard reagent in a second reaction solvent, and after the reaction is finished, a water-containing reagent is added to obtain a compound I and a compound IV, wherein the water-containing reagent is an ammonium chloride aqueous solution, and the reaction temperature is 10-35 ℃.
2. The process for producing a benzocycloheptapyridine compound according to claim 1, characterized in that, in the step of synthesizing the Grignard reagent:
the first reaction solvent comprises at least one of tetrahydrofuran and diethyl ether;
the reaction temperature is 40-100 ℃;
the molar ratio of the initiator to the magnesium is 0.01-1.
3. The process for producing benzocycloheptapyridine compound according to claim 1, wherein, in the step of reacting 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one with the grignard reagent in the second reaction solvent to obtain compound i and compound iv:
the second reaction solvent comprises at least one of tetrahydrofuran and diethyl ether.
4. The process for producing a benzocycloheptapyridine compound according to claim 1, characterized in that, in the step of synthesizing the Grignard reagent:
the molar ratio of the ligand to the magnesium is 1-5.
5. The method for producing a benzocycloheptapyridine compound according to claim 1, wherein the molar ratio of N-methyl-4-chloropiperidine to 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1 to 8; the molar ratio of the magnesium to the 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one is 1-8.
6. The process for preparing benzocycloheptapyridine compound according to claim 1, further comprising, after the step of reacting 8-chloro-5, 6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b ] pyridin-11-one with the Grignard reagent in a second reaction solvent to obtain compound I and compound IV:
and purifying and separating the compound I and the compound IV.
7. The process for preparing benzocycloheptapyridine compound according to claim 6, wherein the purification and isolation of the compound I and the compound IV comprises the steps of:
and (3) extracting, concentrating under reduced pressure and carrying out column chromatography separation on reaction liquid containing the compound I and the compound IV to obtain a pure product of the compound I and a pure product of the compound IV.
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