CN110724135B

CN110724135B - Esalapril Lin Zhongjian body and preparation method thereof

Info

Publication number: CN110724135B
Application number: CN201911126921.1A
Authority: CN
Inventors: 刘潍源; 周伟澄; 林快乐; 吕训磊; 李超超; 臧金鹏; 王成成; 孟雪
Original assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd
Current assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd
Priority date: 2019-11-18
Filing date: 2019-11-18
Publication date: 2023-04-28
Anticipated expiration: 2039-11-18
Also published as: CN110724135A

Abstract

The invention discloses an ilarpu Lin Zhongjian body and a preparation method thereof. The invention provides a preparation method of a chromanone compound shown in a formula 5, which comprises the following steps of (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropylaldehyde to obtain a tetrahydropyranone substance; the tetrahydropyrone substance comprises a chromanone compound shown in a formula 5 and the acid; step (2): and (3) carrying out neutralization reaction shown below on the tetrahydropyranone substance obtained in the step (1) and alkali to obtain the chromanone compound shown in the formula 5. The preparation method of the ilaprine intermediate has the advantages of more economical reagent, short route, high yield, low preparation cost, simple post-treatment and suitability for industrial production.

Description

Esalapril Lin Zhongjian body and preparation method thereof

Technical Field

The invention relates to an ilayp Lin Zhongjian body and a preparation method thereof.

Background

The chemical name of the ilaprin (English name: iclaprim) is: 5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine having the structural formula shown below:

Icplarim is a dihydrofolate reductase inhibitor developed by Motif Bio corporation, and in 2018, it was filed as a therapeutic drug for Acute Bacterial Skin and Skin Structure Infections (ABSSSI) to the us FDA. Iclaprim is currently in phase II clinical trials as a drug for the treatment of Hospital Acquired Bacterial Pneumonia (HABP). In addition, it is currently in preclinical development as a drug for treating staphylococcus aureus lung infection in patients with cystic fibrosis.

In regulatory aspects, iclaprim has been granted qualification for acceptable infectious disease products (QIDP) and rapid channel status by the us FDA. In addition, the FDA awards the status of Iclaprim for the treatment of orphan lung infections of Staphylococcus aureus in cystic fibrosis patients.

At present, in the preparation method of the ilaprin, the main synthesis method is as follows:

the method comprises the following steps: (CN 101115743)

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In this route, starting from the compound 1 trimethoprim, the amino group is protected byWherein R represents-C (CH) ₃ ) ₃ or-CH (CH) ₃ ) ₂ Then Friedel-crafts acetylation, aldol condensation, selective demethylation, ring closure, reduction and elimination, and then hydrolysis reaction are carried out to prepare the ilaprine. The route has a plurality of defects, the reaction route is long, the yield is low by 11.2 percent (the yield of the step of preparing the compound 14 without the compound 13 is not written in the patent). And each step in the preparation of compound 9 to compound 13 requires column chromatography for purification, which is not suitable for industrial production.

The second method is as follows: (CN 1092194C)

In this route, compound 16 and bis (trimethylsilyl) acetylene are used as starting materials to prepare compound 17, wherein the two starting materials are expensive, and a large amount of expensive catalyst cerium (III) chloride heptahydrate is used in the process of preparing compound 18 by reducing carbonyl with compound 17. And compound 20 needs to be prepared by mitsunobu reaction, which has harsh reaction conditions, extremely low yield and difficult post-treatment. In conclusion, the route has high cost, low yield and complex operation, and is not suitable for industrial production.

Disclosure of Invention

The invention aims to overcome the defects that in the existing synthetic method of the ilaprin, expensive reagents are needed, the cost is high, the post-treatment is complex, the route is long, the yield is low, the method is not suitable for industrial production and the like, and provides the ilaprin intermediate and the preparation method thereof. The preparation method of the ilaprine intermediate has the advantages of more economical reagent, short route, high yield, low preparation cost, simple post-treatment and suitability for industrial production.

The invention solves the technical problems through the following technical proposal.

The invention provides a preparation method of a chromanone compound shown in a formula 5, which comprises the following steps of (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropylaldehyde to obtain a tetrahydropyranone substance; the tetrahydropyrone substance comprises a chromanone compound shown in a formula 5 and the acid;

Step (2): the neutralization reaction of the tetrahydropyranone compound obtained in the step (1) and alkali is carried out as shown below to obtain the chromanone compound shown in the formula 5;

in step (1), the organic solvent may be any organic solvent conventionally used in aldol condensation-ring closure reactions of the type known in the art; preferably a nitrile solvent (e.g., acetonitrile).

The dosage of the organic solvent can be the dosage of the conventional chemical reaction in the aldol condensation-ring closure reaction in the field, so as not to influence the reaction; the volume to mass ratio of the organic solvent to the phenol compound represented by formula 4 may be 8ml/g to 20ml/g (e.g., 10ml/g to 15 ml/g).

In step (1), the base may be a base conventional in the aldol condensation-ring closure reaction of this type in the art; for example, organic bases, preferably pyrrolidine and/or piperidine, more preferably pyrrolidine, are preferred in the present invention.

The molar ratio of the base to the phenol compound represented by formula 4 is preferably 1:1 to 2:1 (e.g., 1.45:1 to 1.55:1).

In step (1), the acid may be an acid conventional in the art, such as an organic acid, and is preferably acetic acid and/or propionic acid, more preferably acetic acid in the present invention.

In step (1), the molar ratio of the acid to the phenol compound represented by formula 4 may be 0.5:1 to 2:1 (preferably 1.0:1 to 2:1, more preferably 1.5:1 to 2:1).

In step (1), the molar ratio of the cyclopropylaldehyde to the phenol compound represented by formula 4 is preferably 1:1-2:1 (e.g., 1.2:1-1.5:1).

The temperature of the aldol condensation-ring closure reaction in step (1) may be conventional in the aldol condensation-ring closure reaction of this type, and is preferably from 0℃to 50℃in the present invention (e.g., from 10℃to 30℃at room temperature).

In step (1), the progress of the aldol condensation-ring closure reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally defined as the point at which the phenol compound represented by formula 4 disappears or no longer reacts. The reaction time may be 20 to 40 hours.

In the present invention, the conditions of the aldol condensation-ring closure reaction may be conducted according to the conditions in the art in such a ring closure reaction, except for the above-described specific description.

In one embodiment of the present invention, the tetrahydropyranone compound is composed of the chromanone compound shown in formula 5 and the acid.

In the present invention, part or all of the chromanone compound shown in formula 5 and the acid are preferably present in the form of a salt (it will be understood by those skilled in the art that the "part or all" is determined by the amount of the acid, and when the molar ratio of the acid to the phenol compound shown in formula 4 is less than the equivalent, part of the chromanone compound shown in formula 5 and the acid are preferably present in the form of a salt).

The operation and conditions of the neutralization reaction in step (2) may be those conventional in the art for such neutralization reactions.

The base in step (2) may be a base conventional in the art for such neutralization reactions, for example an alkali metal carbonate (e.g. sodium and/or potassium carbonate) and/or an alkali metal bicarbonate (e.g. sodium and/or potassium bicarbonate). The base may be used in a form conventional in this type of neutralization reaction in the art, for example in the form of an aqueous solution of the base, for example a saturated sodium carbonate solution.

The preparation method can also comprise post-treatment, wherein the post-treatment comprises the following steps: after the aldol condensation-ring closure reaction is finished, filtering and drying a reaction system to obtain the tetrahydropyranone substance;

And/or after the neutralization reaction is finished, filtering and drying the reaction system to obtain the chromanone compound shown in the formula 5.

The preparation method of the chromanone compound shown in the formula 5 can also comprise a scheme 1 or a scheme 2;

scheme 1 comprises the steps of carrying out the following acetamido hydrolysis reaction of a phenol compound shown in formula 8 in the presence of a base in an organic solvent to obtain the phenol compound shown in formula 4;

scheme 2 comprises the steps of carrying out selective demethylation reaction of an acetophenone compound shown in formula 3 in the presence of Lewis acid in an organic solvent to obtain a phenol compound shown in formula 4;

in the above-mentioned scheme 1, the organic solvent may be any organic solvent conventionally used in the art of such acetamido hydrolysis, and the present invention is preferably an alcoholic solvent, for example, one or more of methanol, ethanol, isopropanol, and more preferably methanol.

The organic solvent may be used in an amount that is conventional in the art for such acetamido hydrolysis reactions, so as not to affect the reaction; the volume and mass ratio of the organic solvent to the phenol compound represented by formula 8 is preferably 5ml/g to 20ml/g (e.g., 10ml/g to 15 ml/g).

In the scheme 1, the base can be a conventional base in the field of acetamido hydrolysis reaction; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.

The molar ratio of the base to the phenol compound represented by formula 8 is preferably 0.1:1 to 1:1 (e.g., 0.1:1 to 0.5:1).

In the described scheme 1, the temperature of the acetamido hydrolysis reaction may be conventional in the art of such acetamido hydrolysis reaction, and the present invention is preferably 60 ℃ -82 ℃ (e.g., 65 ℃ -70 ℃).

In scheme 1, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically using the phenol compound of formula 8 as the end point of the reaction when it is lost or no longer reacted. The reaction time may be 0.5 to 2 hours.

In the above-described scheme 1, the conditions of the above-described acetamido hydrolysis reaction may be performed according to the conditions in the art for such acetamido hydrolysis reaction, except for the above-described specific description.

In the above-mentioned scheme 1, the preparation method may further include a post-treatment, where the post-treatment includes the following steps: after the acetamido hydrolysis reaction is finished, the reaction system is subjected to crystallization (for example, under ice bath), filtration, water washing and drying to obtain the phenol compound shown in the formula 4.

In the scheme 2, the organic solvent may be a conventional organic solvent in such selective demethylation reactions in the art; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).

The dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field so as not to influence the reaction; the volume/mass ratio of the organic solvent to the acetophenone compound shown in formula 3 may be 8ml/g to 25ml/g (e.g., 10ml/g to 20 ml/g).

In the embodiment 2, the lewis acid is preferably boron tribromide and/or boron trichloride. The lewis acid may be used in a form conventional in the art, such as in the form of a solution of the organic solvent (again, for example, 1mol/L boron tribromide in methylene chloride).

The molar ratio of the Lewis acid to the acetophenone compound of formula 3 is preferably 1:1-2:1 (e.g., 1.2:1-1.7:1, preferably 1.5:1).

In the scheme 2, the selective demethylation reaction temperature can be the conventional temperature in this type of selective demethylation reaction, and the present invention is preferably-15 ℃ to 35 ℃ (e.g., -6 ℃ to 30 ℃).

In the scheme 2, the Lewis acid is preferably added dropwise (e.g., at-8 ℃) to the acetyl compound of formula 2 and the organic solvent.

In scheme 2, the progress of the selective demethylation reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically by taking the acetophenone compound of formula 3 as the endpoint of the reaction when it is lost or no longer reacted. The reaction time may be 2 to 5 hours.

In scheme 2, the conditions for the selective demethylation reaction may be those employed in the art, except as specifically described above.

In the above-mentioned scheme 2, the preparation method may further include a post-treatment, where the post-treatment includes the following steps: after the selective demethylation reaction, the reaction system is subjected to extraction (e.g., using methanol), concentration (e.g., under vacuum), and recrystallization (e.g., in ethanol) to obtain the phenol compound represented by formula 4.

