CN113956198A

CN113956198A - Impurity of roxasistat, preparation method and application thereof

Info

Publication number: CN113956198A
Application number: CN202110678333.XA
Authority: CN
Inventors: 刘凤伟; 王卓; 罗军; 金红星; 王果; 周春东; 张勇; 杨飞
Original assignee: Jichuan Shanghai Medical Technology Co ltd
Current assignee: Jichuan Shanghai Medical Technology Co ltd
Priority date: 2021-06-18
Filing date: 2021-06-18
Publication date: 2022-01-21

Abstract

The invention discloses impurities of roxasistat, a preparation method and application thereof. Wherein the impurities of the Rosesalpine are represented by formula I or II. The impurity compound can be used as a reference substance for quality control of a roxasistat synthesis intermediate and a roxasistat bulk drug. The invention also discloses a preparation method of the compounds shown in the formulas I and II.

Description

Impurity of roxasistat, preparation method and application thereof

Technical Field

The invention relates to the field of medicines, and particularly relates to impurities of roxasistat, a preparation method and application thereof.

Background

Anemia is a common disease among Chronic Kidney Disease (CKD) patients, and the total number of chronic kidney disease patients in china is about 1.195 million. The roxasistat is a medicine with a brand-new action mechanism, is the first hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor developed globally, and the physiological action of the Hypoxia Inducible Factor (HIF) not only increases the expression of erythropoietin, but also increases the expression of erythropoietin receptors and proteins for promoting iron absorption and circulation. The medicine is developed by the American FibroGen company, is first sold in China through CDE examination and evaluation in 2018 and 12 months, becomes the first new anti-anemia medicine for oral treatment, injection and intravenous iron supplement, and becomes the first class 1 innovative medicine with a brand-new action mechanism and first marketed in China in the world.

The preparation methods of the Rosemastat disclosed in the prior art have the disadvantages of complicated steps, low yield, use of noble metal catalysts and the like, so the inventors develop a preparation method of the Rosemastat more suitable for industrial production, and the synthetic route is as follows:

as a new drug on the market in recent years, there is still no research on intermediate process impurities in the process development process of the brand new preparation method of the aforementioned rosxastat. It is known that the research and control of impurities are an important work content for improving the purity of the medicine and controlling the quality of the medicine, and the impurities introduced by the production process are important sources of the medicine impurities. It is a challenging task to study the types and sources of impurities generated in the novel synthetic routes not reported in the literature, and to effectively control the quality and purity of the drugs. Therefore, identifying impurities generated in the process and developing an efficient impurity synthesis route so as to obtain a large amount of impurity reference substances are important bases for ensuring the development of quality detection work of each batch of process intermediates or raw material medicaments.

Disclosure of Invention

In the process development process of the brand-new preparation method of the Rosemastat, research on intermediate process impurities is still lacked, so that the invention provides the Rosemastat process impurities, the preparation method and the application thereof. The impurity compound can be used as a reference substance to carry out quality control on a roxasistat synthesis intermediate and a roxasistat bulk drug, and is very necessary to control the quality of the roxasistat bulk drug and even a finished product of a preparation.

In the process of the development of the synthesis process of the Rosemastat, a large process impurity (impurity I) is generated in the amplification reaction process of preparing the Rosemastat intermediate M1-A, and the impurity accounts for about 0.5% of the intermediate M1-A and is difficult to completely remove. And further forms a new derivative impurity (impurity II) in step M2-A, which is about 0.3% of the intermediate M2-A. The impurity I and the impurity II have great adverse effects on the quality of the intermediate M1-A and M2-A, and according to the requirement of ICH Q3A (R2) for "impurities in new bulk drug", the potential impurities actually existing and possibly generated in the processes of synthesis, refining and storage in the process of development and declaration of the bulk drug should be researched and evaluated. The quality of the bulk drug can be ensured only by fully researching and evaluating the process impurities which are generated in the synthesis process and affect the quality of the intermediate. Therefore, the structure confirmation and the standard substance preparation of the process impurity I are beneficial to the tracing of the impurity, and a corresponding impurity removal scheme can be formulated according to the physicochemical properties of the impurity compound, so that the method plays a vital role in the process research and the quality monitoring of the raw material medicine of the roxasistat. Since the impurity research requires a sufficient amount of impurity standard, the yield obtained by using the method for preparing liquid chromatographic separation is low, and the requirement of the impurity research is difficult to meet. Therefore, the invention also provides a method for chemically and directionally synthesizing the impurity compound I.

The invention provides a compound shown as a formula I or a salt thereof:

the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:

(1) reacting a compound shown as a formula II with acetyl chloride in a solvent in the presence of an organic base;

(2) reacting the product of the step (1) with morpholine in a solvent to prepare the compound shown in the formula I;

in step (1), the solvent may be a solvent conventionally used in such reactions in the art, including one or more of an alcoholic solvent (e.g., methanol, ethanol, isopropanol), a halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform), a polar aprotic organic solvent (e.g., acetonitrile, DMF, DMSO), an aromatic hydrocarbon organic solvent (e.g., toluene), an ether solvent (e.g., tetrahydrofuran, dioxane), preferably dichloromethane.

In step (1), the organic base may be one or more of organic bases conventionally used in such reactions in the art, such as triethylamine, N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene, pyridine and 4-dimethylaminopyridine, preferably triethylamine.

In step (1), the molar ratio of acetyl chloride to the compound of formula II may be in a ratio conventionally used in such reactions in the art, such as (1-10):1, for example 8:1, and for example 3: 1.

In step (1), the molar ratio of organic base to compound of formula II may be in a ratio conventionally used in such reactions in the art, e.g., (2-20):1, further e.g., (10-11):1, further e.g., 3: 1.

In the step (1), the reaction may be carried out at room temperature.

In step (1), the reaction time is related to the scale of the reaction, and the progress of the reaction can be monitored by a monitoring method (e.g., HPLC or TLC) which is conventional in the art, and the end point of the reaction is usually monitored as the disappearance or no longer reaction of the compound represented by formula II. In some embodiments, the reaction time may be 5 hours.

In step (2), the solvent may be a solvent conventionally used in such reactions in the art, including one or more of an alcoholic solvent (e.g., methanol, ethanol, isopropanol), a halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform), a polar aprotic organic solvent (e.g., acetonitrile, DMF, DMSO), an aromatic hydrocarbon organic solvent (e.g., toluene), an ether solvent (e.g., tetrahydrofuran, dioxane).

In the step (2), the same solvent as in the step (1) may be used, or a solvent different from that in the step (1) may be used; preferably, the same solvent as in step (1) is used; more preferably, the solvent used in step (1) and step (2) is dichloromethane.

The amount of morpholine used in step (2) may be that conventionally used in such reactions in the art, for example the molar ratio of morpholine to the product of step (1) may be (2-30):1, for example 10:1, again for example 2: 1.

In the step (2), the reaction may be carried out at a temperature of 45 to 50 ℃.

In step (2), the reaction time is related to the scale of the reaction, and the progress of the reaction can be monitored by a monitoring method (e.g., HPLC or TLC) which is conventional in the art, and the end point of the reaction is usually monitored as the disappearance or no longer reaction of the product in step (1). In some embodiments, the reaction time may be 25 hours.

In the step (1) and the step (2), after the reaction is completed, a post-treatment step may be further included. One or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment, and beating may be employed as the post-treatment means conventional in the art. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

The preparation method of the compound shown in the formula I can further comprise a preparation method of a compound shown in a formula II, and the preparation method can comprise the following steps: in a solvent, carrying out reductive amination reaction on a compound shown as a formula M1-Z6 and a compound shown as a formula M2-D in the presence of a reducing agent to obtain a compound shown as a formula II;

in the reductive amination reaction, the solvent may be a solvent conventionally used in such reactions in the art, including one or more of an alcohol solvent (e.g., methanol, ethanol, isopropanol or a mixture thereof), a halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform or a mixture thereof), a polar aprotic organic solvent (e.g., acetonitrile, DMF, DMSO or a mixture thereof), an aromatic hydrocarbon organic solvent (e.g., toluene), preferably dichloromethane.

