CN113087672A - Preparation method of ambroxol impurity - Google Patents
Preparation method of ambroxol impurity Download PDFInfo
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- CN113087672A CN113087672A CN202110374595.7A CN202110374595A CN113087672A CN 113087672 A CN113087672 A CN 113087672A CN 202110374595 A CN202110374595 A CN 202110374595A CN 113087672 A CN113087672 A CN 113087672A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
Abstract
The application relates to the field of pharmacy, and particularly discloses a preparation method of ambroxol impurities. Which comprises the following steps: mixing ambroxol and a ring closing reaction reagent for reaction, obtaining an ambroxol impurity crude product by a post-treatment method, and purifying the ambroxol impurity crude product to obtain an ambroxol impurity refined product; wherein the ring closing reaction reagent is
Or
，R1、R2、R3、R4Is an alkyl group. The preparation method has the advantage of providing high-purity ambroxol impurities in an economical and efficient preparation method.
Description
Technical Field
The application relates to the technical field of pharmacy, in particular to a preparation method of ambroxol impurity
Background
Ambroxol is a mucolytic drug, can promote the secretion of pulmonary surfactant and airway liquid, break mucopolysaccharide protein fibers in sputum, promote the dissolution of mucus, reduce the viscosity of the sputum, enhance the ciliary movement of bronchial mucosa and promote the discharge of the sputum, has a certain cough-relieving effect, does not need to be converted and metabolized in vivo, can directly play a pharmacological role, and can be used for treating acute and chronic bronchitis, bronchial asthma, bronchiectasis, emphysema, pulmonary tuberculosis, pneumoconiosis, postoperative cough difficulty and the like.
The ambroxol hydrochloride glucose injection can generate ambroxol impurities in the production process: 4- (6, 8-dibromo-3, 4-dihydroquinazolin-3-yl) cyclohexanol, CAS number for ambroxol impurity is 2088879-81-4. The high-purity ambroxol impurity can be used as a qualitative or quantitative standard substance, can be used for the quality research of the ambroxol hydrochloride product, and is beneficial to the monitoring of the product quality of the ambroxol hydrochloride, so the synthesis research of the high-purity ambroxol impurity has important significance.
The currently reported synthetic method of ambroxol impurities has great limitations, such as complicated and tedious reaction or poor reaction reproducibility, and an economic and stable preparation method of ambroxol impurities for obtaining high-purity ambroxol impurities does not appear in the related technology, so as to fill up the technical vacancy in the field.
Disclosure of Invention
In order to obtain an economical and stable preparation method of ambroxol impurities, which provides high-purity ambroxol impurities, the application provides a preparation method of ambroxol impurities.
The preparation method of the ambroxol impurity provided by the application adopts the following technical scheme:
a process for preparing the ambroxol impurity includes mixing ambroxol with the reagent for ring closing reaction, post-treatingThe method obtains an ambroxol impurity crude product, and the ambroxol impurity crude product is purified to obtain an ambroxol impurity refined product; wherein the ring closing reaction reagent is
R1、R2、R3、R4Is an alkyl group.
By adopting the technical scheme, ambroxol is subjected to ring closing to generate ambroxol impurities under the action of a ring closing reaction reagent, a crude ambroxol impurity product with better purity is obtained through post-treatment, and the ambroxol impurities are purified to improve the purity of the ambroxol impurities, so that a fine ambroxol impurity product is obtained.
The ring-closing reaction reagent comprises one or more of methyl orthoformate, ethyl orthoformate, 4-chlorphenyl orthoformate dimethyl ester, diethylphenyl orthoformate, N-dimethylformamide dimethyl acetal, N-dimethylformamide diethyl acetal, N-dimethylformamide dibutyl acetal, N-dimethylformamide-di-tert-butyl acetal, N-dimethylformamide vinyl acetal and N, N-dimethylformamide dicyclohexyl acetal.