In the above scheme 1, a scheme a may further be included, where the scheme a may include the following steps: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on an acetyl compound shown in a formula 2 to obtain the phenol compound shown in a formula 8;

In the scheme A, the organic solvent can be a conventional organic solvent in the selective demethylation reaction in the field; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).

The dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field so as not to influence the reaction; the volume/mass ratio of the organic solvent to the acetyl compound shown in formula 2 may be 8ml/g-20ml/g (e.g. 10ml/g-15 ml/g).

In the above embodiment A, the Lewis acid is preferably boron tribromide and/or boron trichloride. The lewis acid may be used in a form conventional in the art; for example in the form of a solution of the organic solvent (e.g., 1mol/L boron tribromide in methylene chloride).

The molar ratio of the lewis acid to the acetyl compound of formula 2 may be 1:1 to 2:1 (e.g., 1.2:1 to 1.7:1, preferably 1.5:1).

In the described scheme A, the temperature of the selective demethylation reaction can be conventional in the art for such selective demethylation reactions, and the present invention is preferably-15℃to 35 ℃ (e.g., -8℃to 30 ℃).

In the scheme A, the Lewis acid is preferably added dropwise (e.g., at-8deg.C) to the acetyl compound of formula 2 and the organic solvent.

In scheme a, the progress of the selective demethylation reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically with the acetyl compound of formula 2 disappearing or no longer reacting as the end point of the reaction. The reaction time may be 10 to 20 hours.

In the above scheme A, the conditions for the selective demethylation reaction may be conducted under the conditions in the art for such a selective demethylation reaction, except as specifically described above.

In the scheme a, the method further comprises post-processing, wherein the post-processing comprises the following steps: after the selective demethylation reaction is completed, the reaction system is subjected to extraction (for example, extraction using ice water), pH adjustment to about 6 (for example, using a saturated sodium carbonate aqueous solution), filtration and recrystallization (for example, in isopropanol) to obtain the phenol compound shown in formula 8.

In the above scheme 2, a scheme B may be further included, where the scheme B may include the following steps; in an organic solvent, in the presence of alkali, performing the following acetamido hydrolysis reaction on the acetyl compound shown in the formula 2 to obtain the acetyl benzene compound shown in the formula 3;

In the above-mentioned scheme B, the organic solvent may be an organic solvent commonly used in the art for hydrolyzing acetamido, and the present invention is preferably an alcoholic solvent, such as one or more of methanol, ethanol, and isopropanol, and more preferably methanol.

The organic solvent may be used in an amount that is conventional in the art for such acetamido hydrolysis reactions, so as not to affect the reaction; the volume and mass ratio of the organic solvent to the acetyl compound shown in formula 2 is preferably 5ml/g-15ml/g (e.g. 9ml/g-11 ml/g).

In the scheme B, the alkali can be conventional alkali in the field of acetamido hydrolysis reaction; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.

The molar ratio of the base to the acetyl compound of formula 2 is preferably 0.1:1 to 1:1 (e.g., 0.1:1 to 0.7:1).

In the scheme B, the acetamido hydrolysis reaction temperature can be the conventional temperature in the art of such acetamido hydrolysis reaction, the invention is preferably 60-82 degrees C (such as 65-70 degrees C).

In the scheme B, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and generally the reaction endpoint is the time when the acetyl compound of formula 2 disappears or no longer reacts. The reaction time may be 0.5 to 2 hours.

In the above-mentioned scheme B, the above-mentioned acetamido hydrolysis reaction conditions may be carried out according to the conditions in the art for such acetamido hydrolysis reaction, except for the above-mentioned specific description.

In the scheme B, the method may further include post-processing, where the post-processing includes the following steps: after the acetamido hydrolysis reaction is finished, crystallizing (for example, under ice bath), filtering, washing with water, and drying the reaction system to obtain the acetophenone compound shown in the formula 3.

In the scheme a or the scheme B, the method can further comprise a scheme a or a scheme B;

the scheme a comprises the following steps: in an organic solvent, in the presence of Lewis acid, carrying out an acetylation reaction shown below on trimethoprim (a compound shown as a formula 1) and an acetylation reagent to obtain the acetyl compound shown as a formula 2;

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the scheme b comprises the following steps: in an organic solvent, in the presence of Lewis acid, performing an acetylation reaction shown in the following on an acetamide compound shown in a formula 1a and an acetylating reagent to obtain the acetyl compound shown in a formula 2;

in the above-mentioned scheme a, the organic solvent may be an organic solvent conventionally used in such an acetylation reaction in the art, and the present invention is preferably a halogenated hydrocarbon solvent such as one or more of chloroform, dichloromethane and dichloroethane, more preferably chloroform.

The dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetylation reaction in the field, so as not to influence the reaction; the volume to mass ratio of the organic solvent to the trimethoprim may be 5ml/g to 15ml/g (e.g. 8ml/g to 10 ml/g).

In the scheme a, the acetylating reagent can be a conventional acetylating reagent in the acetylating reaction of the type in the field; acetyl chloride and/or acetic anhydride are preferred in the present invention, and acetic anhydride is more preferred.

In the scheme a, the molar ratio of the acetylating reagent to the trimethoprim is preferably 1.5:1 to 4:1 (e.g., 2:1).

In the scheme a, the lewis acid can be a conventional lewis acid in the art of such acetylation reaction; tin tetrachloride is preferred.

In the scheme a, the molar ratio of the Lewis acid to the trimethoprim is preferably 1:1-3:1 (e.g., 2:1-3:1).

In the described scheme a, the temperature of the acetylation reaction may be a temperature conventional in such acetylation reactions in the art, and the present invention is preferably 25℃to 85 ℃ (e.g., 60℃to 65 ℃).

In scheme a, the progress of the acetylation reaction can be monitored by methods conventional in the art (e.g., TLC, HPLC or NMR), typically with the disappearance of the trimethoprim or no longer being reacted as the end point of the reaction. The reaction time may be 1 to 5 hours.

In the above-mentioned scheme a, the respective conditions of the above-mentioned acetylation reaction may be carried out according to the conditions in the art for such acetylation reaction, except for the above-mentioned specific description.

In the scheme a, the method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetylation reaction is finished, extracting the reaction system (for example, extracting by using ice water), separating liquid to obtain an organic phase and a water phase, washing the organic phase by using water, extracting the water phase by using an organic solvent (the organic solvent can be chloroform), regulating the pH value of the combined organic phase to 7-8 (for example, saturated sodium carbonate aqueous solution), separating liquid to obtain the organic phase, washing the organic phase by using water, drying the organic phase by using organic phase (for example, anhydrous sodium sulfate), filtering, concentrating (for example, vacuum), recrystallizing (for example, recrystallizing in ethylene glycol monomethyl ether), and obtaining the acetyl compound shown in the formula 2.

In the above-mentioned scheme b, the organic solvent may be an organic solvent conventionally used in such an acetylation reaction in the art, and the present invention is preferably a halogenated hydrocarbon solvent such as one or more of chloroform, dichloromethane and dichloroethane, more preferably chloroform.

In the scheme b, the acetylating reagent can be a conventional acetylating reagent in the acetylating reaction of the type in the field; acetyl chloride and/or acetic anhydride are preferred in the present invention, and acetic anhydride is more preferred.

In the scheme b, the molar ratio of the acetylating reagent to the trimethoprim is preferably 1.5:1 to 4:1 (e.g., 2:1).

In the scheme b, the Lewis acid can be a conventional Lewis acid in the art of such acetylation reaction; tin tetrachloride is preferred.

In said scheme b, the molar ratio of said Lewis acid to said trimethoprim is preferably 1:1-3:1 (e.g. 2:1-3:1).

In said scheme b, the temperature of said acetylation reaction may be conventional in the art for such acetylation reactions, and the present invention is preferably 25 ℃ -85 ℃ (e.g. 60 ℃ -65 ℃).

In the scheme b, the progress of the acetylation reaction can be detected by a conventional monitoring method in the art (for example, TLC, HPLC or NMR), and generally, the reaction end point is when the acetamide compound represented by formula 1a disappears or no longer reacts. The reaction time may be 1 to 5 hours.

In the above-mentioned scheme b, the respective conditions of the above-mentioned acetylation reaction may be carried out according to the conditions in the art for such acetylation reaction, except for the above-mentioned specific description.

In the scheme b, the method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetylation reaction is finished, extracting and inactivating (ice water) the reaction system, separating liquid to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent (for example, the organic solvent can be chloroform), regulating the pH of the combined organic phase to 7-8 (for example, saturated sodium carbonate aqueous solution), separating liquid to obtain the organic phase, washing the organic phase with water, drying (for example, anhydrous sodium sulfate), filtering, concentrating (for example, vacuum), and recrystallizing (for example, recrystallizing in ethylene glycol monomethyl ether) to obtain the acetyl compound shown in the formula 2.

The solution b may further include a solution c, where the solution c may include the following steps: performing acetylation reaction on trimethoprim shown in formula 1 under the action of an acetylating reagent in an organic solvent to obtain an acetamide compound shown in formula 1 a;

in the scheme c, the organic solvent may be a solvent commonly used in such acetylation reaction in the art, toluene is particularly preferred in the present invention.

In the scheme c, the amount of the organic solvent may be an amount of chemical reaction which is conventional in the art, and preferably, the volume/mass ratio of the organic solvent to the trimethoprim shown in the formula 1 is in the range of 5-20ml/g (e.g., 9 ml/g).

In the scheme c, the acetylating agent may be an acetylating agent conventional in the art, and acetic anhydride and/or acetyl chloride are preferred in the present invention.

In the scheme c, the amount of the acetylating agent may be an amount conventional in the art for such acetylations, and preferably the molar ratio of the acetylating agent to the trimethoprim of formula 1 is (2-5): 1 (e.g., 2:1, 4:1, 5:1).

In said scheme c, the temperature of said acetylation reaction may be a temperature commonly used in such acetylation reactions in the art, the present invention being particularly preferred to be 100-110 ℃.

In the scheme c, the progress of the acetylation reaction can be monitored according to a detection method conventional in the art (for example, TLC, HPLC or GC), and generally, the time of the acetylation reaction is preferably 1 to 3 hours (for example, 1.5 hours) with the disappearance of trimethoprim as the end point of the reaction.

In the scheme c, the acetylation reaction may further comprise a post-treatment operation, and the post-treatment method and conditions may be conventional methods and conditions for such acetylation reaction in the art, and in the present invention, the following post-treatment steps are preferably included: crystallization (e.g. cooling the reaction system to room temperature, standing for crystallization), filtration and drying.

In the step of the post-treatment of the acetylation reaction in the scheme c, the crystallization method and conditions may be those conventional in the art, and the present invention is particularly preferably to allow standing crystallization after cooling to room temperature.

The invention provides acetate of the chromanone compound shown in the formula 5;

the invention also provides a preparation method of the salt of the chromanone compound shown in the formula 5, which comprises the following steps of carrying out aldol condensation-ring closing reaction on the phenol compound shown in the formula 4 and cyclopropylaldehyde in the presence of alkali and acid in an organic solvent to obtain the salt of the chromanone compound shown in the formula 5 and the acid;

the reaction conditions and the operation of the preparation method of the salt of the chromanone compound shown in the formula 5 are as described in the step (1) in the preparation method of the chromanone compound shown in the formula 5. For example:

the organic solvent may be a conventional organic solvent used in aldol condensation-ring closure reactions of this type in the art; preferably a nitrile solvent (e.g., acetonitrile).