In the reductive amination reaction, the reducing agent may be an organoboron reducing agent conventionally used in such reactions in the art, such as one or more of sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride, preferably sodium triacetoxyborohydride.

The amount of reducing agent used in the reductive amination reaction may be that conventionally used in such reactions in the art, for example the molar ratio of reducing agent to compound of formula M2-D may be (1-3):1, preferably 2: 1.

The molar ratio of the compound of formula M1-Z6 to the compound of formula M2-D in the reductive amination reaction may be the conventional molar ratio of the starting materials in such reactions in the art, and is preferably 1:1.

The reductive amination reaction may be carried out under catalysis of acetic acid.

The reductive amination reaction can be carried out at room temperature.

In the reductive amination reaction, the reaction time is related to the reaction scale, and the progress of the reaction can be monitored by a monitoring method (such as HPLC or TLC) which is conventional in the art, and is generally used as the end point of the reaction when a certain raw material disappears or no longer reacts. In some embodiments, the reaction time may be 4 hours.

In the reductive amination reaction, after the reaction is completed, a post-treatment step can be further included. One or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment, and beating may be employed as the post-treatment means conventional in the art. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

The method for preparing the compound of formula II may include a method for preparing a compound of formula M1-Z6, which may include the steps of: in a solvent, carrying out the following oxidation reaction on a compound shown as a formula M3-A and elemental iodine to obtain a compound shown as a formula M1-Z6;

in the preparation method of the compound shown as the formula M1-Z6, the solvent is a conventional solvent for the reaction in the field, such as a high-boiling polar aprotic organic solvent, preferably DMSO or DMF, and more preferably DMSO.

In the preparation method of the compound shown in the formula M1-Z6, the molar ratio of the elementary iodine to the compound shown in the formula M3-A can be the conventional dosage ratio of the reaction in the field, such as (1.5-3.5):1, and such as 2.5: 1.

The preparation method of the compound shown in the formula M1-Z6 can be carried out at the temperature of 90-125 ℃ (for example, 110-125 ℃, and also 120-125 ℃).

In the preparation method of the compound shown in the formula M1-Z6, the volume mass ratio of the solvent to the compound shown in the formula M3-A can be the conventional dosage ratio of the reaction in the field, such as 10-30mL/g, and 10-20 mL/g.

In the preparation method of the compound represented by the formula M1-Z6, the reaction time is related to the scale of the reaction, and the progress of the reaction can be monitored by a monitoring method (such as HPLC or TLC) which is conventional in the art, and the end point of the reaction is generally monitored when the compound represented by the formula M3-A disappears or is no longer reacted. In some embodiments, the reaction time for the oxidation reaction may be 5 hours.

In some embodiments, the compound of formula M1-Z6 is prepared by a process wherein the solvent is DMSO; the volume-mass ratio of the solvent to the compound shown in the formula M3-A is 10-20 mL/g; the mole ratio of the elementary iodine to the compound shown as the formula M3-A is 2.5: 1; the oxidation reaction is carried out at a temperature of 110-125 ℃.

The preparation method of the compound shown as the formula M1-Z6 can further comprise a post-treatment step after the oxidation reaction is finished. One or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment, and beating may be employed as the post-treatment means conventional in the art. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

The method for preparing the compound represented by the formula M1-Z6 may include a method for preparing the compound represented by the formula M3-a, which may include the steps of: in the presence of a hydrogen source, carrying out reduction reaction on a compound shown as a formula M2-A as shown in the specification to obtain a compound shown as a formula M3-A;

in the preparation method of the compound represented by the formula M3-a, the hydrogen source can be a hydrogen source conventional in such reactions in the art, such as a metal element/hydrogen donor. The metal simple substance is zinc powder, iron powder or a mixture thereof. The amount of said elemental metal may be that conventionally used in such reactions in the art, preferably in a molar ratio to said compound of formula M2-A of from 1:1 to 10:1, such as from 2:1 to 8:1, such as from 2:1 to 6:1, and such as from 2:1 to 3: 1. The hydrogen donor may be a hydrogen donor conventional in the art for such reactions, such as an acid, ammonium formate, ammonium chloride, or a mixture thereof. The hydrogen donor may be used in an amount conventional in the art for such reactions, preferably in a molar ratio to the elemental metal of greater than 1:1, such as greater than 5:1, greater than 10:1, greater than 20:1, greater than 40:1, or greater than 50: 1.

In the preparation method of the compound shown in the formula M3-A, the metal simple substance is preferably zinc powder.

In the process for preparing the compound of formula M3-a, when the hydrogen donor is an acid, the acid is preferably a liquid, which may also act as a solvent. The acid is preferably an inorganic acid, an organic acid or a mixture thereof. The inorganic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof. The organic acid is preferably formic acid, acetic acid, trifluoroacetic acid or a mixture thereof, more preferably acetic acid. The acid may be used in an amount conventional to such reactions in the art, preferably in a volume to mass ratio with the compound of formula M2-A of from 3mL/g to 40mL/g, for example from 8mL/g to 15mL/g, for example from 8mL/g to 10 mL/g.

In the process for the preparation of the compound of formula M3-A, when the hydrogen donor is ammonium formate or ammonium chloride, it may be used in amounts customary in the art for such reactions, preferably in a molar ratio to the compound of formula M2-A of from 1:1 to 50:1, for example from 5:1 to 40:1, for example from 10:1 to 30: 1.

In the preparation method of the compound shown in the formula M3-A, when the hydrogen donor is a mixture of acid and ammonium chloride, the acid is preferably liquid, and is preferably inorganic acid, organic acid or a mixture thereof. The inorganic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof. The organic acid is preferably formic acid, acetic acid, trifluoroacetic acid or a mixture thereof, more preferably acetic acid. The acid may be used in an amount conventional in the art for such reactions, preferably in a volumetric mass ratio to ammonium chloride of from 2mL/g to 10mL/g, such as from 3mL/g to 8mL/g, and further such as 5 mL/g. The ratio of the amount of the acid to the volume to mass of the compound M2-A is 1mL/g to 10mL/g, for example 1mL/g to 5mL/g, and further for example 2 mL/g.

In the preparation method of the compound represented by the formula M3-A, when the hydrogen donor is solid such as ammonium formate or ammonium chloride, the reduction reaction can also be carried out in a solvent. The solvent may be a solvent conventional in such reactions in the art, such as water, an alcohol solvent, an amide solvent, a sulfoxide solvent, or a mixture thereof. The alcohol solvent may be, for example, methanol, ethanol, isopropanol, or a mixture thereof. The amide solvent may be, for example, N-dimethylformamide, N-dimethylacetamide, or a mixture thereof. The sulfoxide solvent may be DMSO, for example. The amount of the solvent can be selected according to actual needs.

In the preparation method of the compound represented by the formula M3-A, the reaction temperature can be a temperature conventional in such a reaction in the field. In the present invention, the reduction reaction may be carried out at a temperature of 25 ℃ to 60 ℃ (e.g., 40 ℃ to 50 ℃, and further, e.g., 50 ℃ to 60 ℃).

The progress of the preparation process of the compound represented by the formula M3-A can be monitored by a detection method (such as TLC, MS, HPLC or NMR, etc.) which is conventional in the art. In the present invention, the progress of the reduction reaction can be monitored by TLC as the end point of the reaction when the compound represented by the formula M2-A disappears or does not react any more.

The process for the preparation of the compound of formula M3-a preferably comprises the steps of: mixing a mixture of a compound shown as a formula M2-A and a hydrogen donor with a metal simple substance to perform the reduction reaction; further preferably comprising the steps of: adding the metal simple substance into the mixture of the compound shown in the formula M2-A and the hydrogen donor, heating to 25-60 ℃, and carrying out the reduction reaction.