The ring-closing reaction reagent comprises one or more of methyl orthoformate, ethyl orthoformate, 4-chlorophenyl dimethyl orthoformate, diethylphenyl orthoformate, N-dimethylformamide dimethyl acetal, N-dimethylformamide diethyl acetal, N-dimethylformamide dibutyl acetal, N-dimethylformamide-di-tert-butyl acetal, N-dimethylformamide vinyl acetal and N, N-dimethylformamide dicyclohexyl acetal, so that the ambroxol is subjected to ring-closing reaction and converted into an ambroxol impurity crude product, and the reaction effect is better.
Preferably, the ring closing reaction reagent comprises one or more of methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal.
By adopting the technical scheme, the ring-closing reaction reagent comprises one or more of methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal, and the ambroxol and one or more of methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal have good reaction effect for synthesizing ambroxol impurities, so that the purity of the ambroxol impurity crude product is favorably further improved, the ambroxol impurity crude product is favorably directly used as a qualitative standard product of the ambroxol impurities, and the product quantity is higher, so that the preparation method of the ambroxol impurities has higher economic benefit.
Preferably, the ambroxol can be free ambroxol or a salt of ambroxol.
By adopting the technical scheme, the ambroxol is free ambroxol or ambroxol hydrochloride, and the free ambroxol or ambroxol hydrochloride is mixed with a ring closing reaction reagent, so that the purity of the high performance liquid chromatography of the generated crude ambroxol impurity product is up to more than 96 percent and is at least 95 percent higher than the requirement of the qualitative requirement of the ambroxol impurity, therefore, the crude ambroxol impurity product directly synthesized by the free ambroxol or ambroxol hydrochloride can be directly used as a standard substance of the qualitative of the ambroxol impurity, and the economic value of the crude ambroxol product is further improved.
Preferably, the post-treatment method of the reaction comprises the steps of removing volatile matters which can be generated in the reaction liquid through distillation or rotary evaporation, then adding water into the residue, adjusting the pH value of the water phase to be 8-12, separating out solid substances, filtering, leaching and drying to obtain the crude product of the ambroxol impurity.
By adopting the technical scheme, in the post-treatment process, the organic solvent A and the volatile matter are removed by distillation, water is added into the distillation residue, the pH value of the water phase is adjusted to 8-12, so that the ambroxol impurity is precipitated in a solid form, the pH value of the water phase of the distillation residue is less than 12, the ambroxol impurity is not easily degraded due to over strong alkalinity, the crude ambroxol impurity product with better purity can be obtained, the purity of the crude ambroxol impurity product obtained by reaction is more than 92%, the product amount of the crude ambroxol converted into the ambroxol impurity product is more than 90%, and the purity of the obtained ambroxol crude ambroxol product is better.
Preferably, in the post-treatment method, after the pH value is adjusted to 8-12, the filtration time is controlled within 1-60 min after the solid matters are separated out.
By adopting the technical scheme, the time for separating out the solid substances is controlled within 1-60 min, and the time for the aqueous solution of the residue to be in a pH state of 8-12 is not more than 60min, so that the ambroxol impurity is not easy to be in an alkaline environment for a long time, the ambroxol impurity is not easy to degrade, and the purity of the crude ambroxol impurity product is further improved.
Preferably, the ratio of the mass of the ambroxol to the volume of the ring closing reaction reagent is 1g (2-20) mL.
By adopting the technical scheme, the ratio of the mass of the ambroxol to the volume of the ring-closing reaction reagent is 1g (2-20) mL, so that the reaction effect of the ambroxol and the ring-closing reaction reagent is better, the reaction rate of the ambroxol to generate the ambroxol impurity is better, the time required by the reaction until the ambroxol disappears is greatly shortened, and the time cost is saved.
Preferably, the organic solvent A comprises one or more of lower alcohols, toluene and tetrahydrofuran.
By adopting the technical scheme, the ambroxol and the ring-closing reaction reagent are quickly dissolved to form a homogeneous phase by adopting the lower alcohol, the toluene or the tetrahydrofuran as the solvent for the reaction, so that the effect of synthesizing the ambroxol impurity by the reaction of the ambroxol and the ring-closing reaction reagent is better.
