CN110790753A - Ealaprilin p-toluenesulfonate, and preparation method and application thereof - Google Patents

Ealaprilin p-toluenesulfonate, and preparation method and application thereof Download PDF

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CN110790753A
CN110790753A CN201911126445.3A CN201911126445A CN110790753A CN 110790753 A CN110790753 A CN 110790753A CN 201911126445 A CN201911126445 A CN 201911126445A CN 110790753 A CN110790753 A CN 110790753A
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CN110790753B (en
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刘潍源
周伟澄
林快乐
吕训磊
李超超
臧金鹏
王成成
孟雪
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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Abstract

The invention discloses elaprine p-toluenesulfonate, and a preparation method and application thereof. The invention discloses a preparation method of elaprine p-toluenesulfonate shown as a formula 7a, which comprises the following steps: in an aprotic solvent, under the action of p-toluenesulfonic acid, carrying out elimination reaction on a chroman compound shown as a formula 6 to obtain elaprine p-toluenesulfonic acid shown as a formula 7 a; the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethylsulfoxide. The preparation of the elaprine by using the elaprine p-toluenesulfonate as an intermediate has the advantages of more economical reagent, short route and high yield,low preparation cost and simple post-treatment, and is suitable for industrial production.

Description

Ealaprilin p-toluenesulfonate, and preparation method and application thereof
Technical Field
The invention relates to elaprine p-toluenesulfonate and a preparation method and application thereof.
Background
The chemical name of the elaprine (English name: Ilaprim) is as follows: 5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine, the structural formula is shown in formula 7:
Figure BDA0002276982640000011
iclaprim, a dihydrofolate reductase inhibitor developed by Motif Bio, was marketed by the FDA in 2018 as a therapeutic for acute bacterial skin and skin structure infection (abssi) indications. Iclaprim is currently in phase II clinical trials as a drug for the treatment of hospital-acquired bacterial pneumonia (HABP). In addition, staphylococcus aureus lung infections are currently in preclinical development as a drug for the treatment of cystic fibrosis patients.
In regulatory terms, Iclaprim has been awarded by the FDA in the united states for qualified infectious disease product Qualification (QIDP) and rapid passage. In addition, the FDA has also awarded Iclaprim the orphan drug status for the treatment of staphylococcus aureus lung infections in cystic fibrosis patients.
At present, the main synthesis method in the preparation method of elaprine is as follows:
the method comprises the following steps: (CN 101115743A)
Figure BDA0002276982640000021
In this route, starting from the compound 1 trimethoprim, by protecting the amino group, where R represents-C (CH)3)3or-CH (CH)3)2Then, Friedel-crafts acetylation, selective demethylation, aldol condensation, ring closing, reduction, hydrolysis reaction after elimination are carried out to prepare the elaprine. The method has the defects that the reaction route is long, and the yield is only 4 percent (the yield of the step for preparing the compound 14 by using the compound 13 is not included, and the patent does not write the yield of the step). And each step in the preparation of compounds 9 to 13 requires column chromatography for purification, which is not suitable for industrial production.
The second method comprises the following steps: (CN 1092194C)
In the route, a compound 16 and bis (trimethylsilyl) acetylene are used as starting materials to prepare a compound 17, wherein the two raw materials are expensive, and a large amount of expensive catalyst cerium (III) chloride heptahydrate is needed in the process of preparing a compound 18 by reducing carbonyl by the compound 17. Moreover, the compound 20 needs to be prepared by mitsnobu reaction, the reaction condition is severe, the yield is extremely low, and the post-treatment is difficult. 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 synthesis method of elaprine, 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 elaprine p-toluenesulfonate and a preparation method and application thereof.
The invention provides an elaprine p-toluenesulfonate shown as a formula 7a,
Figure BDA0002276982640000032
the invention also provides a preparation method of the elaprine p-toluenesulfonate shown as the formula 7a, which comprises the following steps: in an aprotic solvent, under the action of p-toluenesulfonic acid (such as p-toluenesulfonic acid monohydrate), carrying out elimination reaction on a chroman compound shown as a formula 6 to obtain elaprine p-toluenesulfonic acid shown as a formula 7 a;
the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethyl sulfoxide;
Figure BDA0002276982640000041
in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the aprotic solvent is preferably a mixed solvent of tetrahydrofuran and dimethyl sulfoxide (the volume ratio of tetrahydrofuran to dimethyl sulfoxide is, for example, 3:1), tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide or dimethyl sulfoxide.