In the preparation method of the compound shown as the formula M3-A, after the reaction is monitored to be finished, the post-treatment method which is conventional in the field can be adopted for post-treatment, such as one or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment and pulping. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

In one embodiment of the present invention, in the preparation method of the compound represented by the formula M3-a, when the reduction reaction is monitored to be completed, the post-treatment may comprise the following steps: carrying out solid-liquid separation on the reaction liquid after the reaction is finished, concentrating the filtrate, adding an organic solvent to separate out solids, pulping the obtained solids by using the organic solvent, and carrying out solid-liquid separation to obtain a compound shown as a formula M3-A; alternatively, the reaction solution after the completion of the reaction is mixed with water or an aqueous sodium chloride solution to precipitate a solid, and the obtained solid is optionally slurried with an organic solvent and subjected to solid-liquid separation to obtain a compound represented by the formula M3-A.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula M3-a, when the reaction is monitored to be completed, the post-treatment may comprise the following steps: subjecting the reaction solution after the completion of the reaction to solid-liquid separation (e.g., filtration), washing the filter cake with an organic solvent (preferably a mixed solvent of a halogenated hydrocarbon solvent and an alcohol solvent, for example, a mixed solvent of methylene chloride and methanol) (preferably twice), concentrating the filtrate to 1/5-1/15 (for example, 1/7.5-1/10) in the amount of the organic solvent for washing to obtain a concentrated solution, adding a mixed solvent of an alcohol solvent and water (for example, a mixed solvent of isopropyl alcohol and water, the volume ratio of the alcohol solvent to water being, for example, 1:1-1:5, for example, 1:2), the volume ratio of the mixed solvent to the concentrated solution being, for example, 3:1-7.5:1), subjecting the reaction solution to solid-liquid separation (for example, suction filtration), beating the filter cake with a mixed solvent of an alcohol solvent and water (for example, a mixed solvent of methanol and water, the volume ratio of the alcohol solvent to water may be, for example, 1:3), and solid-liquid separation (for example, suction filtration) is carried out to obtain the compound represented by the formula M3-A.

The method for preparing the compound of formula M3-a may include a method for preparing a compound of formula M2-a, which may include the steps of: carrying out deacetylation reaction on the compound shown as the formula M1-A under the action of acid to obtain the compound shown as the formula M2-A;

in the preparation of the compound of formula M2-a, the acid may be an acid conventional in such reactions in the art, such as an inorganic acid, an organic acid, or a mixture thereof. The inorganic acid may be, for example, hydrochloric acid (e.g., concentrated hydrochloric acid with a mass fraction of 36%, or alternatively, an ethanolic hydrogen chloride solution), sulfuric acid, phosphoric acid, or a mixture thereof (wherein the mass fraction of sulfuric acid and phosphoric acid may be, for example, 30% to 85%). The organic acid may be, for example, acetic acid, trifluoroacetic acid, or a mixture thereof. The acid is preferably hydrochloric acid. The acid may be used in amounts conventional in the art for such reactions.

In the preparation method of the compound represented by the formula M2-A, the solvent can be a solvent conventional in the reaction in the field, such as an ether solvent, an alcohol solvent, an amide solvent, a sulfoxide solvent or a mixture thereof. The ether solvent may be, for example, tetrahydrofuran, dioxane or a mixture thereof. The alcohol solvent may be, for example, methanol, ethanol, isopropanol, or a mixture thereof. The amide solvent may be, for example, N-dimethylformamide, N-dimethylacetamide, or a mixture thereof. The sulfoxide solvent may be DMSO, for example.

In the preparation method of the compound shown in the formula M2-A, the reaction solvent can be a single solvent or a mixture of two or more solvents. In one embodiment of the present invention, the solvent is preferably an alcohol solvent, or a mixed solvent of an ether solvent and an alcohol solvent, such as ethanol, or a mixed solvent of tetrahydrofuran and methanol. In the mixed solvent, the volume ratio of the ether solvent to the alcohol solvent may be 0.5:1 to 4:1, for example, 1:1 to 2: 1. The amount of solvent may be that amount conventional in such reactions in the art.

In the preparation method of the compound represented by the formula M2-A, the reaction temperature can be a temperature conventional in such a reaction in the field. In the present invention, the reaction can be carried out at a temperature of from 25 ℃ to 50 ℃ (e.g., from 30 ℃ to 50 ℃, further e.g., from 30 ℃ to 45 ℃).

The progress of the preparation process of the compound represented by the formula M2-A can be monitored by a detection method (such as TLC, MS, HPLC or NMR, etc.) which is conventional in the art. In the present invention, the progress of the deacetylation reaction was monitored by TLC as the end point of the reaction when the compound represented by the formula M1-A disappeared or no longer reacted.

The process for the preparation of the compound of formula M2-a preferably comprises the steps of: the deacetylation reaction was carried out by mixing a mixture of compound M1-A and a solvent, with an acid. Further preferably comprising the steps of: mixing the compound shown as the formula M1-A with a solvent, heating to 25-50 ℃, and then adding acid to carry out the deacetylation reaction.

In the preparation method of the compound shown as the formula M2-A, after the reaction is monitored to be finished, the post-treatment method which is conventional in the field can be adopted for post-treatment, such as one or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment and pulping. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

In one embodiment of the present invention, in the preparation method of the compound represented by the formula M2-a, when the deacetylation reaction is monitored to be completed, the post-treatment may comprise the following steps: and (3) removing the solvent from the reaction liquid after the reaction is finished or adding an anti-solvent with larger polarity difference with the reaction solvent until a large amount of solid is precipitated, carrying out solid-liquid separation, optionally washing the solid with an organic solvent, and drying to obtain the compound shown as the formula M2-A.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula M2-a, when the deacetylation reaction is monitored to be completed, the post-treatment may comprise the following steps: concentrating the reaction solution after the reaction is completed until the solvent is removed or a large amount of solid is precipitated (for example, vacuum concentration), performing solid-liquid separation (for example, suction filtration), washing the filter cake with an alcohol solvent (for example, methanol), and drying (for example, suction drying or vacuum drying) to obtain the compound represented by the formula M2-A.

The method for preparing the compound of formula M2-a may include a method for preparing a compound of formula M1-a, which may include the steps of: under the action of an oxidant, carrying out coupling reaction on a compound SM2 and N, N-dimethylacetamide to obtain a compound shown as a formula M1-A;

in the process for preparing the compound of formula M1-a, the oxidizing agent may be an oxidizing agent conventional in such reactions in the art. In the present invention, the oxidizing agent may be, for example, a persulfate oxidizing agent. The persulfate oxidizer may be, for example, an alkali metal persulfate. The alkali metal persulfate may be sodium persulfate, potassium persulfate, Oxone, or a mixture thereof. In some embodiments, the oxidizing agent is preferably sodium persulfate.

In the preparation method of the compound shown as the formula M1-A, the oxidant can be used in an amount which is conventional in the field of the oxidant for such reaction. In the present invention, the molar ratio of the compound SM2 to the oxidizing agent may be 1:1 to 1:5, such as 1:1.5 to 1:3, and further such as 1: 2.

In the preparation of the compound of formula M1-a, the compounds SM2 and N, N-dimethylacetamide may be used in amounts conventional in such reactions in the art. In the present invention, the molar ratio of the N, N-dimethylacetamide to the compound SM2 may be greater than 1:1, such as greater than 5:1, greater than 10:1, greater than 20:1, greater than 40:1, or greater than 50: 1. In principle, in order to control the cost, the person skilled in the art knows that the amount of N, N-dimethylacetamide should be controlled within a suitable range. Preferably, the molar ratio of the N, N-dimethylacetamide to the compound SM2 is greater than 20: 1.

In the preparation method of the compound shown as the formula M1-A, N, N-dimethylacetamide can be used as a reaction raw material and a solvent at the same time.