The base may be a base conventional in the art for aldol condensation-ring closure reactions; for example, organic bases, preferably pyrrolidine and/or piperidine, more preferably pyrrolidine, are preferred in the present invention.

The acid may be any acid conventional in the art, for example an organic acid, preferably acetic acid and/or propionic acid, more preferably acetic acid in the present invention.

The molar ratio of the acid to the phenolic compound of formula 4 may be 0.5:1-2:1 (preferably 1.0:1-2:1, more preferably 1.5:1-2:1).

The molar ratio of the cyclopropylaldehyde to the phenol compound represented by formula 4 is preferably 1:1-2:1 (e.g., 1.2:1-1.5:1).

The temperature of the aldol condensation-ring closure reaction may be conventional in the aldol condensation-ring closure reaction of this type, and is preferably from 0℃to 50℃in the present invention (e.g., from 10℃to 30℃at room temperature).

The progress of the aldol condensation-ring closure reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically with the phenol compound of formula 4 as the end point of the reaction when it is lost or no longer reacted. The reaction time may be 20 to 40 hours.

The phenol compound shown in the formula 4 can be prepared by adopting the scheme 1 or the scheme 2.

The invention provides a phenol compound shown in a formula 4 and a phenol compound shown in a formula 8;

the invention also provides a preparation method of the phenol compound shown in the formula 4, which comprises the following steps of carrying out the following acetamido hydrolysis reaction on the phenol compound shown in the formula 8 in the presence of alkali in an organic solvent to obtain the phenol compound shown in the formula 4;

the reaction conditions and operation of the preparation method of the phenol compound shown in the formula 4 are as described in scheme 1 in the preparation method of the chromanone compound shown in the formula 5. For example:

The organic solvent may be any organic solvent conventional in the art for such acetamido hydrolysis reactions, and the present invention is preferably an alcoholic solvent, such as one or more of methanol, ethanol, isopropanol, and more preferably methanol.

The base can be a conventional base in the art of such acetamido hydrolysis reactions; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.

The molar ratio of the base to the phenol compound represented by formula 8 is preferably 0.1 to 1 (e.g., 0.1:1).

The temperature of the acetamido hydrolysis reaction may be conventional in the art for such acetamido hydrolysis reactions, and the present invention is preferably 60 ℃ -82 ℃ (e.g., 65 ℃).

The progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is typically used as the end point of the reaction when the phenolic compound shown in formula 8 is lost or no longer reacted. The reaction time may be 0.5 to 2 hours.

In the present invention, the above-mentioned conditions for the acetamido hydrolysis reaction may be carried out according to the conditions in the art for such acetamido hydrolysis reaction, except for the above-mentioned specific description.

In the invention, the preparation method can further comprise post-treatment, wherein the post-treatment comprises the following steps: after the acetamido hydrolysis reaction is finished, the reaction system is subjected to crystallization (for example, under ice bath), suction filtration, water washing and drying, and the phenol compound shown in the formula 4 is obtained.

The phenol compound shown in the formula 8 can be prepared by adopting the scheme A.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

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

The invention has the positive progress effects that: the preparation method of the ilaprine intermediate has the advantages of more economical reagent, short route, high yield, low preparation cost, simple post-treatment and suitability for industrial production.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1

Preparation of Compound 1a (N, N' - (5- (3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diacetamide)

Compound 1 (100.0 g,344.5 mmol), acetic anhydride (176 g,1710.4 mmol) and 900ml toluene are added into a reaction bottle, heated and refluxed for 1.5h, cooled to room temperature, left to stand for crystallization, filtered and dried to obtain 109.0g of white solid 1a, the yield is 84.5%, the mp.201-203 ℃ and the purity is 98.72% by HPLC detection, ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。

example 2

Into a reaction flask were added compound 1 (100.1 g,344.8 mmol), acetyl chloride (98.1 ml,1379.6 mmol) and 900ml toluene, heated under reflux, stirred for 1.5h, cooled to room temperature, left to stand for crystallization, suction filtered, dried to obtain 104.0g of white solid 1a, yield 80.6%, mp.201-203 ℃, purity 98.70% by HPLC detection, ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。

example 3

Compound 1 (100.0 g,344.5 mmol), acetic anhydride (70.3 g,688.5 mmol) and 900ml toluene are added into a reaction bottle, heated and refluxed for 1.5h, cooled to room temperature, left to stand for crystallization, filtered and dried to obtain 102.8g of white solid 1a, the yield is 71.7%, the purity is 98.62% by HPLC detection, ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71(s,6H),3.61(s,3H),2.16(s,6H)。

Example 4

Preparation of Compound 2 (N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diacetamide)

To the reaction flask were added compound 1a (99.9 g,266.8 mmol), acetic anhydride (55.5 g,544.4 mmol) and 1000ml of dichloroethane, and tin tetrachloride (62 ml,537.8 mmol) was slowly added with stirring, followed by heating and refluxing for reaction for 5 hours, cooling to room temperature, pouring the reaction solution into 600ml of ice water, stirring for 20mins, separating the liquid, washing the organic phase with 50ml of water twice, combining the aqueous phase, extracting the aqueous phase with 50ml of dichloroethane for 4 times, combining the organic phase, washing the organic phase with saturated sodium carbonate solution to a pH of about 7, washing the organic phase with 50ml of water for 1 time, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, and recrystallizing with ethylene glycol monomethyl ether to obtain 87.2g of compound 2 in 78.5% yield. mp.204-206 ℃, and the purity of the product is 96.24% by HPLC detection; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS(ESI+):m/z,417([M+H] ⁺ )。

example 5

To a reaction flask, compound 1a (100.0 g,267.1 mmol), acetic anhydride (55.4 g,544.3 mmol) and 1000ml chloroform were added, tin tetrachloride (62 ml,537.8 mmol) was slowly added with stirring, and then the mixture was heated and refluxed for 2 hours, cooled to room temperature, the reaction solution was poured into 600ml ice water and stirred for 20mins, separated, 50ml of water-washed organic phase was twice, the aqueous phase was combined, 50ml of chloroform-extracted aqueous phase was 4 times, the organic phase was combined, saturated sodium carbonate-washed organic phase was brought to pH of about 7, 50ml of water-washed organic phase was 1 time, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and 200ml of ethylene glycol monomethyl ether was recrystallized to obtain 101.3g of compound 2, yield 91.2%. mp.204-206 ℃; purity by HPLC 96.25%; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS(ESI+):m/z,417([M+H] ⁺ )。

Example 6

To the reaction flask were added compound 1a (100.1 g,267.4 mmol), acetyl chloride (76.0 ml,1006.9 mmol) and 1000ml chloroform, tin tetrachloride (62 ml,537.8 mmol) was slowly added with stirring, and then the mixture was heated under reflux for 1.5 hours, cooled to room temperature, the reaction mixture was poured into 600ml ice water and stirred for 20mins, the liquid was separated, the organic phase was washed twice with 50ml water, the aqueous phase was combined, the aqueous phase was washed 4 times with 50ml chloroform, the organic phase was combined, the saturated sodium carbonate solution was washed the organic phase to a pH of about 7, the organic phase was washed 1 time with 50ml water, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and recrystallized from 200ml ethylene glycol monomethyl ether to give 99.3g of compound 2 in 89.3% yield. mp.204-206 ℃; purity by HPLC 96.75%; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS(ESI+):m/z,417([M+H] ⁺ )。

example 7

To a 250ml reaction flask was added compound 1 (trimethoprim) (10.02 g,34.52 mmol), acetic anhydride (17.06 g,167.11 mmol) and 100ml chloroform, tin tetrachloride (8.00 ml,68.36 mmol) was added with stirring, the reaction was refluxed for 1h, the TLC detected the substantial disappearance of the starting material, cooled to room temperature, the reaction solution was poured into 50ml ice water, stirred for 6mins, separated, 5ml of water washed the organic phase 3 times, combined with the aqueous phase, 5ml of chloroform extracted with the aqueous phase 3 times, combined with the organic phase, saturated aqueous sodium carbonate solution Adjusting pH to 7-8, separating liquid, washing the organic phase with 5ml water for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating in vacuum, recrystallizing ethylene glycol monomethyl ether to obtain 13.30g of product, and the yield is 92.63%. mp.203-205 ℃; the purity was 96.72% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI ⁺ ):m/z,417([M+H] ⁺ ).

Example 8

To a 250ml reaction flask were added compound 1 (trimethoprim) (10.00 g,34.45 mmol), acetyl chloride (9.80 ml,138.57 mmol) and 100ml chloroform, tin tetrachloride (8.00 ml,68.36 mmol) was added with stirring, the reaction was refluxed for 1h, cooled to room temperature, the reaction solution was poured into 50ml ice water, stirred for 6mins, separated, 5ml of water-washed organic phase was 3 times, the aqueous phase was combined, 5ml of chloroform-extracted aqueous phase was 3 times, the organic phase was combined, saturated sodium carbonate aqueous solution was adjusted to pH 7 to 8, the separated solution, 5ml of water-organic phase was 1 time, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and ethylene glycol monomethyl ether was recrystallized to obtain 12.98g of product, yield 90.58%. mp.203-205 ℃; the purity was 95.52% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI ⁺ ):m/z,417([M+H] ⁺ ).

Example 9

Into a 250ml reaction flask were added compound 1 (trimethoprim) (10.00 g,34.45 mmol), acetic anhydride (17.06 g,167.11 mmol) and 100ml chloroform, tin tetrachloride (5.30 ml,45.29 mmol) was added with stirring, the reaction was refluxed for 1h, cooled to room temperature, the reaction solution was poured into 50ml ice water, stirred for 6mins, separated, 5ml of water-washed organic phase was 3 times, the aqueous phase was combined, 5ml chloroform-extracted aqueous phase was 3 times, the organic phase was combined, and saturated sodium carbonate aqueous solution was adjusted to pH 7 About 8, separating the liquid, 5ml of water organic phase for 1 time, drying with anhydrous sodium sulfate, filtering, concentrating in vacuum, and recrystallizing ethylene glycol monomethyl ether to obtain 12.08g of product with the yield of 84.30 percent. mp.203-205 ℃; the purity was 95.61% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI ⁺ ):m/z,417([M+H] ⁺ ).

Example 10

To a 250ml reaction flask were added compound 1 (trimethoprim) (10.00 g,34.45 mmol), acetic anhydride (17.04 g,166.90 mmol) and 100ml chloroform, tin tetrachloride (12.00 ml,68.36 mmol) was added with stirring, the reaction was refluxed for 1h, cooled to room temperature, the reaction solution was poured into 50ml ice water, stirred for 6mins, separated, 5ml of water-washed organic phase was 3 times, the aqueous phase was combined, 5ml of chloroform-extracted aqueous phase was 3 times, the organic phase was combined, saturated sodium carbonate aqueous solution was adjusted to pH 7 to 8, the separated solution, 5ml of water-organic phase was 1 time, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and ethylene glycol monomethyl ether was recrystallized to obtain 10.96g of product in 76.48% yield. mp.203-205 ℃; the purity was 95.67% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI ⁺ ):m/z,417([M+H] ⁺ ).