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the amount of the aprotic solvent can be the amount conventionally used in the field for such elimination reaction, and preferably, the volume-to-mass ratio of the aprotic solvent to the chroman compound shown in the formula 6 is in the range of 4 to 15ml/g (e.g. 4ml/g, 5.4ml/g, 10ml/g and 11.8 ml/g).
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the p-toluenesulfonic acid can be used in an amount which is conventional in the field of such elimination reaction, preferably, the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is (0.5-3):1 (such as 1:1, 1.5:1 and 3:1), and more preferably, the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is (1-3): 1.
In the method for preparing the elaprine p-toluenesulfonate represented by the formula 7a, the temperature of the elimination reaction may be a temperature commonly used in the art for such elimination reaction, and the temperature of 60 to 100 ℃ (e.g., 66 ℃, 80 ℃) is particularly preferable in the present invention.
In the preparation method of the esloprine p-toluenesulfonate shown in the formula 7a, the progress of the elimination reaction can be monitored according to a detection method (such as TLC, HPLC or GC) which is conventional in the art, and is generally used as an end point of the reaction when the chroman compound shown in the formula 6 disappears, and the time of the elimination reaction is preferably 0.5 to 15 hours (such as 1 hour, 3 hours, 5 hours and 15 hours), and more preferably 0.5 to 2 hours (such as 1 hour).
In the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, after the elimination reaction is finished, part or all of the obtained product exists in the form of the elaprine p-toluenesulfonate shown in the formula 7a (as can be understood by those skilled in the art, the "part or all" is determined by the amount of p-toluenesulfonic acid, and when the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is less than an equivalent, part of the product preferably exists in the form of the elaprine p-toluenesulfonate shown in the formula 7 a).
In the preparation method of elaprine p-toluenesulfonate shown in formula 7a, the elimination reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for the elimination reaction, such as cooling to precipitate a solid, filtering, and drying. Or adding halogenated hydrocarbon solvent (such as dichloromethane), washing organic phase with water, precipitating solid, filtering, and drying.
In the invention, the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a can also comprise the following steps: in an organic solvent, under the action of a reducing reagent, carrying out a reduction reaction on a chromanone compound shown in a formula 5 and/or a salt of the chromanone compound shown in the formula 5 to obtain a chromane compound shown in a formula 6;
the reducing reagent is sodium borohydride and/or potassium borohydride;
Figure BDA0002276982640000051
in the preparation method of the chromane compound shown in the formula 6, the salt of the chromane compound shown in the formula 5 is formed by the chromane compound shown in the formula 5 and acid in a molar ratio of 1:1, and the acid can be organic acid or inorganic acid which is conventional in the field and can form salt. The acid is particularly preferably acetic acid and/or propionic acid, and further preferably acetic acid.
In the preparation method of the chroman compound shown in the formula 6, the organic solvent can be a solvent commonly used in the reduction reaction in the field, and methanol and/or ethanol are particularly preferred, and methanol is further preferred.
In the preparation method of the chromane compound shown in the formula 6, the amount of the organic solvent can be the amount conventionally used in the reduction reaction in the field, and preferably, the volume-to-mass ratio of the organic solvent to the chromanone compound shown in the formula 5 and/or the salt of the chromanone compound shown in the formula 5 is 5-25ml/g (for example, 19.1ml/g, 20 ml/g).
In the preparation method of the chroman compound shown in the formula 6, the amount of the reducing agent can be the amount conventionally used in the reduction reaction in the field, and preferably, the molar ratio of the reducing agent to the chromanone compound shown in the formula 5 is (0.5-2):1 (e.g., 0.5:1, 0.7:1, 1.0:1, 1.3:1, 1.5: 1); the molar ratio of the reducing reagent to the salt of the chromanone compound shown in the formula 5 is (1.5-2): 1 (e.g., 1.5:1, 1.7:1, 2: 1).
In the preparation method of the chroman compound shown in the formula 6, the temperature of the reduction reaction can be the temperature commonly used in the reduction reaction in the field, and the temperature is particularly preferably-15 ℃ to 30 ℃, and further preferably 20 ℃ to 30 ℃.
In the preparation method of the chroman compounds represented by the formula 6, the progress of the reduction reaction can be monitored according to detection methods (such as TLC, HPLC or GC) which are conventional in the art, and generally used as the end point of the reaction when the raw material disappears, and the time of the reduction reaction is preferably 0.5-3 hours (such as 2.5 hours).
In the preparation method of the chroman-type compound shown in the formula 6, the reduction reaction may further include a post-treatment operation, and the post-treatment method and conditions may be conventional in the art, and in the present invention, the following post-treatment steps are preferably included: removing the solvent (e.g., evaporating to dryness), washing (e.g., washing with water), filtering, and recrystallizing (e.g., in an alcoholic solvent and water).