In the process for preparing the compound represented by the formula M1-A, the reaction temperature may be a temperature conventional in such a reaction in the art. In the present invention, the reaction can be carried out at a temperature of from 30 ℃ to 100 ℃ (e.g., from 50 ℃ to 80 ℃, further e.g., from 60 ℃ to 70 ℃, further e.g., from 65 ℃ to 70 ℃).

In the preparation of the compound of formula M1-A, the progress of the reaction can be monitored by detection methods conventional in the art (e.g., TLC, MS, HPLC, NMR, etc.). In the present invention, the progress of the reaction was monitored by TLC that the compound SM2 disappeared or no longer reacted as the end point of the reaction.

In the method for producing the compound represented by the formula M1-a, the oxidizing agent may be used alone as it is, or may be used in the form of a mixture with water, or may be used in the form of a mixture with an organic solvent. The water is conventional in the art, such as purified water, distilled water, or a mixture thereof. The organic solvent may be, for example, a chlorinated hydrocarbon solvent, an ether solvent, or a mixture thereof. The organic solvent generally has good solubility for the oxidizing agent. The organic solvent may be, for example, dichloromethane, tetrahydrofuran, dioxane, or a mixture thereof. In the mixed solution (water mixed solution or organic solvent mixed solution), the molar ratio of the oxidant to the water or the organic solvent may be 1:1 to 1:50, for example, 1:2 to 1:35, further for example, 1:2 to 1:30, further for example, 1:20 to 1: 35; and for example 1:20 to 1: 30. In some embodiments, the oxidizing agent is used in the form of a mixed liquor having a molar ratio of sodium persulfate to water of from 1:20 to 1: 30.

In the process for preparing the compound represented by the formula M1-a, the reaction preferably comprises the steps of: the reaction is carried out by mixing a mixture of the compound SM2 and N, N-dimethylacetamide with the oxidizing agent. Further preferably, the mixture of the compound SM2 and N, N-dimethylacetamide is heated to 30 ℃ to 100 ℃, and then the oxidizing agent is added to carry out the reaction.

In the preparation method of the compound shown as the formula M1-A, after the reaction is monitored to be finished, the post-treatment method which is conventional in the field can be adopted for post-treatment, such as one or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment and pulping. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

In one embodiment of the present invention, in the method for preparing the compound represented by the formula M1-a, when the reaction is monitored to be completed, the post-treatment may comprise the following steps: extracting the reaction liquid after the reaction is finished by using an organic solvent, concentrating an organic phase, optionally pulping the residue obtained after the concentration by using the organic solvent, carrying out solid-liquid separation, optionally washing the solid by using the organic solvent, and drying to obtain a target compound; alternatively, the reaction mixture after the completion of the reaction is mixed with water, subjected to solid-liquid separation, and the solid is optionally washed with an organic solvent and dried to obtain a compound represented by the formula M1-A.

In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula M1-a, when the reaction is monitored to be completed, the post-treatment may comprise the steps of: the reaction mixture after the completion of the reaction is mixed with water (for example, at room temperature, the amount of water is preferably such that a large amount of solid is generated in the reaction mixture), subjected to solid-liquid separation (for example, suction filtration), and the cake is dried (for example, vacuum drying), to obtain a compound represented by the formula M1-A.

In the preparation method of the compound represented by the formula M1-A, the reaction can be carried out in the absence of light.

The method for preparing the compound of formula II may include a method for preparing a compound of formula M2-D, which may include the steps of: in a solvent, carrying out a deacetylation reaction on a compound shown as a formula M1-D in the presence of an acid to obtain a compound shown as a formula M2-D;

in the preparation method of the compound represented by the formula M2-D, the acid may be an acid conventionally used in such reactions in the art, such as an inorganic acid, an organic acid, or a mixture thereof. The inorganic acid may be, for example, hydrochloric acid (e.g., 36% by mass hydrochloric acid, or a hydrogen chloride ethanol solution), sulfuric acid, phosphoric acid, or a mixture thereof (wherein the mass fraction of sulfuric acid and phosphoric acid may be, for example, 30% to 85%). The organic acid may be, for example, acetic acid, trifluoroacetic acid, or a mixture thereof. The acid is preferably hydrochloric acid, more preferably hydrochloric acid with a mass fraction of 36% or a hydrogen chloride ethanol solution, and the volume mass ratio of the acid to the compound M1 is preferably 0.2mL/g to 5mL/g, such as 0.5mL/g to 5mL/g, further such as 0.2mL/g to 2.5mL/g, and further such as 1mL/g to 2.5 mL/g.

In the preparation method of the compound represented by the formula M2-D, the solvent may be a solvent conventionally used in such reactions in the art, such as an ether solvent, an alcohol solvent, an amide solvent, and a sulfoxide solvent, or a mixture thereof. The ethereal solvent may be, for example, tetrahydrofuran, dioxane, or a mixture thereof. The alcohol solvent may be, for example, methanol, ethanol, isopropanol, or a mixture thereof. The amide solvent may be, for example, N-dimethylformamide, N-dimethylacetamide, or a mixture thereof. The sulfoxide solvent may be, for example, dimethyl sulfoxide.

In the method for preparing the compound represented by the formula M2-D, the reaction solvent may be a single solvent or a mixture of two or more solvents. In one embodiment of the present invention, the solvent is preferably an alcohol solvent, or a mixed solvent of an ether solvent and an alcohol solvent, such as ethanol, or a mixed solvent of tetrahydrofuran and methanol. In the mixed solvent, the volume ratio of the ether solvent to the alcohol solvent may be 0.5:1 to 4:1, for example, 1:1 to 2: 1.

In the process for preparing the compound represented by the formula M2-D, the reaction temperature may be a temperature conventional in such a reaction in the art. In the present invention, the reaction can be carried out at a temperature of from 25 ℃ to 50 ℃ (e.g., from 30 ℃ to 50 ℃, and further e.g., from 30 ℃ to 45 ℃).

In the preparation method of the compound represented by the formula M2-D, the reaction time is related to the reaction scale, and the progress of the reaction can be monitored by a monitoring method (such as HPLC or TLC) which is conventional in the art, and the end point of the reaction is generally determined by monitoring the disappearance or no longer reaction of the compound represented by the formula M1-D.

The process for preparing the compound of formula M2-D preferably comprises the steps of: the deacetylation reaction was carried out by mixing a mixture of compound M1-D and a solvent, with an acid. Further preferably comprising the steps of: mixing the compound shown as the formula M1-D with a solvent, heating to 25-50 ℃, and then adding acid to carry out the deacetylation reaction.

In the preparation method of the compound shown as the formula M2-D, after the reaction is monitored to be finished, the post-treatment method which is conventional in the field can be adopted for post-treatment, such as one or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment and pulping. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

In one embodiment of the present invention, in the method for preparing the compound represented by the formula M2-D, when the reaction is monitored to be completed, the post-treatment comprises the following steps: removing the solvent from the reaction solution, dissolving the residual solid in water, adjusting the pH of the obtained aqueous solution to be alkaline (for example, adjusting the pH with sodium carbonate), extracting (for example, extracting with dichloromethane), concentrating the organic phase to obtain a solid, and pulping the obtained solid (for example, pulping with ethyl acetate) to obtain the compound represented by the formula M2-D.

In one embodiment of the present invention, in the method for preparing the compound represented by the formula M2-D, when the reaction is monitored to be completed, the post-treatment may comprise the following steps: the reaction mixture after the completion of the reaction is concentrated until the solvent is removed or a large amount of solid is precipitated (for example, vacuum concentration), subjected to solid-liquid separation (for example, suction filtration), and dried (for example, suction-dried or vacuum-dried), to obtain the compound represented by the formula M2-D.