The lower alcohol compounds comprise methanol, ethanol, isopropanol and n-butanol, and the dissolving effect of the ambroxol and the ring closing reaction reagent is better and the reaction rate is better through the lower alcohol compounds comprising methanol, ethanol, isopropanol and n-butanol, so that the time required by the reaction until the ambroxol disappears is shortened.
Preferably, the crude ambroxol impurity product is mixed with an organic solvent B for pulping or recrystallization, and after a solid substance is separated out, the crude ambroxol impurity product is filtered and dried to obtain an ambroxol impurity refined product.
By adopting the technical scheme, the crude ambroxol impurity product is mixed with the organic solvent B for pulping or recrystallization treatment, so that the purity of the crude ambroxol impurity product is improved from more than 96% to more than 99%, and the requirement that the purity required by the quantitative determination of the ambroxol impurity is at least 99% is met, therefore, the refined ambroxol impurity product is used quantitatively as the ambroxol impurity, and the economic value of the refined ambroxol impurity product is further improved.
Preferably, the organic solvent B is low molecular ester or liquid alkane, the crude product of the ambroxol impurity is beaten with the low molecular ester or liquid alkane, and the ratio of the mass of the crude product of the ambroxol impurity to the volume of the ester or the alkane is 1.9g (10-15) mL.
By adopting the technical scheme, the crude product of the ambroxol impurity and the low molecular ester or the liquid alkane are mixed and pulped according to a specific proportion, the solubility of the crude product of the ambroxol impurity in the low molecular ester or the liquid alkane is low, the purification effect of the crude product of the ambroxol impurity is good, and thus the high-purity refined product of the ambroxol impurity is obtained.
The low molecular ester can be methyl formate, ethyl acetate, methyl acetate and the like, and the crude product of the ambroxol impurity has poor solubility in methyl formate, ethyl acetate and methyl acetate compared with other substances by mixing the methyl formate, the ethyl acetate, the methyl acetate and the crude product of the ambroxol impurity, so that the purification effect of the ambroxol impurity is better.
The liquid alkane can be normal hexane, normal heptane, normal dodecane, normal tetradecane, isododecane, isoheptane, isooctane and the like, and the crude product of the ambroxol impurity is mixed and pulped by the normal hexane, normal heptane, normal dodecane, normal tetradecane, isododecane, isoheptane, isooctane and the crude product of the ambroxol impurity, and the solubility of the ambroxol impurity in the normal hexane, normal heptane, normal dodecane, normal tetradecane, isododecane, isoheptane and isooctane is poorer than that of other substances, so that the pulping and purifying effects of the ambroxol impurity are better.
Preferably, the organic solvent B is low-molecular alcohol, the crude product of the ambroxol impurity is recrystallized from the low-molecular alcohol, and the mass ratio of the crude product of the ambroxol impurity to the volume of the alcohol is 1.9g (7-12) mL.
By adopting the technical scheme, the ambroxol impurity is recrystallized in the low molecular alcohol, the solubility of the ambroxol impurity in the low molecular alcohol is better, and the influence of temperature on the solubility is large, so that the ambroxol impurity is separated out after the low molecular alcohol is cooled, and the high-purity refined ambroxol impurity is favorably obtained.
The low molecular alcohol can be methanol, ethanol, propanol, butanol and the like, and the crude product of the ambroxol impurity is recrystallized through the methanol, the ethanol, the propanol, the butanol and the crude product of the ambroxol impurity, the crude product of the ambroxol impurity has a better dissolving effect when reflowing in the methanol, the ethanol, the propanol and the butanol, and then the temperature is reduced, so that the solubility of the ambroxol impurity is obviously reduced after the temperature is reduced, the ambroxol impurity is easy to separate out after the temperature is reduced, the purity of the recrystallized separated ambroxol impurity is better, and the purity of the refined ambroxol impurity is better.