In the preparation method of the chroman compound shown in the formula 6, in the post-treatment of the reduction reaction, the filtering step preferably further comprises the following steps: the filter cake is refluxed (e.g. 2-4h, for example 3h) with an alcoholic solvent (e.g. methanol) and after refluxing the solvent is removed (e.g. concentrated in vacuo).
In the preparation method of the chroman compounds shown in the formula 6, in the post-treatment of the reduction reaction, the recrystallization method can be a method which is conventional in the field, and the invention particularly preferably performs recrystallization in a mixture of an alcohol solvent (such as methanol and ethanol) and water (the volume ratio of the alcohol solvent to the water is 5:1, for example).
In the invention, the preparation method of the chroman compound shown as the formula 6 can also comprise the following steps: step (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 cyclopropane formaldehyde to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown as a formula 5 and the acid;
optionally, further comprising step (2): carrying out neutralization reaction on the tetrahydropyranone substance obtained in the step (1) and alkali as shown in the specification to obtain a chromanone compound shown in a formula 5;
Figure BDA0002276982640000061
in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the organic solvent can be a conventional organic solvent in the aldol condensation-ring closure reaction in the field; preferably a nitrile solvent (e.g., acetonitrile).
In the preparation method of the chromanone compound shown in the formula 5, 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-mass ratio of the organic solvent to the phenol compound shown in the formula 4 can be 8ml/g-20ml/g (for example, 10ml/g-15 ml/g).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the alkali can be the alkali which is conventional in the aldol condensation-ring closure reaction in the field; for example, organic bases, in the present invention are preferably pyrrolidine and/or piperidine, more preferably pyrrolidine.
In the preparation method of the chromanone compound shown in the formula 5, the molar ratio of the base to the phenol compound shown in the formula 4 is preferably 1:1-2:1 (for example, 1.45:1-1.55: 1).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the acid may be an acid conventional in the art, such as an organic acid, preferably acetic acid and/or propionic acid in the present invention, more preferably acetic acid,
in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the acid to the phenol compound shown in the formula 4 can be 0.5:1-2:1 (preferably 1.0:1-2:1, more preferably 1.5:1-2: 1).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the cyclopropanecarbaldehyde to the phenol compound shown in the formula 4 is preferably 1:1-2:1 (for example, 1.2:1-1.5: 1).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the temperature of the aldol condensation-ring closure reaction can be a temperature conventional in the field of the aldol condensation-ring closure reaction, and in the present invention, the temperature is preferably 0 ℃ to 50 ℃ (for example, room temperature is 10 ℃ to 30 ℃).
In the preparation method of the chromanone compound shown in the formula 5, in the step (1), the progress of the aldol condensation-ring closure reaction can be detected by a conventional monitoring method (such as TLC, HPLC or NMR) in the art, and the disappearance or no longer reaction of the phenol compound shown in the formula 4 is generally used as a reaction end point. The reaction time may be 20 to 40 hours.
In the preparation method of the chromanone compound shown in the formula 5, the conditions of the aldol condensation-ring closure reaction can be carried out according to the conditions in the ring closure reaction in the field except the conditions specifically described above.
In one embodiment of the present invention, the tetrahydropyranone compound is composed of the chromanone compound represented by the formula 5 and the acid.
In the present invention, in the tetrahydropyranone compounds, a part or all of the chromanone compound shown in formula 5 and the acid preferably exist in the form of "a salt of the chromanone compound shown in formula 5" (as will be understood by those skilled in the art, 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 equivalent, a part of the chromanone compound shown in formula 5 and the acid preferably exist in the form of "a salt of the chromanone compound shown in formula 5"). Preferably, the salt of the benzodihydropyranone compound shown in the formula 5 is formed by the benzodihydropyranone compound shown in the formula 5 and the acid in a molar ratio of 1: 1.
In the preparation method of the chromanone compound shown in the formula 5, in the step (2), the operation and conditions of the neutralization reaction can be the operation and conditions which are conventional in the neutralization reaction in the field.
In the preparation method of the chromanone compound shown in the formula 5, in the step (2), the base can be a base which is conventional in the neutralization reaction in the field, such as an alkali metal carbonate (such as sodium carbonate and/or potassium carbonate) and/or an alkali metal bicarbonate (such as sodium bicarbonate 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 of the chromanone compound shown in the formula 5 can further comprise post-treatment, and preferably, 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 a reaction system to obtain the chromanone compound shown in the formula 5.