The preparation method of the compound shown in the formula M2-D can further comprise a preparation method of the compound shown in the formula M1-D, which can comprise the following steps: carrying out the following coupling reaction on a compound shown as a formula SM2 and N-methylacetamide in the presence of an oxidant to obtain a compound shown as a formula M1-D;

in the process for preparing the compound represented by the formula M1-D, the oxidizing agent may be an oxidizing agent conventionally used in such reactions in the art, and may be, for example, a persulfate oxidizing agent. The persulfate oxidizer may be, for example, an alkali metal persulfate. The alkali metal persulfate may be, for example, sodium persulfate, potassium persulfate, Oxone, or a mixture thereof. In some embodiments, the oxidizing agent is preferably sodium persulfate.

In the process for preparing the compound of formula M1-D, the oxidizing agent may be used in an amount conventional in the art for such reactions. In the present invention, the molar ratio of the compound SM2 to the oxidizing agent can be 1:1 to 1:5, such as 1:1.5 to 1:3, and further such as 1: 2.

In the preparation of the compound of formula M1-D, the compounds SM2 and N-methylacetamide may be used in amounts conventional in such reactions in the art. In the present invention, the molar ratio of N-methylacetamide to the compound SM2 may be greater than 1:1, such as greater than 5:1, greater than 10:1, greater than 20:1, greater than 40:1, or greater than 50: 1. In principle, it is known to those skilled in the art that the amount of N-methylacetamide to be used should be controlled within a suitable range in order to control the cost. Preferably, the molar ratio of N-methylacetamide to compound SM2 is greater than 20: 1.

In the preparation method of the compound represented by the formula M1-D, N-methylacetamide can be used as a reaction raw material and a solvent at the same time.

In the process for preparing the compound represented by the formula M1-D, the reaction temperature may be a temperature conventional in such a reaction in the art. In the present invention, the reaction can be carried out at a temperature of from 30 ℃ to 100 ℃ (e.g., from 50 ℃ to 80 ℃, further e.g., from 60 ℃ to 70 ℃, further e.g., from 65 ℃ to 70 ℃).

In the preparation of the compound of formula M1-D, the reaction time is related to the reaction scale, and the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., HPLC or TLC), and the end point of the reaction is generally monitored as the disappearance or no longer reaction of the compound of formula SM 2.

In the method for producing the compound represented by the formula M1-D, the oxidizing agent may be used alone as it is, or may be used in the form of a mixture with water, or may be used in the form of a mixture with an organic solvent. The water is conventional in the art, such as purified water, distilled water, or a mixture thereof. The organic solvent may be, for example, a chlorinated hydrocarbon solvent, an ether solvent, or a mixture thereof. The organic solvent generally has good solubility for the oxidizing agent. The organic solvent may be, for example, dichloromethane, tetrahydrofuran, dioxane, or a mixture thereof. In the mixed solution (water mixed solution or organic solvent mixed solution), the molar ratio of the oxidant to the water or the organic solvent may be 1:1 to 1:50, for example, 1:2 to 1:35, further for example, 1:2 to 1:30, further for example, 1:20 to 1: 35; and for example 1:20 to 1: 30. In some embodiments, the oxidizing agent is used in the form of a mixed liquor having a molar ratio of sodium persulfate to water of from 1:20 to 1: 30.

In the process for preparing the compound represented by the formula M1-D, the reaction preferably comprises the steps of: and mixing the mixture of the compound SM2 and N-methylacetamide with the oxidant to carry out the reaction. Further preferably, the mixture of the compound SM2 and N-methylacetamide is heated to 30 ℃ to 100 ℃, and then the oxidizing agent is added to carry out the reaction.

In the preparation method of the compound shown as the formula M1-D, after the reaction is monitored to be finished, the post-treatment method which is conventional in the field can be adopted for post-treatment, such as one or more of concentration, solid-liquid separation, filtration/suction filtration, extraction, washing, pH adjustment and pulping. The extraction may be with organic solvents conventional in the art, such as dichloromethane, chloroform or ethyl acetate. The beating may be performed by selecting a suitable solvent, such as one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, n-heptane, water, from among the solvents commonly used in the art according to the properties of the products obtained from the respective reactions. Preferably, a purification step is further included after the post-treatment step to increase the purity of the resulting product. One or more of recrystallization, column chromatography, preparative liquid chromatography separation, etc. can be used for purification means conventional in the art.

In one embodiment of the present invention, in the method for preparing the compound represented by the formula M1-D, when the reaction is monitored to be completed, the post-treatment further comprises the steps of: the reaction solution is extracted and washed (for example, extracted with ethyl acetate, washed with water or brine solution), the organic phase is concentrated and then slurried (for example, slurried with a mixed solvent of ethyl acetate and n-heptane; the volume ratio of ethyl acetate to n-heptane may be 1:2) to obtain the compound represented by the formula M1-D.

The invention also provides a compound represented by formula II:

the invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: in a solvent, carrying out reductive amination reaction on a compound shown as a formula M1-Z6 and a compound shown as a formula M2-D in the presence of a reducing agent to obtain a compound shown as a formula II;

in the preparation method of the compound shown in the formula II, the reaction conditions can be the same as those described above.

The invention also provides application of the compound shown in the formula I or the salt thereof in quality control of the roxarsone.

The invention also provides application of the compound shown in the formula II or the salt thereof in quality control of the roxarsone.

In the present invention, preferably, in the application, the preparation process of the rasagiline base can be as follows:

in the present invention, the reaction temperature or the operation temperature which is not mentioned is generally room temperature, and room temperature is generally ambient temperature, for example, 0 ℃ to 40 ℃, preferably 10 ℃ to 30 ℃, more preferably 25 ℃.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the invention provides impurities of roxasistat, a preparation method and application thereof. The impurity compound can be used as a reference substance for quality control of a roxasistat synthesis intermediate and a roxasistat bulk drug.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

HPLC purity detection method:

the instrument equipment comprises: high performance liquid chromatograph, chromatographic column: watres Xbridge C18 (4.6X 100mm,3.5 μm), chromatographic conditions: mobile phase A: 0.08% aqueous formic acid, mobile phase B: acetonitrile/water/formic acid (900:100:0.8), detection wavelength: 295nm, column temperature: 40 ℃, flow rate: 1.0ml/min, run time: 60min, sample injection amount: 8 μ L, needle wash solvent: ACN-H₂O (50:50), gradient elution. Mobile phase elution gradient: 35min for 70% A/30% B to 20% A/80% B, followed by 4min for 20% A/80% B to 100% B, 10min for 100% B, and 1min for a return to 70% A/30% B, maintaining this gradient for 10 min.

An LC-MS detection method comprises the following steps:

the model is as follows: agilent liquid chromatography mass spectrometer 1260/6120; an ion source: ESI; sample preparation: and (3) acetonitrile.

Example (b):

preparation example 1: synthesis of Rosxastat

1.1 Synthesis of intermediate M1-A

3.1g (about 0.01mol) of the compound SM2 (obtainable according to CN201210152768.1 example D-7) were heated in 31.0g (about 0.36mol) of N, N-Dimethylacetamide (DMA) to complete dissolution at 60 ℃ to 70 ℃, and 4.8g (about 0.02mol) of sodium persulfate dissolved in 9.6g of water (about 0.53mol) were added to the solution and stirred for 1 hour. TLC monitors the reaction to be complete, the reaction liquid is cooled to room temperature, 50g of water is added, the mixture is stirred and filtered, and a filter cake is dried in vacuum to obtain 3.3g of off-white solid, the yield is 85.7%, and the purity is 98.46%.

MS(ESI)m/z：417.16[M+Na]⁺，1H-NMR(400MHz,DMSO-d₆)δ＝11.66(d,J＝22.8Hz,1H),8.32(t,J＝9.0Hz,1H),7.68(dd,J＝14.5,2.2Hz,1H),7.44-7.57(m,3H),7.12-7.30(m,3H),4.88d,J＝34.0Hz,2H),4.44(q,J＝14.0,7.0Hz,2H),2.83(d,J＝40.0Hz,3H),1.97(d,J＝8.3Hz,3H),1.39(t,J＝7.1Hz,3H).