Example 11

Into a 250ml reaction flask were added compound 1 (trimethoprim) (10.00 g,34.45 mmol), acetic anhydride (17.03 g,166.80 mmol) and 100ml dichloromethane, tin tetrachloride (8.00 ml,102.54 mmol) was added under stirring, the reaction was refluxed for 1h, cooled to room temperature, the reaction solution was poured into 50ml ice water, stirred for 6mins, separated, 5ml of water-washed organic phase was 3 times, the aqueous phase was combined, 5ml of chloroform extracted aqueous phase was 3 times, the organic phase was combined, and saturated sodium carbonate aqueous solution was adjusted to pH 7 8, separating liquid, 5ml of water organic phase for 1 time, drying by anhydrous sodium sulfate, filtering, concentrating in vacuum, and recrystallizing ethylene glycol monomethyl ether to obtain 12.93g of product, wherein the yield is 90.23%. mp.203-205 ℃; the purity was 95.72% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):10.03(s,1H),9.20(s,1H),8.41,(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,2H),3.68(s,3H),2.60(s,3H),2.48(s,3H),2.19(s,3H)；MS(ESI ⁺ ):m/z,417([M+H] ⁺ ).

Example 12

Preparation of Compound 3 (1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2,3, 4-trimethoxyphenyl) ethanone)

Adding compound 2 (65.00 g,156.25 mmol), potassium carbonate (15.090 g,109.35 mmol) and 600ml methanol into a reaction bottle, stirring and refluxing for 1.5h, stopping heating, cooling to room temperature, placing under ice bath, stirring, slowly stirring for crystallization, suction filtering, washing with water, and drying to obtain 47.00g white solid compound 3, yield of 90.5%, mp.121-123 ℃; the purity was 97.22% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.28(s,1H),6.66(s,1H),6.12,(s,2H),5.70(s,2H),3.82(s,3H),3.75(d,6H,4Hz),3.42(s,2H),2.29(s,3H).

Example 13

Adding compound 2 (65.01 g,156.49 mmol), potassium carbonate (15.091 g,109.36 mmol) and 600ml ethanol into a reaction bottle, heating and refluxing for 1.5h, stopping heating, cooling to room temperature, placing under ice bath, stirring, slowly stirring for crystallization, suction filtering, washing with water, and drying to obtain 45.00g of white solid compound 3, wherein the yield is 86.7%, and the temperature is mp.121-123 ℃; the purity was 97.32% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.28(s,1H),6.66(s,1H),6.12,(s,2H),5.70(s,2H),3.82(s,3H),3.75(d,6H,4Hz),3.42(s,2H),2.29(s,3H).

Example 14

Preparation of Compound 4 (1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)

Into a 1L reaction flask were charged compound 3 (30.00 g,90.36 mmol) and 600ml of dichloromethane, cooled to-6℃in an ice-salt bath, 135.5ml of 1mol/L boron tribromide dichloromethane solution was slowly added dropwise, and the reaction was carried out at room temperature for 5 hours after the addition. Cooling to 0 ℃, quenching with 300ml of methanol, stirring for 1h, concentrating the dry solvent in vacuum, and recrystallizing with ethanol to obtain 25.50g of white solid compound 4 with a yield of 88.74%. mp.217 ℃; the purity was 96.10% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 15

To a 500ml reaction flask were added compound 3 (20.01 g,60.27 mmol) and 200ml chloroform, cooled to-6℃in an ice-salt bath, and 90.5ml of a 1mol/L solution of boron tribromide in methylene chloride was slowly added dropwise, and the mixture was allowed to react at room temperature for 5 hours. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 16.02g of white solid compound 4 with a yield of 83.58%. mp.217 ℃; the purity was 96.08% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 16

Into a 250ml reaction flask were charged compound 3 (10.02 g,30.18 mmol) and 100ml chloroform, cooled to-6℃in an ice-salt bath, and 1mol/L boron trichloride was added dropwiseA solution of 45.3ml of methylene chloride was added thereto, and the mixture was allowed to stand at room temperature for 5 hours. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.88g of white solid compound 4 with a yield of 82.10%. mp.217 ℃; the purity was 96.13% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 17

To a 500ml reaction flask were added compound 3 (10.11 g,30.45 mmol) and 200ml dichloromethane, cooled to-6℃in an ice-salt bath, 45.7ml of 1mol/L boron trichloride dichloromethane solution was added dropwise, and the mixture was allowed to react at room temperature for 5 hours. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.96g of white solid compound 4 with a yield of 82.20%. mp.217 ℃; the purity was 96.09% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 18

Into a 1L reaction flask were charged compound 3 (30.00 g,90.36 mmol) and 600ml of dichloromethane, cooled to-6℃in an ice-salt bath, and 108.5ml of 1mol/L boron tribromide dichloromethane solution was slowly added dropwise thereto, and the reaction was carried out at room temperature for 5 hours after the addition. Cooling to 0 ℃, quenching with 300ml of methanol, stirring for 1h, concentrating the dry solvent in vacuum, and recrystallizing with ethanol to obtain 21.73g of white solid compound 4 with a yield of 75.62%. mp.217 ℃; the purity was 96.19% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 19

Into a 1L reaction flask were charged compound 3 (30.00 g,90.36 mmol) and 600ml of dichloromethane, cooled to-6℃in an ice-salt bath, 153.5ml of 1mol/L boron tribromide dichloromethane solution was slowly added dropwise, and the reaction was carried out at room temperature for 5 hours after the addition. Cooling to 0 ℃, quenching with 300ml of methanol, stirring for 1h, concentrating the dry solvent in vacuum, and recrystallizing with ethanol to obtain 24.73g of white solid compound 4 with the yield of 86.06%. mp.217 ℃; the purity was 96.10% by HPLC. ¹ H-NMR(300MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 20

Into a 250ml reaction flask were charged compound 3 (10.00 g,30.12 mmol) and 100ml chloroform, cooled to-6℃in an ice-salt bath, 51.5ml of 1mol/L boron trichloride dichloromethane solution was added dropwise, and the reaction was carried out at room temperature for 5 hours after the addition. Cooling to 0 ℃, quenching with methanol, stirring for 1h, concentrating the dry solvent in vacuum, and recrystallizing with ethanol to obtain 7.83g of white solid compound 4 with a yield of 81.75%. mp.217 ℃; the purity was 96.25% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 21

Into a 250ml reaction flask were charged compound 3 (10.00 g,30.12 mmol) and 100ml chloroform, cooled to-6℃in an ice-salt bath, 46.5ml of 1mol/L boron trichloride dichloromethane solution was added dropwise, and the reaction was carried out at room temperature for 5 hours after the addition. Cooling to 0deg.C, quenching with methanol, stirring for 1 hr, and vacuum concentratingThe solvent was dried and recrystallized from ethanol to give 7.58g of compound 4 as a white solid in 79.14% yield. mp.217 ℃; the purity was 96.21% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 22

Preparation of Compound 8 (N, N' - (5- (2-acetyl-3-hydroxy-4, 5-dimethoxybenzyl) pyrimidine-2, 4-diyl) diacetamide)

To the reaction flask was added compound 2 (10.005 g,24.050 mmol) and 100ml dichloromethane and the ice salt bath was cooled to-8 ℃. A solution of boron tribromide in methylene chloride (36 ml,36.000 mmol) was slowly added dropwise thereto, and after 1h of reaction, the reaction was allowed to proceed to room temperature for 19h. The reaction solution was poured into 90ml of ice water, the pH of the saturated aqueous sodium carbonate solution was adjusted to about 6, suction filtration was performed, and the cake isopropanol was recrystallized to obtain 8.730g of Compound 8, yield 90.336%. mp 203-205 ℃; the purity was 97.53% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):11.22(s,1H),8.94(s,1H),8.38(s,1H),6.83(s,1H),6.19(s,1H),3.90(s,3H),3.77(s,5H),2.69(s,3H),2.50(s,3H),2.19(s,3H).

Example 23

To the reaction flask was added compound 2 (10.000 g,24.038 mmol) and 100ml dichloromethane and the ice salt bath was cooled to-8 ℃. A solution of boron trichloride in methylene chloride (36 ml,36.000 mmol) was slowly added dropwise thereto, and after 1 hour of reaction, the reaction was allowed to proceed at room temperature for 15 hours. The reaction solution was poured into 90ml of ice water, the pH of the saturated aqueous sodium carbonate solution was adjusted to about 6, and the solution was suction-filtered. The filter cake was recrystallized from isopropanol to give 8.700g of compound 8 in 90.023% yield. mp.203-205 ℃; the purity was 97.49% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):11.22(s,1H),8.94(s,1H),8.38(s,1H),6.83(s,1H),6.19(s,1H),3.90(s,3H),3.77(s,5H),2.69(s,3H),2.50(s,3H),2.19(s,3H).

Example 24

Into the reaction flask were added compound 8 (5.000 g,12.438 mmol), potassium carbonate (0.172 g,1.244 mmol) and 50ml methanol, and the mixture was heated under reflux for 1.5h, and after cooling to room temperature, the mixture was stirred under ice bath, stirred slowly, stirred for crystallization, suction filtered, washed with water and dried to give 3.901g of compound 4 as a white solid, yield 98.63%, mp.121-123 ℃. The purity was 98.97% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):9.66(s,1H),8.31(s,1H),7.91(s,1H),7.54(s,2H),7.14(s,1H),6.46(s,1H),3.77(s,3H),3.69(s,3H),3.48(s,2H),2.42(s,3H)；MS(ESI ⁺ ):m/z,319([M+H] ⁺ ).

Example 25

Preparation of Compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxy chroman-4-one)

Into a 100ml reaction flask were charged compound 4 (4.01 g,12.58 mmol), cyclopropylaldehyde (1.07 g,15.29 mmol) and 40ml acetonitrile, and pyrrolidine (1.34 g,18.87 mol) and acetic acid (1.13 g,18.83 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, suction filtered, and dried to give 4.57g of an off-white solid compound 5 acetate in a yield of 84.28%, mp168-171 ℃. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),2.78-2.85(m,1H),2.64-2.69(m,1H),1.89(s,3H),1.19-1.25(m,1H)0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,373([M+H] ⁺ ).

Compound 5Acetate (4.57 g,10.63 mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.93g of an off-white solid in 84.23% yield. mp.152-155 ℃; the purity was 96.13% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.18(s,1H),6.47(s,1H),6.11,(s,2H),5.63(s,2H),3.91-3.99(m,2H),3.77-3.85(m,1H),3.76(s,3H),3.70(s,3H),2.79-2.83(m,1H),2.65-2.69(m,1H),1.20-1.24(m,1H),0.55-0.62(m,2H),0.47-0.48(m,1H),0.40-0.41(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Example 26

To a 250ml reaction flask were added compound 4 (11.00 g,34.59 mmol), cyclopropylaldehyde (3.63 g,51.86 mmol) and 110ml acetonitrile, and pyrrolidine (3.68 g,51.83 mmol) and propionic acid (2.557 g,34.56 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, dried to give propionate of compound 5, which was stirred in a saturated sodium carbonate solution for 1h, dried to give 11.11g of compound 5 in 86.81% yield. mp.152-155 ℃; the purity was 96.15% by HPLC. MS (ESI) ⁺ ):m/z,371([M+H] ⁺ ).

Example 27

To a 100ml reaction flask were added compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.05 g,15.00 mmol) and 40ml acetonitrile, piperidine (1.55 g,18.22 mmol) and acetic acid (1.12 g,18.67 mmol) were slowly added dropwise with stirring, stirring was performed at room temperature for 36h, suction filtration, and drying to give 4.68g of acetate as an off-white solid compound 5 in a yield of 86.52%.