In the present invention, the preparation method of the chromanone compound shown in formula 5 may further include the following scheme 1 or scheme 2:
the method comprises the following steps of carrying out the following acetylamino hydrolysis reaction on a phenol compound shown as a formula 8 in an organic solvent in the presence of alkali to obtain the phenol compound shown as a formula 4;
Figure BDA0002276982640000081
the scheme 2 comprises the following steps of carrying out selective demethylation reaction on an acetophenone compound shown as a formula 3 in an organic solvent in the presence of Lewis acid to obtain a phenol compound shown as a formula 4;
in the scheme 1, the organic solvent can be an organic solvent which is conventional in the field of such an acetamido hydrolysis reaction, and the invention is preferably an alcoholic solvent, such as one or more of methanol, ethanol, and isopropanol, and more preferably methanol.
In the scheme 1, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetamido hydrolysis reaction in the field, so as not to influence the reaction; the volume mass ratio of the organic solvent to the phenol compound shown in the formula 8 is preferably 5ml/g-20ml/g (for example 10ml/g-15 ml/g).
In scheme 1, the base may be a base conventional in the hydrolysis reaction of acetylamino group of this type in the art; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.
In the above scheme 1, the molar ratio of the base to the phenol compound represented by the formula 8 is preferably 0.1:1 to 1:1 (for example, 0.1:1 to 0.5: 1).
In scheme 1, the temperature of the hydrolysis reaction of the acetamido group can be the temperature conventional in such hydrolysis reaction of acetamido group in the art, and the temperature of the present invention is preferably 60 ℃ to 82 ℃ (e.g., 65 ℃ to 70 ℃).
In the scheme 1, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is generally determined by the disappearance or no longer reaction of the phenolic compound shown in the formula 8. The reaction time may be 0.5 to 2 hours.
In scheme 1, the hydrolysis of the acetamido group can be carried out under the same conditions as those in the hydrolysis of the acetamido group in the art except as specifically described above.
In the embodiment 1, the preparation method may further include a post-treatment, and the post-treatment includes the following steps: after the acetylamino hydrolysis reaction is finished, crystallizing the reaction system (for example, in an ice bath), filtering, washing with water, and drying to obtain the phenol compound shown as the formula 4.
In scheme 2, the organic solvent can be an organic solvent conventional in such selective demethylation reactions in the art; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).
In the scheme 2, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the acetophenone compound shown in formula 3 can be 8ml/g-25ml/g (for example, 10ml/g-20 ml/g).
In the scheme 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, for example, in the form of a solution of the organic solvent (again, for example, a 1mol/L solution of boron tribromide in methylene chloride).
In the scheme 2, the molar ratio of the lewis acid to the acetophenone compound shown in the formula 3 is preferably 1:1 to 2:1 (e.g. 1.2:1 to 1.7:1, preferably 1.5: 1).
In scheme 2, the temperature of the selective demethylation reaction can be as conventional in such selective demethylation reactions in the art, and the present invention is preferably from-15 ℃ to 35 ℃ (e.g., -6 ℃ to 30 ℃).
In the scheme 2, the Lewis acid is preferably dripped (for example, at-8 ℃) into the acetyl compound shown in the formula 2 and the organic solvent.
In the scheme 2, the progress of the selective demethylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetophenone compound shown in the formula 3 is generally used as the reaction end point. The reaction time may be 2 to 5 hours.
In scheme 2, the conditions for the selective demethylation reaction, except those specifically mentioned above, can be carried out according to the conditions in the selective demethylation reaction of the type described in the art.
In the scheme 2, the preparation method can further comprise post-treatment, and the post-treatment comprises the following steps: after the selective demethylation reaction is finished, the reaction system is subjected to extraction and extinction (for example, methanol is used), concentration (for example, in vacuum) and recrystallization (for example, in ethanol) to obtain the phenol compound shown in the formula 4.
In the scheme 1, the method can further comprise a scheme A, and the scheme A can comprise the following steps: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetyl compound shown as the formula 2 as shown in the specification to obtain the phenol compound shown as the formula 8;
Figure BDA0002276982640000101
in the scheme A, the organic solvent can be an organic solvent which is conventional in the selective demethylation reaction in the field; preferably a halogenated hydrocarbon solvent (e.g., dichloromethane and/or chloroform).
In the scheme A, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the selective demethylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 can be 8ml/g-20ml/g (for example, 10ml/g-15 ml/g).
In the above-mentioned scheme 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 said organic solvent (e.g. a 1mol/L solution of boron tribromide in dichloromethane).
In the embodiment a, the molar ratio of the lewis acid to the acetyl compound shown in formula 2 may be 1:1 to 2:1 (e.g. 1.2:1 to 1.7:1, preferably 1.5: 1).