1.2 Synthesis of intermediate M2-A

3.0g (about 0.008mol) of intermediate M1-A was dissolved by heating to 30 deg.C-40 deg.C in tetrahydrofuran (10mL) and methanol (5 mL). Concentrated hydrochloric acid (5mL, 36% by mass hydrochloric acid) was added with stirring, and the mixture was stirred for 5 hours. TLC monitors the reaction to be complete, and the reaction solution is concentrated in vacuum until a large amount of solid is separated out, filtered, washed by a small amount of methanol and dried by suction to obtain 2.8g of white solid with the yield of 94.7 percent (calculated as hydrochloride) and the purity of 98.40 percent.

MS(ESI)m/z：353.16[M+H]⁺，1H-NMR(400MHz,DMSO-d₆)δ＝11.72(s,1H),9.32(s,2H),8.42(d,J＝9.1Hz,1H),7.75(d,J＝2.2Hz,1H),7.60(dd,J＝9.1,2.3Hz,1H),7.49(t,J＝7.9Hz,2H),7.27(t,J＝7.4Hz,1H),7.19(d,J＝7.7Hz,2H),4.67(s,2H),4.50(q,J＝7.1Hz,2H),2.74(s,3H),1.41(t,J＝7.1Hz,3H).

1.3 Synthesis of intermediate M3-A

2.5g (about 0.007mol) of intermediate M2-A was dissolved in acetic acid (25mL), 2.6g (0.04mol) of zinc powder was added, heated to 50 deg.C-60 deg.C, and stirred for 6 hours. TLC monitored the reaction completion, the reaction was filtered, the filter cake was washed with a mixed solvent of dichloromethane (20mL) and methanol (10mL), the filtrates were combined and concentrated to at least a small volume of solvent (e.g., the volume of the concentrate was about 2-3mL), isopropanol (4mL) and water (8mL) were added, the mixture was stirred and filtered, the filter cake was slurried in methanol/water (1:3/v: v, 12mL) and filtered to give 1.6g of an off-white solid with a yield of 76.7% and a purity of 96.90%.

MS(ESI)m/z：346.10[M+Na]⁺，1H-NMR(400MHz,DMSO-d₆)δ＝11.63(s,1H),8.32(d,J＝9.0Hz,1H),7.58(d,J＝2.0Hz,1H),7.55-7.44(m,3H),7.27(t,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.44(q,J＝7.1Hz,2H),2.64(s,3H),1.37(q,J＝7.3Hz,3H).

1.4 Synthesis of Rosxastat

1.5g of intermediate M3-A was added to 15g of ethanol, 1.4g of sodium glycinate was added, and the mixture was heated to 105 ℃ to 115 ℃ in a pressure-resistant vessel and stirred for 8 hours. Cooling the reaction liquid to room temperature, carrying out suction filtration, washing with a small amount of methanol, and draining to obtain crude product of the sodium salt of the roxasistat, dissolving the crude product of the sodium salt of the roxasistat with 25g of water, washing the water phase with 10mL of ethyl acetate, slowly adding acetic acid into the water phase under the stirring state, adjusting the pH to be less than 7, separating out a large amount of solids, carrying out suction filtration, washing the filter cake with water, draining, and carrying out vacuum drying to obtain 1.3g of finished product of the roxasistat, wherein the yield is 83.4%, and the purity is 99.57%.

MS(ESI)m/z：353.2[M+H]⁺，1H-NMR(400MHz,DMSO-d₆)δ＝13.28(s,1H),9.08(t,J＝5.8Hz,1H),8.25(t,J＝12.0Hz,1H),7.59(s,1H),7.55-7.41(m,3H),7.24(t,J＝7.3Hz,1H),7.16(d,J＝7.9Hz,2H),4.04(d,J＝5.9Hz,2H),2.68(s,3H).

Preparation example 2: synthesis of intermediate M1-A

750g (2.43mol) of SM2 and 5.5L of N, N-dimethylacetamide are added into a 20L reaction kettle, the temperature is raised to 60-65 ℃ by stirring, sodium persulfate aqueous solution (1130g of sodium persulfate is dissolved in 3.5L of water) is added dropwise, the internal temperature is raised to 80 ℃ after about 2 hours of dropwise addition, and the raw materials are completely reacted by TLC detection. And (3) cooling the reaction liquid to be lower than 40 ℃, dropwise adding 2.25L of water, cooling to room temperature, carrying out suction filtration, washing (750mL) for three times, carrying out suction drying, carrying out vacuum drying at 50 ℃ for 16 hours, and stopping drying to obtain 727g of yellow solid which is an intermediate M1-A, wherein the yield is 76%, and the purity is 93.53% (retention time is 19.94min) by HPLC (high performance liquid chromatography) detection, wherein the content of the impurity compound I is 0.51% (retention time is 37.37 min).

Concentrating the filtrate under vacuum and reduced pressure to obtain concentrate (containing 1.03% of impurity compound I), separating and purifying 100g of the concentrate with preparative liquid chromatography (Shimadzu liquid chromatography system, JCGK-HC-prepLC-01; chromatographic column: Welch-Xitinate-C18-10 μm-300 g; sample amount: 9 mL/needle; mobile phase A: water; mobile phase B: acetonitrile: isopropanol 1: 1; elution gradient: 0 min: 55% A/45% B; 0 → 2 min: 55% A/45% B; 2 → 2.5 min: 35% A/65% B; 2.5 → 20.5 min: 5% A/95% B; flow rate 80 mL/min; detecting impurities with wavelength of 220nm and 295nm) to obtain 125mg of white solid, purity: 99 percent.

MS(ESI)：m/z＝702.40(M+H)⁺；

¹H-NMR(400MHz,CDCl₃)δ＝11.58(d,J＝6.8Hz,2H),8.26(d,J＝9.7Hz,1H),8.15(d,J＝9.1Hz,1H),7.71(s,1H),7.45-7.29(m,7H),7.24-7.16(m,2H),7.06(d,J＝8.3Hz,4H),5.07(s,2H),4.89(s,2H),4.52-4.38(m,4H),2.33(s,3H),1.50-1.40(m,6H)；

¹³C-NMR(400MHz,CDCl₃)δ＝172.043,170.708,170.632,158.998,158.950,156.295,156.157,155.820,155.461,146.585,144.770,131.835,130.825,130.332,130.225,126.041,125.362,124.801,124.495,123.483,122.366,122.004,119.828,119.768,119.083,118.664,112.656,110.086,62.147,61.995,49.252,48.662,22.158,14.395,14.270。

Example 1: synthesis of Compound M2-D

1.1. Synthesis of Compound M1-D

3.1g (about 0.01mol) of the compound SM2 (obtainable according to CN201210152768.1 example D-7) were dissolved in 31.0g (about 0.425mol) of N-methylacetamide by heating to 65 ℃ to 70 ℃ and 4.8g (about 0.02mol) of sodium persulfate was dissolved in 9.6g (about 0.53mol) of water and added to the above solution and stirred for 5 hours. TLC monitored small amount of the starting material remained, cooled to room temperature, added ethyl acetate (80mL), washed with water (50 mL. times.4), concentrated the organic phase, slurried with a mixed solvent of ethyl acetate and n-heptane (1:2/v: v) (12mL), filtered with suction, and the filter cake was vacuum dried to dryness to give 2.3g of off-white solid, 73.5% yield and 95.61% purity.

MS(ESI)m/z：403.1[M+Na]⁺，¹H-NMR(400MHz,DMSO-d₆)δ＝11.66(s,1H),8.33(d,J＝9.0Hz,2H),7.67(s,1H),7.53(dd,J＝9.1,1.9Hz,1H),7.44(t,J＝7.8Hz,2H),7.22(t,J＝7.4Hz,1H),7.12(d,J＝7.9Hz,2H),4.59(d,J＝5.5Hz,2H),4.43(q,J＝7.1Hz,2H),1.74(s,3H),1.36(t,J＝7.1Hz,3H).