In summary, the present application has the following beneficial effects:
1. because the ambroxol is adopted to react with the ring closing reaction reagent, the purity of the ambroxol impurity refined product is up to 99.3 percent through post-treatment and purification operation, the ambroxol impurity refined product can be directly used as a qualitative and quantitative standard product of the ambroxol impurity, the crude ambroxol impurity product is obtained through the direct one-step reaction of the ambroxol and the ring closing reaction reagent, the product quantity of the ambroxol impurity generated by the ambroxol is up to more than 90 percent, the crude ambroxol impurity product obtained through the reaction has high purity, the reaction raw materials are convenient to obtain, the reaction is simple, the operability is strong, the labor cost and the production cost are favorably reduced, the popularization of industrial production is favorably realized, and the characteristics of economy and high efficiency are realized.
2. According to the method, the ring-closing reaction reagent is one or more of methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal, so that the purity of the obtained crude ambroxol impurity product is high, and the quality of the obtained crude ambroxol impurity product is good.
3. In the application, the reaction effect of generating the ambroxol impurity by adopting the free ambroxol, the free ambroxol hydrochloride and the ring closing reaction reagent is good, so that the purity of the crude ambroxol impurity product after the reaction is over 96 percent, the crude ambroxol impurity product can be directly used as a qualitative standard product of the ambroxol impurity, and the economic value is high.
Drawings
FIG. 1 is a high performance liquid chromatogram of the crude ambroxol impurity prepared in example 1 of the present application.
FIG. 2 is a high performance liquid chromatogram of the refined ambroxol impurity prepared in example 1 of the present application.
FIG. 3 is the NMR spectrum of the refined ambroxol impurity prepared in example 1 of the present application.
FIG. 4 is a mass spectrum of the refined ambroxol impurity prepared in example 1 of the present application.
FIG. 5 is a high performance liquid chromatogram of the crude ambroxol impurity prepared in example 2 of the present application.
FIG. 6 is a high performance liquid chromatogram of the refined ambroxol impurity prepared in example 2 of the present application.
FIG. 7 is a high performance liquid chromatogram of the crude ambroxol impurity prepared in example 3 of the present application.
FIG. 8 is a high performance liquid chromatogram of the refined ambroxol impurity prepared in example 3 of the present application.
FIG. 9 is a high performance liquid chromatogram of the crude ambroxol impurity prepared in example 4 of the present application.
FIG. 10 is a high performance liquid chromatogram of the refined ambroxol impurity prepared in example 4 of the present application.
FIG. 11 is a high performance liquid chromatogram of the crude ambroxol impurity prepared in example 5 of the present application.
Detailed Description
The present application will be described in further detail with reference to the following drawings and examples.
According to the technical scheme, ambroxol is used as a raw material and is mixed with a ring closing reaction reagent for reaction under mild reaction conditions, so that an ambroxol impurity crude product can be quickly and efficiently synthesized.
The synthesis route designed by the application is as follows:
example 1
A preparation method of nitrogen bromine impurities comprises the following steps:
step (1), preparing a crude product of ambroxol impurity: 2.08g of ambroxol hydrochloride (5.0mmol) is put into a solanaceous bottle, 10mL of methyl orthoformate and 20mL of methanol are added, stirring and refluxing are carried out at 50 ℃ at the rotating speed of 100r/min, and the mixture is monitored by thin-layer chromatography until the ambroxol hydrochloride disappears.
And (2) post-reaction treatment: cooling the eggplant-shaped bottle to room temperature, distilling to remove the solvent and the volatile matters to obtain a residue, adding 20mL of water for dissolving, adding 10% sodium carbonate solution to adjust the pH value of the aqueous solution of the residue to 10, stirring to separate out the solid matters, filtering to obtain the solid matters, controlling the filtering time to be 30min after the solid matters are separated out, leaching the solid matters for 3 times by using water, wherein the ratio of the mass of the solid matters to the volume of the water is 1g: 2ml, and vacuum drying at 55 deg.C in a vacuum drying oven to obtain crude ambroxol impurity product 1.90g with purity of 97.67% by high performance liquid chromatography (see figure 1). The product amount was 91.3%.