In scheme A, the temperature of the selective demethylation reaction may be that conventional in the art for such selective demethylation reactions, and the present invention is preferably from-15 ℃ to 35 ℃ (e.g., -8 ℃ to 30 ℃).
In the scheme A, the Lewis acid is preferably dripped (for example, at-8 ℃) into the acetyl compound shown in the formula 2 and the organic solvent.
In the scheme A, the progress of the selective demethylation reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetyl compound shown in the formula 2 is generally used as the reaction end point. The reaction time may be 10 to 20 hours.
In the scheme A, the conditions of the selective demethylation reaction can be performed according to the conditions in the selective demethylation reaction in the field except the conditions specifically described above.
In the scheme A, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the selective demethylation reaction is finished, the reaction system is extracted and extinguished (for example, ice water is used for extraction and extinction), the pH is adjusted to about 6 (for example, saturated sodium carbonate aqueous solution is used), and the phenol compound shown in the formula 8 can be obtained through filtration and recrystallization (for example, in isopropanol).
In the scheme 2, the method can further comprise a scheme B, and the scheme B can comprise the following steps; in an organic solvent, in the presence of alkali, performing the following acetylamino hydrolysis reaction on an acetyl compound shown as a formula 2 to obtain an acetophenone compound shown as a formula 3;
Figure BDA0002276982640000111
in the embodiment B, the organic solvent may be an organic solvent commonly used in the field of such an acetamido hydrolysis reaction, and the present invention is preferably an alcoholic solvent, such as one or more of methanol, ethanol, and isopropanol, and more preferably methanol.
In the scheme B, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetamido hydrolysis reaction in the field, so that the reaction is not influenced; the volume mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is preferably 5ml/g-15ml/g (for example 9ml/g-11 ml/g).
In the scheme B, the base can be a base which is conventional in the acetylamino hydrolysis reaction in the class of the prior art; the present invention is preferably an alkali metal carbonate, such as sodium carbonate and/or potassium carbonate.
In the embodiment B, the molar ratio of the base to the acetyl compound represented by the formula 2 is preferably 0.1:1 to 1:1 (e.g., 0.1:1 to 0.7: 1).
In the embodiment B, the temperature of the hydrolysis reaction of the acetamido group can be the temperature conventional in the field of such hydrolysis reaction of the acetamido group, and the temperature of the invention is preferably 60 ℃ to 82 ℃ (for example 65 ℃ to 70 ℃).
In the scheme B, the progress of the acetamido hydrolysis reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no longer reaction of the acetyl compound represented by the formula 2 is generally used as the reaction endpoint. The reaction time may be 0.5 to 2 hours.
In the above-mentioned embodiment B, the respective conditions of the hydrolysis reaction of the acetylamino group may be carried out according to the conditions in the hydrolysis reaction of the acetylamino group as described in the art except those specifically mentioned above.
In the scheme B, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the hydrolysis reaction of the acetamido, crystallizing the reaction system (for example, in an ice bath), filtering, washing with water, and drying to obtain the acetophenone compound shown in formula 3.
In the scheme A or the scheme B, the following scheme a or scheme B can be further included:
the scheme a comprises the following steps: in an organic solvent, under the existence of Lewis acid, carrying out acetylation reaction on trimethoprim shown in a formula 1 and an acetylation reagent shown in the following formula to obtain an acetyl compound shown in a formula 2;
Figure BDA0002276982640000121
the scheme b comprises the following steps: in an organic solvent, in the presence of Lewis acid, performing acetylation reaction on an acetamide compound shown in a formula 1a and an acetylation reagent as shown in the specification to obtain an acetyl compound shown in a formula 2;
Figure BDA0002276982640000131
in the scheme a, the organic solvent can be an organic solvent which is conventional in such acetylation reaction in the field, and the invention is preferably a halogenated hydrocarbon solvent, such as chloroform, one or more of dichloromethane and dichloroethane, and more preferably chloroform.
In the scheme a, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetylation reaction in the field, so that the reaction is not influenced; the volume-mass ratio of the organic solvent to the trimethoprim as shown in the formula 1 can be 5ml/g-15ml/g (for example, 8ml/g-10 ml/g).
In the scheme a, the acetylation reagent can be an acetylation reagent which is conventional in the acetylation reaction in the field; in the present invention, acetyl chloride and/or acetic anhydride are preferred, and acetic anhydride is more preferred.
In the embodiment a, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is preferably 3:1 to 6:1 (e.g., 4:1 to 5: 1).
In scheme a, the lewis acid may be a lewis acid conventional in this type of acetylation reaction in the art; tin tetrachloride is preferred.