1.2. Synthesis of Compound M2-D

Adding M1-D (1.1g, 2.89mmol) and 50mL of absolute ethanol into a 100mL three-necked flask in sequence, slowly adding 10mL of HCl/EtOH solution (a hydrogen chloride ethanol solution with the mass fraction of about 30% -35%), stirring and heating to 50 ℃, maintaining the temperature for reaction for 6 hours, monitoring the completion of the reaction of raw materials by TLC, stopping heating, cooling to room temperature, carrying out vacuum concentration to remove the solvent, dissolving the solid in 100mL of water, adding a sodium carbonate solution to adjust the pH to be alkaline, extracting with 300mL of dichloromethane, separating an organic phase, carrying out concentration to remove the solvent, pulping the solid with 5mL of ethyl acetate for 1 hour, carrying out suction filtration, and carrying out vacuum drying to obtain 0.93g of yellow solid M2-D, wherein the yield is as follows: 95.2%, purity 95.62% by HPLC.

MS(ESI)m/z：339.1[M+H]⁺，1H-NMR(400MHz,DMSO-d₆)δ＝11.69(s,1H),8.39(d,J＝9.2Hz,4H),7.73(s,1H),7.57(d,J＝9.1Hz,1H),7.46(t,J＝7.8Hz,2H),7.25(t,J＝7.4Hz,1H),7.16(d,J＝7.9Hz,2H)，7.44-7.52(m,4H),1.38(t,J＝7.1Hz,3H).

1.3. Synthesis of Compound M2-D

3.0g (about 0.008mol) of intermediate M1-D was dissolved by heating to 30 deg.C-40 deg.C in tetrahydrofuran (10mL) and methanol (10 mL). Concentrated hydrochloric acid (5mL, 36% by mass hydrochloric acid) was added with stirring, and stirring was continued for 5 hours after the addition. TLC monitors the reaction to be complete, and the reaction solution is concentrated in vacuum until the volume of the concentrated solution is about 2-4mL, a large amount of solid is separated out, the filtration is carried out, and the filter cake is dried in vacuum, so that 2.8g of white solid is obtained, the yield is 92.4% (calculated as hydrochloride), and the purity is 88.40%.

Example 2: synthesis of Compound II

2.1. Synthesis of Compound M1-Z6

Intermediate M3-A (4.9g, 15mmol, prepared according to preparation example 1.3) and elemental iodine (9.5g, 37.5mmol) were added to dimethyl sulfoxide (98mL) and the reaction was stirred at 110 ℃ for 5 hours. TLC monitors the reaction completion, after cooling, 500mL ethyl acetate and 500mL water are added, liquid separation is carried out, the organic phase is washed with saturated brine, and the organic phase is separated. The organic phase was concentrated in vacuo, slurried with methyl tert-butyl ether for 1 hour, filtered to give a yellow-green solid, which was dried in vacuo to give 2.55g of product in 50.2% yield. The resulting solid was approximately 96.13% pure by HPLC as M1-Z6.

MS(ESI)：m/z＝336.0875(M-H)；¹H-NMR(400Hz，DMSO-d₆)：δ＝12.241(s,1H)，9.943(s,1H)，8.553(d,J＝2.4Hz,1H)，8.393(d,J＝9.2Hz,1H)，7.663(dd,J₁＝8.8Hz,J₂＝2.4Hz,1H)，7.517-7.557(m,2H)，7.341(t,J＝7.6Hz,1H)，7.240-7.360(m,2H)，4.497(q,J＝4.4Hz,2H)，1.408(t,J＝1.4Hz,3H)。

2.2. Synthesis of Compound II

M1-Z6(1.00g, 2.96mmol), M2-D (1.00g, 2.96mmol) and 50mL of DCM were put into a 100mL three-necked flask in this order, stirred at room temperature, added with 4 drops of catalytic amount of acetic acid, stirred at room temperature for 2 hours, then cooled to an internal temperature of 4-5 ℃ and added with sodium triacetoxyborohydride (1.26g, 5.92mmol, STAB) to the reaction solution, and stirred at room temperature for 4 hours. After TLC detection, the reaction solution was washed with saturated sodium bicarbonate (20 mL. times.2), the aqueous phase was extracted once with 30mL DCM, the organic phases were combined, the organic phase was washed once with 20mL water, the organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated to give 2.08g of crude compound II with 84.11% HPLC purity.

Taking 2g of the crude compound II, and separating and purifying the crude compound II by preparative liquid chromatography (Shimadzu liquid chromatography system JCGK-HC-PrepLC-01; chromatographic column: YMC-Trairt C187 μm 250 x 50.0mm I.D.; mobile phase: phase A is water, phase B is acetonitrile: isopropanol: 1; mobile phase gradient: 0-2 min: 40% A/60% B, 2-2.5 min: 40% A/60% B to 20% A/80% B, 2.5-20.5 min: 20% A/80% B to 100% B; flow rate: 80 mL/min; wavelength: 220nm and 295 nm); sample introduction amount: 7.5 mL/needle; this gave 0.95g of compound II as a yellow solid with a purity of 93.71% by HPLC.

MS(ESI)m/z：660.30[M+H]⁺；

H-NMR(400MHz,CDCl₃)δ＝11.83(s,1H),8.33(d,J＝9.1Hz,1H),7.61(d,J＝2.3Hz,1H),7.38(dd,J＝9.1,2.4Hz,1H),7.36–7.31(m,2H),7.18–7.13(m,1H),7.08–7.04(m,2H),4.49(q,J＝7.1Hz,2H),4.27(s,2H),1.42(t,3H)。

Example 3: synthesis of Compound I

Adding an impurity compound II (530mg, 0.803mmol), 25mL of dichloromethane and 1.2mL of triethylamine into a 100mL single-neck bottle, cooling to 0-10 ℃ in an ice bath, adding 0.5mL of acetyl chloride, heating the reaction solution to room temperature after the addition is finished, stirring for 5 hours, detecting the reaction by TLC, adding 100mL of dichloromethane for dilution, washing with 30mL of water twice respectively, washing with 30mL of saturated saline water once, separating an organic phase, and concentrating the organic phase under reduced pressure to obtain 0.80g of a concentrate. Adding 20.0mL of dichloromethane and 2.0mL of morpholine into the concentrate, stirring, heating to 45-50 ℃, stirring for 25 hours, cooling to room temperature after TLC detection reaction, adding 100mL of dichloromethane, washing with 30mL of water twice respectively, washing with 30mL of saturated saline once again, separating an organic phase, drying and filtering the organic phase through anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 1.21g of crude product of the impurity compound I. To this crude product was added 50mL of acetonitrile to dilute, slurried for 0.5 h, filtered, and the solid was vacuum dried to give 0.22g of a white solid as impurity Compound I, 94.38% purity by HPLC, 39.1% yield, MS (ESI): m/z 702.40(M + H)⁺The hydrogen spectrum data thereof was in accordance with that of preparation example 2.

Claims

1. A process for the preparation of a compound of formula I, comprising the steps of:

2. the method for preparing the compound shown in the formula I according to claim 1, wherein in the step (1) and the step (2), the solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, a polar aprotic organic solvent, an aromatic hydrocarbon organic solvent and an ether solvent; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the halogenated hydrocarbon solvent can be one or more of dichloromethane, dichloroethane and chloroform; the polar aprotic organic solvent may be one or more of acetonitrile, DMF and DMSO; the aromatic hydrocarbon organic solvent can be toluene; the ether solvent can be tetrahydrofuran, dioxane or a mixture thereof; preferably, the same solvent is used in the step (1) and the step (2); more preferably, the solvent used in step (1) and step (2) is dichloromethane;

and/or, in the step (1), the organic base is one or more of triethylamine, N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene, pyridine and 4-dimethylaminopyridine, preferably triethylamine.