And (3) purifying the crude product of the ambroxol impurity: pulping 1.90g of crude ambroxol impurity product in 10mL of isopropanol at room temperature for purification, separating out solid substances, filtering at room temperature, and drying at 55 ℃ under reduced pressure by using a vacuum drying oven to obtain 1.54g of refined ambroxol impurity product with the purity of high performance liquid chromatography of 99.3% (see figure 2).
The nuclear magnetic resonance hydrogen spectrogram detection data of the ambroxol impurity competitive product is as follows: 1H NMR (600MHz, DMSO) δ 7.55(d, J ═ 2.0Hz,1H),7.25(s,1H), 7.13-7.08 (m,1H),4.64(d, J ═ 4.5Hz,1H),4.48(s,2H), 3.42-3.35 (m,1H),3.24(tt, J ═ 11.8,3.6Hz,1H),1.89(d, J ═ 11.4Hz,2H),1.69(d, J ═ 11.4Hz,2H),1.61(qd, J ═ 12.7,2.9Hz,2H),1.25(td, J ═ 12.9,3.3Hz, 2H). The nuclear magnetic resonance hydrogen spectrum of the refined ambroxol impurity is shown in figure 3.
The mass spectrum of the refined ambroxol impurity is shown in figure 4.
Example 2
Step (1), preparing a crude product of ambroxol impurity: 2.08g of ambroxol hydrochloride (5.0mmol) is put into a solanaceous bottle, 8mL of ethyl orthoformate and 16mL of ethanol are added, stirring is carried out at room temperature under the rotation speed of 120r/min, and monitoring is carried out by thin-layer chromatography until the ambroxol hydrochloride disappears.
And (2) post-reaction treatment: cooling the eggplant-shaped bottle to room temperature, removing the solvent and the volatile matters by rotary evaporation to obtain a residue, adding 18mL of water for dissolving, adding 5% sodium hydroxide solution for adjusting the pH value of the aqueous solution of the residue to 8, stirring until the solid matters are separated out, filtering to obtain the solid matters, controlling the filtering time to be 1min after the solid matters are separated out, leaching the solid matters for 3 times by using water, wherein the ratio of the mass of the solid matters to the volume of the water is 1g: 5ml, and vacuum drying at 60 deg.C in a vacuum drying oven to obtain crude ambroxol impurity product 1.92g, with purity of high performance liquid chromatography 97.22% (see figure 5). The product amount was 92.3%.
And (3) purifying the crude product of the ambroxol impurity: pulping 1.90g of crude ambroxol impurity product in 15mL of ethyl acetate at room temperature for purification, separating out solid substances, filtering at room temperature, and drying under reduced pressure at 60 ℃ by using a vacuum drying oven to obtain 1.62g of refined ambroxol impurity product with the purity of high performance liquid chromatography of 99.19% (see figure 6 for detection results).
Example 3
Step (1), preparing a crude product of ambroxol impurity: 2.08g of ambroxol hydrochloride (5.0mmol) is put into a eggplant-shaped bottle, 12mL of LN, N-dimethylformamide dimethyl acetal and 24mL of tetrahydrofuran are added, stirring and refluxing are carried out at 70 ℃, and thin-layer chromatography is carried out until the ambroxol hydrochloride disappears.
And (2) post-reaction treatment: cooling the eggplant-shaped bottle to room temperature, removing the solvent and the volatile matters by rotary evaporation to obtain a residue, adding 18mL of water for dissolving, adding a sodium hydroxide solution with the mass concentration of 5% to adjust the pH value of the aqueous solution of the residue to 12, stirring until solid matters are separated out, filtering to obtain the solid matters, controlling the solid matters to be separated out for 60min, leaching the solid matters for 3 times by using water, wherein the ratio of the mass of the solid matters to the volume of the water is 1g: 10ml, and vacuum drying at 50 deg.C to obtain crude ambroxol impurity product 1.87g with high performance liquid chromatography purity of 96.40% (see figure 7). The product amount was 90.0%.