Acetate of compound 5 (4.68 g,10.88 mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 4.02g of an off-white solid in 86.38% yield. mp.152-155 ℃; the purity was 96.17% by HPLC.

Example 28

To a 100ml reaction flask was added compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.08 g,15.429 mmol) and 40ml acetonitrile, piperidine (1.57 g,18.44 mmol) and propionic acid (1.38 g,18.67 mmol) were slowly added dropwise with stirring, stirring at room temperature for 36h, suction filtration to give propionate of compound 5, stirring in saturated sodium carbonate solution for 1h, filtering, drying to give 3.98g of off-white solid in 85.52%. mp.152-155 ℃; the purity was 96.11% by HPLC.

Example 29

Into a 100ml reaction flask were charged compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.05 g,15.00 mmol) and 40ml acetonitrile, and pyrrolidine (1.35 g,19.01 mol) and acetic acid (1.51 g,25.17 mmol) were slowly added dropwise with stirring, and stirring was carried out at room temperature for 36 hours, suction filtration and drying to give 4.57g of an acetate as an off-white solid compound 5 in a yield of 84.28%.

Acetate of compound 5 (4.54 g,10.56 mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.91g of an off-white solid in 84.01% yield. mp.152-155 ℃; the purity was 96.11% by HPLC.

Example 30

To a 100ml reaction flask were added compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.05 g,15.00 mmol) and 40ml acetonitrile, and pyrrolidine (1.36 g,19.15 mmol) and acetic acid (0.75 g,12.50 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, suction filtered, stirred in saturated sodium carbonate solution for 1h, filtered, dried to give 3.23g of an off-white solid in a total yield of 78.5% (based on compound 4, 12.58 mmol). mp.152-155 ℃; the purity was 96.25% by HPLC.

Example 31

To a 100ml reaction flask was added compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.05 g,15.00 mmol) and 40ml acetonitrile, and pyrrolidine (1.34 g,18.87 mol) and acetic acid (0.38 g,6.33 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, suction filtered, dried, stirred in saturated sodium carbonate solution for 1h, filtered, dried, ethanol recrystallized to give 2.82g of off-white solid in 60.59% yield. mp.152-155 ℃; the purity was 96.01% by HPLC.

Example 32

Preparation of Compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxy chroman-4-ol)

To the reaction flask were added compound 5 (4.00 g,10.81 mmol) and 80ml methanol, cooled to 4℃in an ice bath, sodium borohydride (0.21 g,5.56 mmol) was added, reacted at room temperature for 2.5h, the methanol was evaporated to dryness, 40ml water was added, stirred for 10min, suction filtered, the filter cake was refluxed with methanol for 3h, concentrated in vacuo, and ethanol and water (volume ratio of ethanol to water: 5:1) were recrystallized to give 3.88g of compound 6 as a white solid in 96.48% yield. mp.211-213 ℃; purity by HPLC 99.23%; ¹ H-NMR(400MHz,CDCl3).δ(ppm):7.49(s,1H),6.17-6.2(d,3H),5.58-5.64(m,3H),4.93-4.94(d,1H),3.78-3.82(d,1H),3.63(s,3H),3.62(s,3H),3.53-3.57(m,1H),2.24-2.28(m,1H),1.96-2.02(m,1H),1.34-1.37(m,1H)，0.49-0.1(d,2H),0.31-0.36(m,2H)；MS(ESI+):m/z,373([M+H]+)。

example 33

Into a reaction flask were added compound 5 (4.00 g,10.81 mmol) and 80ml methanol, cooled to 4℃in an ice bath, sodium borohydride (0.40 g,10.58 mmol) was added, reacted at room temperature for 2.5h, the methanol was evaporated to dryness, 40ml water was added, stirred for 10min, suction filtered, the filter cake was refluxed with methanol for 3h, ethanol and water were recrystallized to give 3.90g of white solid compound 6, yield 96.98%. mp.211-213 ℃; purity was 99.21% by HPLC; .

Example 34

Into a reaction flask were added compound 5 (4.00 g,10.81 mmol) and 80ml methanol, cooled to 4℃in an ice bath, sodium borohydride (0.29 g,7.67 mmol) was added, reacted at room temperature for 2.5h, the methanol was evaporated to dryness, 40ml water was added, stirred for 10min, suction filtered, the filter cake was refluxed with methanol for 3h, concentrated in vacuo, ethanol and water were recrystallized to give 3.89g of white solid compound 6 in 96.73% yield. mp.211-213 ℃; the purity was 99.25% by HPLC.

Example 35

Acetate (4.00 g,9.30 mmol) of compound 5 and 80ml of methanol were added to the reaction flask, the temperature was reduced to 4℃in an ice bath, sodium borohydride (0.53 g,14.02 mmol) was added, the reaction was carried out at room temperature for 2.5 hours, vacuum concentration was carried out, 40ml of water was added, stirring was carried out for 10 minutes, suction filtration was carried out, methanol was added to the filter cake to reflux for 3 hours, vacuum concentration was carried out, and ethanol and water were recrystallized to obtain 3.18g of white solid compound 6 in 91.90% yield. mp.211-213 ℃; the purity was 99.19% by HPLC.

Example 36

Acetate (4.00 g,9.30 mmol) of compound 5 and 80ml of methanol were added to the reaction flask, the temperature was reduced to 4℃in an ice bath, sodium borohydride (0.70 g,18.52 mmol) was added, the reaction was carried out at room temperature for 2.5 hours, vacuum concentration was carried out, 40ml of water was added, stirring was carried out for 10 minutes, suction filtration was carried out, methanol was added to the filter cake to reflux for 3 hours, vacuum concentration was carried out, and ethanol and water were recrystallized to obtain 3.20g of compound 6 as a white solid, the yield was 92.47%. mp.211-213 ℃; the purity was 99.23% by HPLC.

Example 37

Acetate (4.00 g,9.30 mmol) of compound 5 and 80ml of methanol were added to the reaction flask, the temperature was reduced to 4℃in an ice bath, sodium borohydride (0.60 g,15.87 mmol) was added, the reaction was carried out at room temperature for 2.5 hours, vacuum concentration was carried out, 40ml of water was added, stirring was carried out for 10 minutes, suction filtration was carried out, methanol was added to the filter cake to reflux for 3 hours, vacuum concentration was carried out, and ethanol and water were recrystallized to obtain 3.17g of white solid compound 6 in 91.61% yield. mp.211-213 ℃; the purity was 99.27% by HPLC.

Example 38

To the flask were added compound 5 (7.85 g,18.26 mmol) and 150ml ethanol, cooled to 4℃in an ice bath, sodium borohydride (0.69 g,26.46 mmol) was added, reacted at room temperature for 2.5h, concentrated in vacuo, 70ml water was added, stirred for 10mins, filtered off with suction, the filter cake was refluxed with methanol for 3h, concentrated in vacuo, ethanol and water were recrystallized to give 6.71g of compound 6 as a white solid in 85.02% yield. mp.211-213 ℃; the purity was 99.24% by HPLC.

Example 39

Into a reaction flask were added compound 5 (4.00 g,10.81 mmol) and 80ml methanol, cooled to 4℃in an ice bath, added potassium borohydride (0.76 g,14.09 mmol), reacted at room temperature for 2.5h, concentrated in vacuo, added 40ml water, stirred for 10mins, filtered off with suction, the filter cake refluxed with methanol for 3h, concentrated in vacuo, ethanol and water recrystallized to give 3.78g of compound 6 as a white solid in 93.99% yield. mp.211-213 ℃; the purity was 99.26% by HPLC.

Example 40

Preparation of Compound 7 (5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)

Compound 6 (2.01 g,5.40mmol, 99.23% purity by hplc) and 20ml tetrahydrofuran are added to a reaction flask, p-toluenesulfonic acid monohydrate (1.54 g,8.10 mmol) is added under stirring, the mixture is heated and refluxed for 1h, no substantial raw material remains by tlc detection, the mixture is cooled to room temperature, a large amount of white solid is precipitated, filtered and dried to obtain 2.54g of p-toluenesulfonate of white solid compound 7, the yield of which is 89.27%; mp.208 ℃; purity by HPLC 99.91%; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):8.06(b,2H),7.45-7.49(m,3H),7.10-7.12(d,2H),6.85(s,1H),6.47(s,1H),6.39-6.42(m,1H),5.75-5.78(m,1H),4.24-4.27(m,1H),3.74(s,3H),-3.72(s,3H),3.57(b,2H),2.28(s,3H),1.12-1.20(m,1H),0.29-0.54(m,4H)，MS(ESI+):m/z,355([M+H] ⁺ ). P-toluenesulfonate (2.54 g,4.83 mmol) of compound 7 was stirred in a saturated sodium carbonate solution for 1h, filtered off with suction and dried to give 1.71g of compound 7 as a white solid in a total yield of 89.40%. mp.215 ℃; purity by HPLC 99.96%; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):7.07(s,1H),6.45-6.46(d,1H),6.42(s,1H),6.19(s,2H),5.70-5.72(m,1H),5.68(s,2H),4.24-4.26(m,1H),3.70(s,3H),3.71(s,3H),3.52(d,2H),1.11-1.15(m,1H),0.43-0.51(m,2H),0.35-0.39(m,1H),0.30-0.33(m,1H)；MS(ESI+):m/z,355([M+H] ⁺ )。

Example 41

Compound 6 (2.00 g,5.38mmol, 99.23% purity by hplc) and 8ml of dimethyl sulfoxide are added into a reaction flask, p-toluenesulfonic acid monohydrate (1.54 g,8.10 mmol) is added under stirring to react for 1h at 80 ℃, no raw material basically remains in tlc detection, cooling to room temperature, adding dichloromethane, washing the dichloromethane phase for 5 times, separating out a large amount of white solid by dichloromethane layer, filtering and drying to obtain 2.53g of p-toluenesulfonic acid salt of compound 7 as white solid, yield 89.36%, mp.208 ℃; HPLC purity 99.92%.

P-toluenesulfonate (2.53 g,4.81 mmol) of compound 7 was stirred in a saturated sodium carbonate solution for 1h, suction filtered and dried to give 1.70g of compound 7 as a white solid in a total yield of 89.32%. mp.215 ℃; the purity was 99.95% by HPLC.

Example 42

Compound 6 (2.00 g,5.38mmol, 99.23% purity by hplc) and 20ml methyltetrahydrofuran were added to a reaction flask, p-toluenesulfonic acid monohydrate (1.55 g,8.15 mmol) was added with stirring and reacted for 1h at 80 ℃, tlc detection was performed with substantially no starting material remaining, cooling to room temperature, adding dichloromethane, washing the dichloromethane phase 5 times, separating out a large amount of white solid from the dichloromethane layer, filtering, oven drying to give 2.50g of p-toluenesulfonic acid salt of compound 7 as a white solid, yield 88.30%, mp.208 ℃; HPLC purity 99.94%.

P-toluenesulfonate (2.50 g,4.75 mmol) of compound 7 was stirred in a saturated sodium carbonate solution for 1h, suction filtered and dried to give 1.69g of compound 7 as a white solid in a total yield of 88.80%. mp.215 ℃; the purity was 99.96% by HPLC.