In the scheme a, the molar ratio of the lewis acid to the trimethoprim shown in the formula 1 is preferably 1:1-3:1 (for example, 2:1-3: 1).
In said scheme a, the temperature of said 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 the scheme a, the progress of the acetylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the termination point of the reaction is generally determined when the trimethoprim shown in the formula 1 disappears or no longer reacts. The reaction time may be 1 to 5 hours.
In the scheme a, the acetylation reaction conditions can be performed according to the conditions in the acetylation reaction in the art except the conditions specifically described above.
In the scheme a, the method can further comprise post-treatment, wherein the post-treatment comprises the following steps: after the acetylation reaction is finished, performing extraction and quenching (for example, using ice water for extraction and quenching), liquid separation to obtain an organic phase and a water phase, washing the organic phase with water, extracting the water phase with an organic solvent (the organic solvent may be chloroform), adjusting the pH of the combined organic phase to 7-8 (for example, a saturated sodium carbonate aqueous solution), liquid separation to obtain an organic phase, washing the organic phase with water, drying the organic phase (for example, anhydrous sodium sulfate), filtering, concentrating (for example, vacuum), and recrystallizing (for example, using ethylene glycol monomethyl ether for recrystallization), so as to obtain the acetyl compound shown in the formula 2.
In the scheme b, the organic solvent can be an organic solvent which is conventional in such acetylation reaction in the field, and the invention is preferably a halogenated hydrocarbon solvent, such as chloroform, one or more of dichloromethane and dichloroethane, and more preferably chloroform.
In the scheme b, the dosage of the organic solvent can be the dosage of the conventional chemical reaction in the acetylation reaction in the field, so that the reaction is not influenced; the volume mass ratio of the organic solvent to the acetamide compound shown in the formula 1a can be 5ml/g-15ml/g (for example, 8ml/g-10 ml/g).
In the scheme b, the acetylation reagent can be an acetylation reagent which is conventional in the acetylation reaction in the field; in the present invention, acetyl chloride and/or acetic anhydride are preferred, and acetic anhydride is more preferred.
In the embodiment b, the molar ratio of the acetylating agent to the acetamide compound of formula 1a is preferably 1.5:1 to 4:1 (e.g., 2: 1).
In said scheme b, said lewis acid may be a lewis acid conventional in this type of acetylation reaction in the art; tin tetrachloride is preferred.
In the embodiment b, the molar ratio of the lewis acid to the acetamide compound represented by the formula 1a is preferably 1:1 to 3:1 (for example, 2:1 to 3: 1).
In said scheme b, the temperature of said 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 the scheme b, the progress of the acetylation reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is generally determined when the acetamide compound shown in the formula 1a disappears or does not react any more. The reaction time may be 1 to 5 hours.
In the scheme b, the acetylation reaction conditions can be performed according to the conditions in the acetylation reaction in the art except those specifically mentioned above.
In the scheme b, the method also comprises post-treatment, wherein the post-treatment comprises the following steps: after the acetylation reaction is finished, performing extraction and quenching (ice water) on a reaction system, separating 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), adjusting the pH value of the combined organic phase to 7-8 (for example, a saturated sodium carbonate aqueous solution), separating to obtain an organic phase, washing the organic phase with water, drying (for example, anhydrous sodium sulfate), filtering, concentrating (for example, vacuum), and recrystallizing (for example, using ethylene glycol monomethyl ether to recrystallize), so as to obtain the acetyl compound shown in the formula 2.
In the scheme b, the method can further comprise a scheme c, and the scheme c can comprise the following steps: in an organic solvent, under the action of an acetylation reagent, carrying out acetylation reaction on trimethoprim shown in a formula 1 to obtain an acetamide compound shown in a formula 1 a;
in the scheme c, the organic solvent can be a solvent commonly used in such acetylation reaction in the field, and toluene is particularly preferred in the invention.
In the embodiment c, the amount of the organic solvent may be the amount conventionally used in chemical reactions in the art, and preferably, the volume-to-mass ratio of the organic solvent to the trimethoprim shown in formula 1 is in the range of 5-20ml/g (e.g. 9 ml/g).
In the scheme c, the acetylation reagent can be conventional acetylation reagent in the art, and acetic anhydride and/or acetyl chloride are preferred in the invention.
In the scheme c, the amount of the acetylation reagent can be the amount conventionally used in such acetylation reactions in the art, and preferably, the molar ratio of the acetylation reagent to the trimethoprim of formula 1 is (2-5):1 (e.g. 2:1, 4:1, 5: 1).