And (3) purifying the crude product of the ambroxol impurity: taking 1.90g of crude ambroxol impurity product, refluxing and recrystallizing in 7mL of ethanol, cooling to room temperature, separating out solid substances, cooling to room temperature, filtering, and drying under reduced pressure at 50 ℃ by using a vacuum drying oven to obtain 1.36g of refined ambroxol impurity product with the purity of high performance liquid chromatography of 99.22% (see figure 8).
Example 4
The only difference from example 1 is:
in the step (1), free ambroxol is adopted to replace ambroxol hydrochloride with equal volume, and toluene with equal volume is adopted to replace methanol. 1.90g of crude product of ambroxol impurity with the product amount of 91.3 percent is obtained. The purity of the HPLC solution was 92.05% (see FIG. 9 for the results of the detection).
The preparation method of the free ambroxol comprises the following steps: 8g of ambroxol hydrochloride (19.28mmol) is dispersed in 100mL of water, sodium hydroxide is added to adjust the pH value to 10, then 200mL of ethyl acetate is added for extraction, the extract is extracted for a plurality of times in small amount, and the organic phase is concentrated to obtain free ambroxol. In the step (3), 12mL of ethanol is added for recrystallization, so as to obtain 1.26g of ambroxol impurity refined product with the purity of 99.30% by high performance liquid chromatography (see figure 10 for detection results).
Example 5
The only difference from example 1 is:
in step (1), 40mL of methyl orthoformate was used instead of 10mL of methyl orthoformate.
In the step (2), the purity of the crude ambroxol impurity product detected by high performance liquid chromatography is 97.11% (see figure 11 for detection results), and the product amount of the crude ambroxol impurity product is 90.5%.
Example 6
The only difference from example 1 is:
in step (1), 4mL of methyl orthoformate was used instead of 10mL of methyl orthoformate.
In the step (2), the purity of the ambroxol impurity crude product is detected to be 37.56% by high performance liquid chromatography.
Comparative example 1: the preparation method for synthesizing the ambroxol impurity through one-step reaction comprises the following steps:
comparative example 1.1
8g of ambroxol hydrochloride and 50mL of isobutyl formate are directly mixed, reflux stirring is carried out for 6 hours at the rotating speed of 100r/min, the stirring is carried out for cooling to 4 ℃, the heat preservation stirring is carried out for 3 hours, and the detection reaction is carried out by a high performance liquid chromatograph, so that the product amount is 0.1%.
Comparative example 1.2
The only difference from example 1 is:
8g of ambroxol free alkali prepared by the preparation method of ambroxol free alkali in the embodiment 4 is mixed with 50mL of isobutyl formate, the mixture is stirred for 6 hours at the temperature of 130 ℃ at the rotating speed of 100r/min, the stirring temperature is reduced to 4 ℃, the mixture is stirred for 3 hours under the heat preservation condition, and the product amount is 2.89% after the detection reaction by a high performance liquid chromatograph.
Comparative example 2: the preparation route for synthesizing the ambroxol impurity by the two-step reaction is as follows:
by referring to patent document CN109810066A specification example 1 to synthesize compound 3(4- (6, 8-dibromo-1, 4-dihydroquinazolin-3 (2H) -yl) -cyclohexanol hydrochloride) from compound 2 (ambroxol hydrochloride), in comparative example 2, the inventors used 4 different oxidation systems to carry out the reaction so that compound 3 synthesizes compound 1 (ambroxol impurity hydrochloride) by oxidation, as follows:
comparative example 2.1
1mmol of compound 3, 0.6mmol of sodium dichloroisocyanurate, 10mL of ethyl acetate and 10mL of water are mixed in a eggplant-shaped bottle, the mixture is stirred for 10 hours at 10 ℃ at the rotating speed of 100r/min, and the reaction is detected by a high performance liquid chromatograph, so that the product amount is 5.0 percent.