Example 43

Compound 6 (2.00 g,5.38mmol, 99.23% purity by hplc) and 20ml acetone were added to a reaction flask, p-toluenesulfonic acid monohydrate (1.53 g,8.04 mmol) was added with stirring, reaction was carried out for 1h at 80 ℃, tlc detection was carried out with substantially no starting material remaining, cooling to room temperature, dichloromethane was added, water washing was carried out for 5 times, a large amount of white solid was separated out by dichloromethane layer, filtration and drying to obtain 2.52g of p-toluenesulfonic acid salt of compound 7 as a white solid, yield 89.01%, mp.208 ℃; HPLC purity 99.95%.

P-toluenesulfonate (2.52 g,4.79 mmol) of compound 7 was stirred in a saturated sodium carbonate solution for 1h, suction filtered and dried to give 1.70g of compound 7 as a white solid in a total yield of 89.32%. mp.215 ℃; the purity was 99.97% by HPLC.

Example 44

Compound 6 (2.01 g,5.40mmol, 99.23% hplc purity) and 20ml dimethylformamide are added to a reaction flask, p-toluenesulfonic acid monohydrate (1.53 g,8.04 mmol) is added with stirring and reacted for 1h at 80 ℃, tlc detection shows substantially no starting material remaining, cooling to room temperature, adding dichloromethane, washing dichloromethane phase 5 times, separating out a large amount of white solid from dichloromethane layer, filtering, drying to obtain 2.49g of p-toluenesulfonic acid salt of white solid compound 7, yield 87.51%, mp.208 ℃; HPLC purity 99.96%.

P-toluenesulfonate (2.49 g,4.73 mmol) of compound 7 was stirred in a saturated sodium carbonate solution for 1h, suction filtered and dried to give 1.67g of compound 7 as a white solid in a total yield of 87.30%. mp.215 ℃; the purity was 99.96% by HPLC.

Example 45

To the reaction flask was added compound 6 (1.70 g,4.57mmol, 99.23% purity by HPLC) and 7ml of dimethyl sulfoxide, trifluoroacetic acid (1.56 g,13.68 mmol) was added with stirring, reacted for 5 hours at 80℃until no substantial material remained by TLC detection, cooled to room temperature, dichloromethane was added, the pH was adjusted to 9 with saturated sodium carbonate solution, separated, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, the organic phases were washed 5 times with water, dried over anhydrous sodium sulfate, concentrated in vacuo, recrystallized from ethanol, and dried to give 1.39g of compound 7 in 85.92% yield. mp.215 ℃; the purity was 98.96% by HPLC.

Example 46

To the reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% purity by HPLC) and 20ml of methyltetrahydrofuran, trifluoroacetic acid (1.84 g,16.14 mmol) was added with stirring, the reaction was carried out for 5 hours at 80℃until no substantial starting material remained by TLC detection, cooled to room temperature, dichloromethane was added, the pH was adjusted to 9 with saturated sodium carbonate solution, the solution was separated, the aqueous phase was extracted with dichloromethane 3 times, the organic phases were combined, the organic phases were washed 5 times with water, dried over anhydrous sodium sulfate, concentrated in vacuo, recrystallized from ethanol, and dried to give 1.65g of compound 7 in 86.17% yield. mp.215 ℃; the purity was 98.95% by HPLC.

Example 47

To the reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% purity by HPLC) and 20ml of acetone, trifluoroacetic acid (1.83 g,16.05 mmol) was added with stirring, the reaction was carried out at 80℃for 5 hours, the TLC detection was carried out with substantially no starting material remaining, cooling to room temperature, methylene chloride was added, the pH was adjusted to 9 with saturated sodium carbonate solution, the liquid was separated, the aqueous phase was extracted 3 times with methylene chloride, the organic phases were combined, the organic phases were washed 5 times with water, dried over anhydrous sodium sulfate, concentrated in vacuo, recrystallized from ethanol, and dried to give 1.67g of compound 7, the yield was 87.5%. mp.215 ℃; the purity was 98.97% by HPLC.

Example 48

To the reaction flask was added compound 6 (2.01 g,5.40mmol, 99.23% purity by HPLC) and 20ml dimethylformamide, trifluoroacetic acid (1.84 g,16.14 mmol) was added with stirring, the reaction was carried out for 5 hours at 80℃until no substantial starting material remained by TLC detection, cooled to room temperature, dichloromethane was added, the pH was adjusted to 9 with saturated sodium carbonate solution, the solution was separated, the aqueous phase was extracted with dichloromethane 3 times, the organic phase was combined, the organic phase was washed with water 5 times, dried over anhydrous sodium sulfate, concentrated in vacuo, recrystallized from ethanol, and dried to give 1.69g of compound 7 in 88.8% yield. mp.215 ℃; the purity was 98.99% by HPLC.

Example 49

To a reaction flask was added compound 6 (1.69 g,4.54mmol, 99.23% purity by HPLC) and 20ml of tetrahydrofuran, trifluoroacetic acid (1.56 g,13.68 mmol) was added with stirring, the reaction was heated under reflux for 15h, no substantial material remained by TLC detection, dichloromethane was added after tetrahydrofuran was distilled off, the organic phase was adjusted to pH 9 with saturated sodium carbonate solution, separated, the aqueous phase was extracted with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, recrystallized from ethanol, and dried to give 1.43g of compound 7 in 88.44% yield. mp.215 ℃; the purity was 98.89% by HPLC.

Example 50

To the reaction flask was added a mixed solution of compound 6 (2.21 g,5.94mmol, hplc purity 99.23%), 12ml of tetrahydrofuran and 4ml of dimethyl sulfoxide, methanesulfonic acid (0.856 g,8.91 mmol) was added with stirring, the reaction was heated to reflux for 3h, tlc was allowed to leave substantially no starting material, cooled to room temperature, tetrahydrofuran was concentrated in vacuo, dichloromethane was added, pH was adjusted to 9 with saturated sodium carbonate solution, the layers were separated, the dichloromethane phase was washed 3 times with water, the solvent was distilled off, ethanol was recrystallized, suction filtered, and dried to give 1.52g of compound 7 as a white solid, yield 72.28%. mp.215 ℃; the purity was 98.93% by HPLC.

Example 51

To a reaction flask, compound 6 (2.00 g,5.38mmol, HPLC purity: 99.23%) and 20ml of tetrahydrofuran were added, concentrated sulfuric acid (0.53 g,5.41 mmol) was added under stirring, the reaction was heated under reflux for 3 hours, cooled to room temperature, suction filtered, and dried to obtain sulfate of compound 7, the filter cake was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to obtain 1.72g of compound 7 as a white solid in a total yield of 90.37%. mp.215 ℃; the purity was 98.90% by HPLC.

Example 52

To a reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% purity by HPLC) and 8ml of dimethyl sulfoxide, concentrated sulfuric acid (0.54 g,5.50 mmol) was added with stirring, the reaction was heated to reflux for 3h, TLC was allowed to leave substantially no starting material, cooled to room temperature, dichloromethane was added, the organic phase was adjusted to pH 9 with saturated sodium carbonate solution, separated, the aqueous phase was extracted with dichloromethane 3 times, the organic phase was combined, the organic phase was washed with water 5 times, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, recrystallized from ethanol, suction filtered, and dried to give 1.75g of compound 7 in 91.95% yield. mp.215 ℃; the purity was 98.98% by HPLC.

Example 53

To a reaction flask, compound 6 (2.00 g,5.38mmol, HPLC purity: 99.23%) and 20ml methyltetrahydrofuran were added, concentrated sulfuric acid (0.54 g,5.51 mmol) was added under stirring, and the mixture was heated under reflux for 3 hours, cooled to room temperature, suction filtered, and dried to give sulfate of compound 7, and the filter cake was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to give 1.71g of compound 7 as a white solid in a total yield of 89.85%. mp.215 ℃; the purity was 98.92% by HPLC.

Example 54

To a reaction flask were added compound 6 (2.00 g,5.38mmol, HPLC purity 99.23%) and 20ml acetone, concentrated sulfuric acid (0.55 g,5.61 mmol) was added under stirring, and the mixture was heated under reflux for 3 hours, cooled to room temperature, suction filtered, and dried to give sulfate of compound 7, and the filter cake was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to give 1.72g of compound 7 as a white solid in a total yield of 90.37%. mp.215 ℃; the purity was 98.95% by HPLC.

Example 55

To a reaction flask, compound 6 (1.71 g,4.60mmol, HPLC purity: 99.23%) and 20ml dimethylformamide were added, sulfuric acid (0.48 g,4.90 mmol) was added under stirring, and the mixture was heated under reflux for 3 hours, cooled to room temperature, suction filtered, and dried to give sulfate of compound 7, and the cake was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to give 1.46g of compound 7 as a white solid in a total yield of 89.72%. mp.215 ℃; the purity was 98.97% by HPLC.

Comparative example 1

To a 50ml reaction flask were added compound 1a (2.576 g,6.888 mmol), acetic anhydride (3.510 g,34.438 mmol) and 20ml chloroform, and aluminum trichloride (2.230 g,16.724 mmol) was slowly added with stirring and reacted under reflux for 10 hours without the formation of the target substance.

Comparative example 2

To a reaction flask, compound 1a (100.0 g,267.1 mmol), acetic anhydride (55.4 g,544.3 mmol) and 1000ml of methylene chloride were added, tin tetrachloride (62 ml,537.8 mmol) was slowly added under stirring, and then the mixture was heated under reflux for 3 hours, cooled to room temperature, the reaction mixture was poured into 600ml of ice water, stirred for 20mins, separated, and the organic phase was washed twice with 50ml of water, the aqueous phase was combined, the aqueous phase was washed with 50ml of methylene chloride 4 times, the organic phase was combined, the organic phase was washed with saturated sodium carbonate solution to a pH of about 7, the organic phase was washed with 50ml of water 1 time, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and recrystallized from 200ml of ethylene glycol monomethyl ether to give 60.2g of Compound 2 in 54.2% yield. mp.204-206 ℃; purity by HPLC 96.05%; ¹ H-NMR(400MHz,CDCl ₃ ).δ(ppm):10.03(s,1H),9.20(s,1H),8.41(s,1H),7.26(s,1H),6.34(s,1H),3.95(s,3H),3.84(s,3H),3.76(s,3H),3.68(s,2H),2.60(s,3H),2.48(s,3H),2.48(s,3H)；MS(ESI+):m/z,417([M+H] ⁺ )。

comparative example 3

To a 50ml reaction flask were added compound 1 trimethoprim (2.000 g,6.889 mmol), acetic anhydride (3.516 g,34.440 mmol) and 20ml chloroform, and aluminum trichloride (2.235 g,16.762 mmol) was slowly added with stirring, and the reaction was heated under reflux for 10 hours without the formation of the target substance.

Comparative example 4

To a 50ml reaction flask were added compound 1 trimethoprim (2.000 g,6.889 mmol), acetic anhydride (3.502 g,34.303 mmol) and 20ml chloroform, and iron trichloride (2.234 g,13.773 mmol) was slowly added with stirring, and the mixture was heated to reflux for 12 hours and cooled to room temperature, whereby no target substance was formed.

Comparative example 5

To a 100ml reaction flask were added compound 3 (3.000 g,9.036 mmol) and 60ml dichloromethane, and aluminum trichloride (2.410 g,18.077 mmol) was slowly added with stirring, and the reaction was heated under reflux for 10 hours, whereby no target compound was formed.

Comparative example 6

To a 100ml reaction flask was added compound 3 (4.000 g,12.048 mmol), 20ml acetic acid and 48% hydrobromic acid 10ml, and the reaction was heated under reflux for 1h, and the TLC detection of the starting material was essentially complete but no target compound was formed.