3. The method of claim 1, wherein the method of preparing a compound of formula I further comprises a method of preparing a compound of formula II, comprising the steps of: in a solvent, carrying out reductive amination reaction on a compound shown as a formula M1-Z6 and a compound shown as a formula M2-D in the presence of a reducing agent to obtain a compound shown as a formula II;

4. the process for preparing a compound of formula I according to claim 3, wherein in the reductive amination reaction, the solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, a polar aprotic organic solvent and an aromatic hydrocarbon organic solvent; the alcohol solvent can be one or more of methanol, ethanol and isopropanol; the halogenated hydrocarbon solvent can be one or more of dichloromethane, dichloroethane and chloroform; the polar aprotic organic solvent may be one or more of acetonitrile, DMF and DMSO; the aromatic hydrocarbon organic solvent can be toluene; the solvent is preferably dichloromethane;

and/or in the reductive amination reaction, the reducing agent is one or more of sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride, and preferably sodium triacetoxyborohydride.

5. The process of claim 3, wherein the process for the preparation of a compound of formula II further comprises a process for the preparation of a compound of formula M1-Z6, comprising one or more of the following reactions 1-4;

reaction 1 comprises the following steps: in a solvent, carrying out the following oxidation reaction on a compound shown as a formula M3-A and elemental iodine to obtain a compound shown as a formula M1-Z6;

reaction 2 comprises the following steps: in the presence of a hydrogen source, carrying out reduction reaction on a compound shown as a formula M2-A to obtain a compound shown as a formula M3-A;

reaction 3 comprises the following steps: carrying out deacetylation reaction on the compound shown as the formula M1-A under the action of acid to obtain a compound shown as a formula M2-A;

reaction 4 comprises the following steps: under the action of an oxidant, carrying out coupling reaction on a compound SM2 and N, N-dimethylacetamide to obtain a compound shown as a formula M1-A;

6. the process for the preparation of the compound of formula I according to claim 5, wherein in the oxidation reaction of reaction 1, the solvent is a polar aprotic organic solvent, preferably DMSO or DMF, more preferably DMSO;

and/or the oxidation reaction of the reaction 1 is carried out at a temperature of 90-125 ℃, for example 110-125 ℃, for example 120-125 ℃;

and/or in the reduction reaction of the reaction 2, the hydrogen source is a metal simple substance/hydrogen donor; the metal simple substance can be zinc powder, iron powder or a mixture thereof; the hydrogen donor can be acid, ammonium formate, ammonium chloride or a mixture thereof; wherein, when the hydrogen donor is an acid, the acid can be an inorganic acid, an organic acid or a mixture thereof; the inorganic acid can be hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof; the organic acid can be formic acid, acetic acid, trifluoroacetic acid or a mixture thereof; the metal simple substance is preferably zinc powder; the hydrogen donor is preferably acetic acid;

and/or the reduction reaction of reaction 2 is carried out at a temperature of from 25 ℃ to 60 ℃, such as from 40 ℃ to 50 ℃, for example from 50 ℃ to 60 ℃;

and/or, in the deacetylation reaction of the reaction 3, the acid is an inorganic acid, an organic acid or a mixture thereof; the inorganic acid can be hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof; the organic acid can be acetic acid, trifluoroacetic acid or a mixture thereof; the acid is preferably hydrochloric acid;

and/or in the deacetylation reaction of the reaction 3, the solvent is one or more of an ether solvent, an alcohol solvent, an amide solvent and a sulfoxide solvent; the ether solvent can be tetrahydrofuran, dioxane or a mixture thereof; the alcohol solvent can be methanol, ethanol, isopropanol or mixture thereof; the amide solvent can be N, N-dimethylformamide, N-dimethylacetamide or a mixture thereof; the sulfoxide solvent is DMSO; the solvent is preferably an alcohol solvent or a mixed solvent of the alcohol solvent and an ether solvent; the solvent is more preferably ethanol or a mixed solvent of methanol and tetrahydrofuran;

and/or, the deacetylation reaction of reaction 3 is carried out at a temperature of 25 ℃ to 50 ℃, such as 30 ℃ to 50 ℃, for example, 30 ℃ to 45 ℃;

and/or, in the coupling reaction of the reaction 4, the oxidant is a persulfate oxidant; wherein the persulfate oxidizer can be an alkali metal persulfate; the alkali metal persulfate can be sodium persulfate, potassium hydrogen persulfate composite salt or a mixture thereof; the oxidant is preferably sodium persulfate;

and/or the coupling reaction of reaction 4 is carried out at a temperature of from 30 ℃ to 100 ℃, such as from 50 ℃ to 80 ℃, for example, further from 60 ℃ to 70 ℃, for example, from 65 ℃ to 70 ℃.

7. The process of claim 3, wherein the process of preparing the compound of formula II further comprises a process of preparing a compound of formula M2-D, which comprises one or both of the following reactions I-II;

reaction I comprises the following steps: in a solvent, carrying out deacetylation reaction on a compound shown as a formula M1-D in the presence of an acid to obtain a compound shown as a formula M2-D;

reaction II comprises the following steps: carrying out the following coupling reaction on a compound shown as a formula SM2 and N-methylacetamide in the presence of an oxidant to obtain a compound shown as a formula M1-D;

8. the method for preparing the compound represented by the formula I according to claim 7, wherein in the deacetylation reaction of the reaction I, the solvent is one or more of an ether solvent, an alcohol solvent, an amide solvent and a sulfoxide solvent; the ether solvent can be tetrahydrofuran, dioxane or a mixture thereof; the alcohol solvent can be methanol, ethanol, isopropanol or mixture thereof; the amide solvent can be N, N-dimethylformamide, N-dimethylacetamide or a mixture thereof; the sulfoxide solvent can be dimethyl sulfoxide; the solvent is preferably an alcohol solvent or a mixed solvent of the alcohol solvent and an ether solvent; the solvent is more preferably ethanol or a mixed solvent of methanol and tetrahydrofuran;

and/or, in the deacetylation reaction of reaction I, the acid is an inorganic acid, an organic acid or a mixture thereof; the inorganic acid can be hydrochloric acid, sulfuric acid, phosphoric acid or a mixture thereof; the organic acid can be acetic acid, trifluoroacetic acid or a mixture thereof; the acid is preferably hydrochloric acid;

and/or the deacetylation reaction of reaction I is carried out at a temperature of 25 ℃ to 50 ℃, such as 30 ℃ to 50 ℃, for example, 30 ℃ to 45 ℃;

and/or, in the coupling reaction of reaction II, the oxidant is a persulfate oxidant; the persulfate oxidizer may be an alkali metal persulfate; the alkali metal persulfate can be sodium persulfate, potassium hydrogen persulfate composite salt or a mixture thereof; the oxidant is preferably sodium persulfate;

and/or the coupling reaction of reaction II is carried out at a temperature of from 30 ℃ to 100 ℃, such as from 50 ℃ to 80 ℃, further such as from 60 ℃ to 70 ℃, further such as from 65 ℃ to 70 ℃.

9. A method for preparing a compound of formula II, comprising the steps of: in a solvent, carrying out reductive amination reaction on a compound shown as a formula M1-Z6 and a compound shown as a formula M2-D in the presence of a reducing agent to obtain a compound shown as a formula II; the reaction conditions are as defined in claim 3 or 4;

10. the process for the preparation of a compound of formula II according to claim 9, wherein the process for the preparation of a compound of formula II further comprises a process for the preparation of a compound of formula M1-Z6 and/or a process for the preparation of a compound of formula M2-D, wherein the process for the preparation of a compound of formula M1-Z6 is as defined in claim 5 or 6, and wherein the process for the preparation of a compound of formula M2-D is as defined in claim 7 or 8.