Comparative example 2.2
1mmol of compound 3, 0.6mmol of sodium dichloroisocyanurate, 10mL of toluene and 10mL of water are mixed in a eggplant-shaped bottle, the mixture is stirred for 10 hours at the rotation speed of 100r/min and the temperature of 10 ℃, and the reaction is detected by a high performance liquid chromatograph, so that the product amount is 3.5 percent.
Comparative example 2.3
1mmol of compound 3, 2mmol of 2, 3-dichloro-5, 6-dicyan p-benzoquinone and 4mL of dichloromethane are mixed in an eggplant-shaped bottle, the mixture is stirred for 10 hours at 25 ℃ at the rotating speed of 120r/min, the detection reaction is carried out by a high performance liquid chromatograph, the detection reaction is carried out by the high performance liquid chromatograph, and the product content is 10.34 percent.
Comparative example 2.4
1mmol of compound 3, 4mLN, N-dimethylformamide and 6% palladium acetate are adopted as catalysts for mixing, stirring is carried out for 10 hours at the temperature of 60 ℃, and the detection reaction is carried out by a high performance liquid chromatograph, so that the product amount is 66.7%.
Comparative example 3
The only difference from example 1 is: in the step (2), 5 mass percent of sodium hydroxide is used for adjusting the pH value of the aqueous solution of the residue to be 13, the mixture is stirred for 2 hours at room temperature, and the purity of the crude product of the ambroxol impurity is reduced from 97.7 percent to 85.4 percent.
Experiment 1
The product amount of the crude ambroxol impurity in each example and comparative example is recorded and shown in table 1.
The amounts (%) of the products of examples 1 to 5, comparative examples 1.1 to 1.2 and comparative examples 2.1 to 2.4 are shown in Table 1.
TABLE 1
| Amount of product (%) | |
| Example 1 | 91.3 |
| Example 2 | 92.3 |
| Example 3 | 90.0 |
| Example 4 | 91.2 |
| Example 5 | 90.5 |
| Comparative example 1.1 | 0.1 |
| Comparative example 1.2 | 2.89 |
| Comparative example 2.1 | 5.0 |
| Comparative example 2.2 | 3.5 |
| Comparative example 2.3 | 10.34 |
| Comparative example 2.4 | 66.7 |
According to the comparison between comparative example 1.1 and example 1 in table 1, the product amount after the mixed reaction of isopropyl formate and ambroxol hydrochloride is 0.1%, and the product amount after the reaction of methyl orthoformate and ambroxol hydrochloride is up to 91.3%, which proves that the ambroxol impurity is obtained by the direct mixed reaction of methyl orthoformate and ambroxol hydrochloride, the product amount of the ambroxol impurity is high, the purity of the crude ambroxol impurity product is high, the further purification is facilitated to be used as a standard for the sizing or quantification of the ambroxol impurity, and the effect of converting ambroxol hydrochloride into the ambroxol impurity is good.
According to the comparison between comparative example 1.2 and example 1 in table 1, the amount of the product obtained by directly mixing ambroxol hydrochloride and methyl orthoformate is significantly higher than the amount of the free ambroxol base and isobutyl formate, which proves that the effect of directly reacting ambroxol hydrochloride and methyl orthoformate is better.
According to the comparison between comparative examples 2.1-2.4 in table 1 and example 1, the product amount obtained by using compound 3 to prepare ambroxol impurity through oxidation reaction is obviously lower than that obtained by directly mixing ambroxol hydrochloride and methyl orthoformate, which proves that ambroxol hydrochloride and methyl orthoformate have higher reaction activity after mixing, so that the product amount of ambroxol impurity is higher, and the purity of the obtained crude product of ambroxol impurity is higher and less impurity is obtained.