In the scheme c, the temperature of the acetylation reaction can be the temperature commonly used in the acetylation reaction in the field, and the temperature is particularly preferably 100-110 ℃.
In the scheme c, the progress of the acetylation reaction can be monitored according to the conventional detection method in the art (such as TLC, HPLC or GC), and is generally used as the end point of the reaction when the trimethoprim shown in the formula 1 disappears, and the acetylation reaction time is preferably 1-3 hours (such as 1.5 hours).
In the embodiment c, the acetylation reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for such acetylation reaction, and in the present invention, the following post-treatment steps are preferably included: crystallizing (for example, standing the reaction system to room temperature for crystallization), filtering, and drying.
In the scheme c, in the post-treatment step of the acetylation reaction, the crystallization method and conditions may be those conventional in the art, and the present invention particularly preferably performs crystallization by standing after cooling to room temperature.
The invention also provides an application of the eplerenone p-toluenesulfonate shown in the formula 7a, wherein the application comprises a method for preparing the eplerenone shown in the formula 7 from the eplerenone p-toluenesulfonate shown in the formula 7a, and the method comprises the following steps of: under the action of alkali, performing neutralization reaction on the tosylate by the elaprine shown in the formula 7a to obtain the elaprine shown in the formula 7;
Figure BDA0002276982640000161
in the application of the esloprine p-toluenesulfonate shown in formula 7a, the method and conditions for the neutralization reaction can be those conventional in the art for such neutralization reactions. For example, the salt of elaprine p-toluenesulfonate shown in formula 7a is mixed with an aqueous solution of the base (e.g., a saturated aqueous solution of sodium carbonate).
In the application of the elaprine p-toluenesulfonate shown in the formula 7a, the base can be a base commonly used in the field for such neutralization reaction, such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like, and the invention particularly preferably adopts sodium carbonate, especially saturated sodium carbonate aqueous solution.
In the application of the esloprine p-toluenesulfonate shown in formula 7a, the neutralization reaction may further include a post-treatment operation, and the post-treatment method and conditions may be those conventional in the art for such neutralization reaction, such as filtration and drying.
In the invention, the concentrated sulfuric acid refers to a sulfuric acid aqueous solution with the mass fraction of 95-98%.
In the invention, the room temperature is 10-30 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: by using the elaprine p-toluenesulfonate shown in the formula 7a as an intermediate, the elaprine can be prepared with high purity, column chromatography is not required, and post-treatment is simple.
The preparation method of elaprine by using the elaprine intermediate provided by the invention has the advantages of more economical reagents, short route, high yield, low preparation cost and simple post-treatment, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Preparation of Compound 1a (N, N' - (5- (3,4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1(100.0g, 344.5mmol), acetic anhydride (176g, 1710.4mmol) and 900ml toluene into a reaction bottle, heating and refluxing for reaction for 1.5h, cooling to room temperature, standing for crystallization, suction filtering, drying to obtain 109.0g white solid 1a with yield of 84.5%, mp.201-203 ℃, purity of 98.72% by HPLC,1H-NMR(400MHz, CDCl3).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
Preparation of Compound 1a (N, N' - (5- (3,4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1(100.1g, 344.8mmol), acetyl chloride (98.1ml, 1379.6mmol) and 900ml toluene into a reaction bottle, heating, refluxing, stirring for 1.5h, cooling to room temperature, standing, crystallizing, filtering, drying to obtain 104.0g white solid 1a with yield of 80.6%, mp.201-203 deg.C, purity of 98.70% by HPLC,1H-NMR(400MHz, CDCl3).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
Preparation of Compound 1a (N, N' - (5- (3,4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1(100.0g, 344.5mmol), acetic anhydride (70.3g, 688.5mmol) and 900ml toluene into a reaction bottle, heating and refluxing for reaction for 1.5h, cooling to room temperature, standing for crystallization, suction filtering, drying to obtain 102.8g white solid 1a with yield of 71.7%, mp.201-203 ℃, purity of 98.62% by HPLC,1H-NMR(400MHz, CDCl3).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) diethylamide)
Figure BDA0002276982640000181