Comparative example 7

To a 100ml reaction flask were added compound 2 (4.000 g, 9.015 mmol), 60ml dichloromethane and aluminum trichloride (2.412 g,18.089 mmol), and the reaction was heated under reflux for 10 hours without the formation of the objective compound.

Comparative example 8

Into a 100ml reaction flask were charged compound 2 (4.000 g, 9.616 mmol), 20ml acetic acid and 48% hydrobromic acid 10ml, and the reaction was heated under reflux for 2 hours, and the TLC detection of the starting material was essentially complete but no target compound was formed.

Comparative example 9

To a 100ml reaction flask were added compound 4 (4.000 g,12.579 mmol), cyclopropylaldehyde (1.071 g,15.300 mmol) and 40ml acetonitrile, and pyrrolidine (1.38 g,19.437 mmol) was slowly added dropwise, stirred at room temperature for 36h, concentrated in vacuo, and isolated and purified by thin layer column chromatography to give 0.156g of compound 5 in 3.9% yield. mp.152-155 ℃. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Comparative example 10

To a 100ml reaction flask were added compound 4 (4.01 g, 12.313 mmol), cyclopropylaldehyde (1.072 g,15.314 mmol) and 40ml acetonitrile, piperidine (1.607 g,18.875 mol) was slowly added dropwise, stirred at room temperature for 48h, concentrated in vacuo to dryness, and isolated and purified by thin layer column chromatography to give 0.105g of compound 5 in 2.25% yield. mp.152-155 ℃. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Comparative example 11

Into a 100ml reaction flask, compound 4 (4.000 g,12.579 mmol), cyclopropylaldehyde (1.082 g,15.457 mmol) and 40ml acetonitrile were added slowly and pyrrolidine (1.377 g,18.841 mol) was added dropwise, stirred at room temperature for 50h, concentrated in vacuo and separated and purified by thin layer column chromatographyTo 0.175g of Compound 5, yield 3.76%. mp.152-155 ℃. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Comparative example 12

A100 ml reaction flask was charged with compound 4 (4.000 g,12.579 mmol), cyclopropylaldehyde (1.070 g, 15.284 mmol), 40ml of methanol and potassium hydroxide (1.060 g,18.687 mol), and the reaction was heated under reflux for 10 hours, without the formation of the objective compound 5.

Comparative example 13

A100 ml reaction flask was charged with compound 4 (4.001 g, 12.284 mmol), cyclopropylaldehyde (1.072 g,15.314 mmol), 40ml of tetrahydrofuran and potassium tert-butoxide (2.090 g,18.629 mol), and the reaction was heated under reflux for 8 hours, without the formation of the objective compound 5.

Comparative example 14

Into a 100ml reaction flask were charged compound 4 (4.018 g,12.635 mmol), cyclopropylaldehyde (1.082 g,15.457 mmol) and 40ml isopropyl alcohol, and pyrrolidine (1.347g, 18.972 mol) was slowly added dropwise, stirred at room temperature for 36 hours, dried solvent was concentrated in vacuo, and isolated and purified by thin layer column chromatography to give 0.598g compound 5 in 15.0% yield. mp.152-155 ℃. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Comparative example 15

To a 100ml reaction flask was added compound 4 (4.00 g,12.58 mmol), cyclopropylaldehyde (1.05 g,15.00 mmol) and 40ml acetonitrile, and pyrrolidine (1.35 g,19.01 mol) was slowly added dropwise with stirring, stirred at room temperature for 36h, suction filtered, dried, ethanol recrystallized to give 2.15g of off-white solid with a yield of 46.20%. mp.152-155 ℃; the purity was 96.63% by HPLC. ¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.13(s,1H),6.49(s,1H),6.31,(s,2H),5.92(s,2H),3.89-4.00(m,2H),3.78-3.86(m,4H),3.71(s,3H),1.89(s,3H),1.19-1.25(m,1H),0.53-0.63(m,2H),0.45-0.51(m,1H),0.37-0.43(m,1H)；MS(ESI ⁺ ):m/z,371([M+H] ⁺ ).

Comparative example 16

Preparation of Compound 7 (5- ((2-cyclopropyl-7, 8-dimethoxy-2H-benzopyran-5-yl) methyl) pyrimidine-2, 4-diamine)

To the reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% pure by HPLC), 20ml of methanol and p-toluenesulfonic acid monohydrate (1.53 g,8.04 mmol), and after stirring at room temperature for 0.5h, the starting material was substantially disappeared by TLC but no target compound was formed. Methanol was concentrated in vacuo, pH was adjusted to 9 by addition of 20ml of saturated aqueous sodium carbonate, extraction was performed three times with 10ml of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to give dichloromethane, and the crude product was recrystallized from isopropanol and water (isopropanol: water=2:1) in solvent to give 1.75g of an alcoholic hydroxymethylated compound of compound 6 (5- ((2-cyclopropyl-4, 7, 8-trimethoxybenzopyran-5-yl) methyl) pyrimidine-2, 4-diamine) in a yield of 84.3%.

mp.237-240℃； ¹ H-NMR(600MHz,DMSO).δ(ppm):7.44(s,1H),6.30(s,1H),6.15(s,2H),5.74(s,2H),4.41-4.42(t,1H),3.70(s,6H),3.57-3.59(d,1H),3.49-3.52(d,1H),3.39-3.42(m,4H),2.39-2.42(d,2H),1.65-1.70(m,1H),1.20-1.24(m,1H),0.61-0.69(m,2H),0.52-0.56(m,1H),0.38-0.42(m,1H)；MS(ESI ⁺ ):m/z,387([M+H] ⁺ )。

Comparative example 17

To the reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% HPLC purity), 20ml toluene and 3.07g,26.9mmol of trifluoroacetic acid, and after stirring under heating and refluxing for 2 hours, the TLC examined the substantial disappearance of the starting material but no target compound.

Comparative example 18

To the reaction flask, compound 6 (2.00 g,5.38mmol, HPLC purity: 99.23%) and 20ml of dilute sulfuric acid (2 mol/L) were added, and after stirring at room temperature for 2 hours, the TLC detected substantial disappearance of starting material but no formation of the objective product.

Comparative example 19

To the reaction flask was added compound 6 (2.00 g,5.38mmol, 99.23% pure by HPLC), 20ml of methanol and p-toluenesulfonic acid monohydrate (1.54 g,8.10 mmol), and after stirring under reflux for 0.5h, the starting material was substantially disappeared by TLC but no target compound was formed. Methanol was concentrated in vacuo, pH was adjusted to 9 by addition of 20ml of saturated aqueous sodium carbonate, extraction was performed three times with 10ml of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo to give dichloromethane, and the crude product was recrystallized from isopropanol and water (isopropanol: water=2:1) in solvent to give 1.80g of the alcoholic hydroxymethylated compound of compound 6 (5- ((2-cyclopropyl-4, 7, 8-trimethoxybenzopyran-5-yl) methyl) pyrimidine-2, 4-diamine) in 86.7% yield.

mp.237-240℃； ¹ H-NMR(600MHz,DMSO).δ(ppm):7.44(s,1H),6.30(s,1H),6.15(s,2H),5.74(s,2H),4.41-4.42(t,1H),3.70(s,6H),3.57-3.59(d,1H),3.49-3.52(d,1H),3.39-3.42(m,4H),2.39-2.42(d,2H),1.65-1.70(m,1H),1.20-1.24(m,1H),0.61-0.69(m,2H),0.52-0.56(m,1H),0.38-0.42(m,1H)；MS(ESI+):m/z,387([M+H]+)。

Comparative example 20

To the reaction flask, compound 6 (2.01 g,5.40mmol, HPLC purity: 99.23%) and 20ml of dilute sulfuric acid (2 mol/L) were added, and after stirring under heating and refluxing for 1 hour, the TLC detected substantial disappearance of starting material but no formation of the objective product.

Comparative example 21

To the reaction flask was added compound 1b (2.000 g, 4.640 mmol), 10ml DCM and acetic anhydride (1.513 g, 14.812 mmol) under nitrogen, followed by a slow dropwise addition of (2.7 ml,23.072 mmol) tin chloride under ice-bath. Stirring was carried out at room temperature for 18 hours, without formation of compound 2 a.

On the basis that the compound 2a cannot be obtained, the target compound cannot be prepared by continuously referring to the reaction route of the invention.

Claims

1. The preparation method of the chromanone compound shown in the formula 5 is characterized by comprising the following steps of (1): in an organic solvent, in the presence of alkali and acid, carrying out aldol condensation-ring closure reaction on a phenol compound shown as a formula 4 and cyclopropylaldehyde to obtain a tetrahydropyranone substance; the tetrahydropyrone substance comprises a chromanone compound shown in a formula 5 and the acid;

Step (2): neutralizing the tetrahydropyranone compound obtained in the step (1) with alkali to obtain a chromanone compound shown in a formula 5;

in the step (1), the alkali is pyrrolidine and/or piperidine;

in the step (1), the acid is acetic acid and/or propionic acid.

2. The process for producing a chromanone compound of formula 5 according to claim 1,

in the step (1), the organic solvent is a nitrile solvent;

and/or in the step (1), the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 4 is 8-20 mL/g;

and/or in the step (1), the molar ratio of the alkali to the phenol compound shown in the formula 4 is 1:1-2:1;

and/or in the step (1), the molar ratio of the acid to the phenol compound shown in the formula 4 is 0.5:1-2:1;

and/or in the step (1), the molar ratio of the cyclopropylaldehyde to the phenol compound shown as the formula 4 is 1:1-2:1;

and/or, in the step (1), the temperature of the aldol condensation-ring closure reaction is 0-50 ℃;

and/or the tetrahydropyranone compound is composed of the chromanone compound shown in the formula 5 and the acid;

And/or, in the step (2), the alkali is carbonate of alkali metal and/or bicarbonate of alkali metal;

and/or, in step (2), the base is in the form of an aqueous solution of the base;

and/or, the preparation method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the aldol condensation-ring closure reaction is finished, filtering and drying a reaction system to obtain the tetrahydropyranone substance;

3. The process for producing a chromanone compound of formula 5 according to claim 2,

in the step (1), the organic solvent is acetonitrile;

and/or in the step (1), the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 4 is 10mL/g-15mL/g;

and/or, in the step (1), the molar ratio of the alkali to the phenol compound shown in the formula 4 is 1.45:1-1.55:1;

and/or in the step (1), the molar ratio of the acid to the phenol compound shown in the formula 4 is 1.0:1-2:1;

And/or in the step (1), the molar ratio of the cyclopropylaldehyde to the phenol compound shown as the formula 4 is 1.2:1-1.5:1;

and/or, in the step (1), the temperature of the aldol condensation-ring closure reaction is 10-30 ℃;

and/or, part or all of the chromanone compound shown in formula 5 exists in the form of salt with the acid;

and/or, in the step (2), the carbonate of the alkali metal is sodium carbonate and/or potassium carbonate; the alkali metal bicarbonate is sodium bicarbonate and/or potassium bicarbonate.