According to the data of the embodiment 1 and the embodiments 2 to 3 in the table 1, the ambroxol hydrochloride can be reacted with methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal to obtain the product with the purity of more than 90%, the purity of the crude ambroxol impurity product is close to 97%, the ambroxol impurity with high purity can be stably obtained, meanwhile, the post-treatment operation of the reaction is simple, the post-treatment process difficulty of the ambroxol impurity is greatly reduced, the cost of the purification operation of the crude ambroxol impurity product is favorably reduced, the purity of the fine ambroxol impurity product can reach the qualitative or quantitative standard product of the ambroxol impurity in the glucose hydrochloride injection, and the results prove that the ambroxol hydrochloride or the free ambroxol and the methyl orthoformate, ethyl orthoformate and N which are used as a ring-closing reaction reagent, the reaction of the N-dimethylformamide dimethyl acetal is direct and simple, and the post-treatment process is simple and convenient, so that the preparation method of the ambroxol impurity has the characteristics of economy and high efficiency.
The preparation of the ambroxol impurity in example 1 was repeated twice and the results were recorded. The experimental data are detailed in table 2.
TABLE 2
As can be seen from the experimental results in Table 2, when the experiment 1 is repeated, the product amount and purity of the crude ambroxol impurity product and the refined ambroxol impurity product are kept in a stable state, and the result proves that the ambroxol impurity synthesized from ambroxol hydrochloride and the ring-closing reaction reagent has the advantages of good reaction stability and good reaction repeatability.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A preparation method of ambroxol impurity is characterized by comprising the following steps: mixing ambroxol and a ring closing reaction reagent for reaction, obtaining an ambroxol impurity crude product by a post-treatment method, and purifying the ambroxol impurity crude product to obtain an ambroxol impurity refined product; wherein the ring closing reaction reagent is
Or
，R1、R2、R3、R4Is an alkyl group.
2. The method for preparing ambroxol impurity according to claim 1, characterized in that: the ring closing reaction reagent comprises one or more of methyl orthoformate, ethyl orthoformate and N, N-dimethylformamide dimethyl acetal.
3. The method for preparing ambroxol impurity according to claim 1 or 2, characterized in that: the ambroxol can be free ambroxol or a salt of ambroxol.
4. The method for preparing ambroxol impurity according to claim 1, characterized in that: and the post-treatment method of the reaction comprises the steps of removing volatile matters which can be generated in the reaction liquid through distillation or rotary evaporation, then adding water into the residue, adjusting the pH value of the water phase to be 8-12, separating out solid substances, filtering, leaching and drying to obtain the crude product of the ambroxol impurity.
5. The method for preparing ambroxol impurity according to claim 4, characterized in that: in the post-treatment method, after the pH value is adjusted to 8-12, the filtration time is controlled within 1-60 min after solid substances are separated out.
6. The method for preparing ambroxol impurity according to claim 1, characterized in that: the ratio of the mass of the ambroxol to the volume of the ring closing reaction reagent is 1g (2-20) mL.
7. The method for preparing ambroxol impurity according to claim 1, characterized in that: the organic solvent A comprises one or more of lower alcohols, toluene and tetrahydrofuran.
8. The method for preparing ambroxol impurity according to claim 1, characterized in that: and mixing the crude ambroxol impurity product with an organic solvent B, pulping or recrystallizing, filtering to obtain a solid substance after the solid substance is separated out, and drying the solid substance to obtain an ambroxol impurity refined product.
9. The method for preparing ambroxol impurity according to claim 8, characterized in that: the organic solvent B is low molecular ester or liquid alkane, the crude product of the ambroxol impurity is taken to be pulped with the low molecular ester or the liquid alkane, and the ratio of the mass of the crude product of the ambroxol impurity to the volume of the ester or the alkane is 1.9g (10-15) mL.
10. The method for preparing ambroxol impurity according to claim 8, characterized in that: and the organic solvent B is low-molecular alcohol, the crude product of the ambroxol impurity is recrystallized with the low-molecular alcohol, and the mass ratio of the crude product of the ambroxol impurity to the volume of the alcohol is 1.9g (7-12) mL.
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