4. The method for preparing a chromanone compound of formula 5 according to claim 1, wherein the method for preparing a chromanone compound of formula 5 further comprises scheme 1 or scheme 2;

the scheme 1 comprises the following steps of carrying out the following acetamido hydrolysis reaction on a phenol compound shown in a formula 8 in the presence of alkali in an organic solvent to obtain the phenol compound shown in a formula 4;

the scheme 2 comprises the following steps of carrying out selective demethylation reaction of an acetophenone compound shown in a formula 3 in the presence of Lewis acid in an organic solvent to obtain a phenol compound shown in a formula 4;

5. The process for producing a chromanone compound of formula 5 according to claim 4,

in the scheme 1, the organic solvent is an alcohol solvent;

and/or in the scheme 1, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 8 is 5mL/g-20mL/g;

and/or, in the above scheme 1, the base is an alkali metal carbonate;

and/or, in the scheme 1, the molar ratio of the alkali to the phenol compound shown in the formula 8 is 0.1:1-1:1;

and/or, in the scheme 1, the temperature of the acetamido hydrolysis reaction is 60-82 ℃;

and/or, in the scheme 1, the preparation method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetamido hydrolysis reaction is finished, crystallizing, filtering, washing and drying the reaction system to obtain the phenol compound shown in the formula 4;

and/or, in the above-mentioned scheme 2, the organic solvent is a halogenated hydrocarbon solvent;

and/or in the scheme 2, the volume-mass ratio of the organic solvent to the acetophenone compound shown in the formula 3 is 8-25 mL/g;

And/or, in the scheme 2, the lewis acid is boron tribromide and/or boron trichloride;

and/or in the scheme 2, the molar ratio of the Lewis acid to the acetophenone compound shown in the formula 3 is 1:1-2:1;

and/or, in the solution 2, the lewis acid is in the form of a solution of the organic solvent;

and/or, in said scheme 2, the temperature of said selective demethylation reaction is from-15 ℃ to 35 ℃;

and/or, in the scheme 2, the lewis acid is added dropwise to the acetophenone compound shown in the formula 3 and the organic solvent;

and/or, in the scheme 2, the preparation method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the selective demethylation reaction is finished, the reaction system is subjected to extraction, concentration and recrystallization to obtain the phenol compound shown in the formula 4.

6. The process for producing a chromanone compound of formula 5 according to claim 5,

in the scheme 1, the organic solvent is one or more of methanol, ethanol and isopropanol;

And/or in the scheme 1, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 8 is 10mL/g-15mL/g;

and/or, in the scheme 1, the alkali is sodium carbonate and/or potassium carbonate;

and/or, in the scheme 1, the molar ratio of the alkali to the phenol compound shown in the formula 8 is 0.1:1-0.5:1;

and/or, in the scheme 1, the temperature of the acetamido hydrolysis reaction is 65-70 ℃;

and/or, in the scheme 2, the organic solvent is dichloromethane and/or chloroform;

and/or in the scheme 2, the volume-mass ratio of the organic solvent to the acetophenone compound shown in the formula 3 is 10mL/g-20mL/g;

and/or, in the solution 2, the lewis acid is boron tribromide;

and/or in the scheme 2, the molar ratio of the Lewis acid to the acetophenone compound shown in the formula 3 is 1.2:1-1.7:1;

and/or, in said scheme 2, said selective demethylation reaction is at a temperature of from-6 ℃ to 30 ℃.

7. The method for preparing a chromanone compound of formula 5 according to claim 4, wherein when the method for preparing a chromanone compound of formula 5 further comprises scheme 1, scheme a further comprises the steps of: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on an acetyl compound shown in a formula 2 to obtain the phenol compound shown in a formula 8;

And/or, when the preparation method of the chromanone compound shown in the formula 5 further comprises a scheme 2, the scheme B further comprises the following steps: in an organic solvent, in the presence of alkali, performing the following acetamido hydrolysis reaction on the acetyl compound shown in the formula 2 to obtain the acetyl benzene compound shown in the formula 3;

8. the process for producing a chromanone compound of formula 5 according to claim 7,

in the scheme A, the organic solvent is a halogenated hydrocarbon solvent;

and/or, in the scheme A, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 8mL/g-20mL/g;

and/or, in the scheme A, the Lewis acid is boron tribromide and/or boron trichloride;

and/or, in the scheme A, the molar ratio of the Lewis acid to the acetyl compound shown in the formula 2 is 1:1-2:1;

and/or, in the solution A, the Lewis acid is in the form of a solution of the organic solvent;

and/or, in the scheme A, the temperature of the selective demethylation reaction is-15 ℃ to 35 ℃;

And/or, in the scheme A, the Lewis acid is dropwise added into the acetyl compound shown in the formula 2 and the organic solvent;

and/or, in the scheme A, the method further comprises post-processing, wherein the post-processing comprises the following steps: after the selective demethylation reaction is finished, extracting the reaction system, adjusting the pH to about 6, filtering and recrystallizing to obtain the phenol compound shown in the formula 8;

and/or, in the scheme B, the organic solvent is an alcohol solvent;

and/or in the scheme B, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 5mL/g-15mL/g;

and/or, in the scheme B, the alkali is alkali metal carbonate;

and/or in the scheme B, the molar ratio of the alkali to the acetyl compound shown in the formula 2 is 0.1:1-1:1;

and/or, in the scheme B, the temperature of the acetamido hydrolysis reaction is 60-82 ℃;

and/or, in the scheme B, the preparation method further comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetamido hydrolysis reaction is finished, the reaction system is subjected to crystallization, filtration, water washing and drying to obtain the acetophenone compound shown in the formula 3.

9. The process for producing a chromanone compound of formula 5 according to claim 8,

in the scheme A, the organic solvent is dichloromethane and/or chloroform;

and/or, in the scheme A, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 10mL/g-15mL/g;

and/or, in the scheme A, the Lewis acid is boron tribromide;

and/or, in the scheme A, the molar ratio of the Lewis acid to the acetyl compound shown in the formula 2 is 1.2:1-1.7:1;

and/or, in the scheme A, the temperature of the selective demethylation reaction is-8 ℃ to 30 ℃;

and/or in the scheme B, the organic solvent is one or more of methanol, ethanol and isopropanol;

and/or in the scheme B, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 9-11 mL/g;

and/or, in the scheme B, the alkali is sodium carbonate and/or potassium carbonate;

and/or in the scheme B, the molar ratio of the alkali to the acetyl compound shown in the formula 2 is 0.1:1-0.7:1;

And/or, in the scheme B, the temperature of the acetamido hydrolysis reaction is 65-70 ℃.

10. The method for preparing a chromanone compound of formula 5 according to claim 7, wherein the method for preparing a chromanone compound of formula 5 further comprises scheme a or scheme b;

the scheme a comprises the following steps: in an organic solvent, in the presence of Lewis acid, carrying out an acetylation reaction shown below on trimethoprim and an acetylation reagent to obtain the acetyl compound shown in the formula 2;

11. the process for producing a chromanone compound of formula 5 according to claim 10,

in the scheme a, the organic solvent is a halogenated hydrocarbon solvent;

and/or in the scheme a, the volume-mass ratio of the organic solvent to the trimethoprim is 5-15 mL/g;

And/or, in the scheme a, the acetylating reagent is acetyl chloride and/or acetic anhydride;

and/or, in the scheme a, the molar ratio of the acetylation reagent to the trimethoprim is 1.5:1-4:1;

and/or, in the scheme a, the Lewis acid is tin tetrachloride;

and/or, in the scheme a, the molar ratio of the Lewis acid to the trimethoprim is 1:1-3:1;

and/or, in the scheme a, the temperature of the acetylation reaction is 25-85 ℃;

and/or, in the scheme a, the method further comprises post-processing, wherein the post-processing comprises the following steps: after the acetylation reaction is finished, extracting and removing the reaction system to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent, regulating the pH value of the combined organic phase to 7-8, separating the water phase to obtain the organic phase, washing the organic phase with water, drying the organic phase, filtering, concentrating, and recrystallizing to obtain the acetyl compound shown in the formula 2;

and/or, in the scheme b, the organic solvent is a halogenated hydrocarbon solvent;

and/or in the scheme b, the volume-mass ratio of the organic solvent to the trimethoprim is 5-15 mL/g;

And/or, in the scheme b, the acetylating reagent is acetyl chloride and/or acetic anhydride;

and/or, in the scheme b, the molar ratio of the acetylation reagent to the trimethoprim is 1.5:1-4:1;

and/or, in the scheme b, the Lewis acid is tin tetrachloride;

and/or in the scheme b, the molar ratio of the Lewis acid to the trimethoprim is 1:1-3:1;

and/or, in the scheme b, the temperature of the acetylation reaction is 25-85 ℃;

and/or, in the scheme b, the method further comprises post-processing, wherein the post-processing comprises the following steps: after the acetylation reaction is finished, extracting and removing the reaction system to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent, regulating the pH value of the combined organic phase to 7-8, separating the water phase to obtain the organic phase, washing the organic phase with water, drying the organic phase, filtering, concentrating, and recrystallizing to obtain the acetyl compound shown in the formula 2.

12. The process for producing a chromanone compound of formula 5 according to claim 11,

in the scheme a, the organic solvent is one or more of chloroform, dichloromethane and dichloroethane;

And/or in the scheme a, the volume-mass ratio of the organic solvent to the trimethoprim is 8-10 mL/g;

and/or, in the scheme a, the acetylating reagent is acetic anhydride;

and/or, in the scheme a, the molar ratio of the acetylating reagent to the trimethoprim is 2:1;

and/or, in the scheme a, the molar ratio of the Lewis acid to the trimethoprim is 2:1-3:1;

and/or, in the scheme a, the temperature of the acetylation reaction is 60-65 ℃;

and/or in the scheme b, the organic solvent is one or more of chloroform, dichloromethane and dichloroethane;

and/or in the scheme b, the volume-mass ratio of the organic solvent to the trimethoprim is 8-10 mL/g;

and/or, in the scheme b, the acetylating agent is acetic anhydride;

and/or, in the scheme b, the molar ratio of the acetylating reagent to the trimethoprim is 2:1;

and/or in the scheme b, the molar ratio of the Lewis acid to the trimethoprim is 2:1-3:1;

and/or, in the scheme b, the temperature of the acetylation reaction is 60 ℃ to 65 ℃.

13. The method for preparing a chromanone compound of formula 5 according to claim 11 or 12, wherein when the method for preparing a chromanone compound of formula 5 further comprises the scheme b, the method for preparing a chromanone compound of formula 5 further comprises the scheme c, wherein the scheme c comprises the steps of: performing acetylation reaction on trimethoprim shown in formula 1 under the action of an acetylating reagent in an organic solvent to obtain an acetamide compound shown in formula 1 a;

14. a preparation method of a salt of a chromanone compound shown in a formula 5 is characterized in that,

the method comprises the following steps of carrying out aldol condensation-ring closure reaction on a phenol compound shown in a formula 4 and cyclopropylaldehyde in an organic solvent in the presence of alkali and acid to obtain a salt formed by a chromanone compound shown in a formula 5 and the acid;

wherein the reaction conditions and the operation of the preparation method of the salt of the chromanone compound shown in the formula 5 are as shown in the step (1) of any one of claims 1 to 13.

15. The method for preparing a salt of a chromanone compound of formula 5 according to claim 14, wherein the method for preparing a salt of a chromanone compound of formula 5 further comprises a method for preparing a phenol compound of formula 4;

the preparation method of the phenol compound shown in the formula 4 comprises the following steps of carrying out the following acetamido hydrolysis reaction on the phenol compound shown in the formula 8 in the presence of alkali in an organic solvent to obtain the phenol compound shown in the formula 4;

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wherein the reaction conditions and operations of the preparation method of the phenol compound shown in the formula 4 are shown in the scheme 1 of any one of claims 7 to 13.