Adding the compound 1a (99.9g, 266.8mmol), acetic anhydride (55.5g, 544.4mmol) and 1000ml of dichloroethane into a reaction flask, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating, refluxing for 5h, cooling to room temperature, pouring the reaction liquid into 600ml of ice water, stirring for 20mins, separating, washing twice with 50ml of water of an organic phase, combining the water phases, extracting the water phase for 4 times with 50ml of dichloroethane, combining the organic phases, washing the organic phase with a saturated sodium carbonate solution to pH of about 7, washing the organic phase for 1 time with 50ml of water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing ethylene glycol monomethyl ether to obtain 87.2g of the compound 2 with yield of 78.5%. mp.204-206 deg.C, purity 96 by HPLC.24％；1H-NMR(400 MHz,CDCl3).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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding the compound 1a (100.0g, 267.1mmol), acetic anhydride (55.4g, 544.3mmol) and 1000ml of chloroform into a reaction bottle, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating for reflux reaction for 2h, cooling to room temperature, pouring the reaction liquid into 600ml of ice water, stirring for 20mins, separating, washing the organic phase twice with 50ml of water, combining the aqueous phase, extracting the aqueous phase 4 times with 50ml of chloroform, combining the organic phases, washing the organic phase with saturated sodium carbonate to pH of about 7, washing the organic phase 1 time with 50ml of water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing 200ml of ethylene glycol monomethyl ether to obtain 101.3g of the compound 2, wherein the yield is 91.2%. mp.204-206 ℃; the purity of the product is 96.25% by HPLC detection;1H-NMR(400MHz, CDCl3).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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding the compound 1a (100.1g, 267.4mmol), acetyl chloride (76.0ml, 1006.9mmol) and 1000ml chloroform into a reaction bottle, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating, refluxing for 1.5h, cooling to room temperature, pouring the reaction liquid into 600ml ice water, stirring for 20mins, separating, washing the organic phase twice with 50ml water, combining the water phases, washing the water phase 4 times with 50ml chloroform, combining the organic phases, washing the organic phase with saturated sodium carbonate solution to pH 7, washing the organic phase 1 time with 50ml water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing with 200ml ethylene glycol monomethyl ether to obtain 99.3g of the compound 2 with yield of 89.3%. mp.204-206 ℃; HPLC detection thereofThe purity is 96.75%;1H-NMR(400 MHz,CDCl3).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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1 (trimethoprim) (10.02g, 34.52mmol), acetic anhydride (17.06g, 167.11mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 68.36mmol) under stirring, carrying out reflux reaction for 1h, detecting the basic disappearance of raw materials by TLC, cooling to room temperature, pouring the reaction solution into 50ml ice water, stirring for 6mins, carrying out liquid separation, washing an organic phase with 5ml water for 3 times, combining aqueous phases, extracting the aqueous phases with 5ml chloroform for 3 times, combining the organic phases, adjusting the pH of a saturated sodium carbonate aqueous solution to 7-8, carrying out liquid separation, washing the organic phase with 5ml water for 1 time, drying anhydrous sodium sulfate, filtering, carrying out vacuum concentration, and recrystallizing ethylene glycol monomethyl ether to obtain 13.30g of a product, wherein the yield is 92.63%. mp.203-205 ℃; purity by HPLC was 96.72%.1H-NMR(300MHz,CDCl3)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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetyl chloride (9.80ml, 138.57mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 68.36mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction solution into 50ml ice water, stirring for 6mins, separating, washing the organic phase with 5ml water for 3 times, combining the aqueous phases, extracting the aqueous phase with 5ml chloroform for 3 times, combining the organic phases, and saturating carbonic acidAdjusting the pH of the sodium aqueous solution to 7-8, separating liquid, carrying out 1 time on a 5ml water organic phase, drying by using anhydrous sodium sulfate, filtering, carrying out vacuum concentration, and recrystallizing ethylene glycol monomethyl ether to obtain 12.98g of a product with the yield of 90.58%. mp.203-205 ℃; purity was 95.52% by HPLC.1H- NMR(300MHz,CDCl3)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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.06g, 167.11mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (5.30ml, 45.29mmol) under stirring, carrying out reflux reaction for 1h, cooling to room temperature, pouring the reaction liquid into 50ml ice water, stirring for 6mins, carrying out liquid separation, washing an organic phase for 3 times by 5ml water, combining aqueous phases, extracting the aqueous phase for 3 times by 5ml chloroform, combining the organic phases, adjusting the pH value to 7-8 by saturated sodium carbonate aqueous solution, carrying out liquid separation, and carrying out organic phase 1 time by 5ml water, drying by anhydrous sodium sulfate, filtering, carrying out vacuum concentration, and recrystallizing ethylene glycol monomethyl ether to obtain 12.08g of a product, wherein the yield is 84.30%. mp.203-205 ℃; purity was 95.61% by HPLC.1H-NMR(300 MHz,CDCl3)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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.04g, 166.90mmol) and 100ml chloroform into a 250ml reaction bottle, adding tin tetrachloride (12.00ml, 68.36mmol) under stirring, refluxing for 1h, cooling to room temperature, pouring the reaction solution into 50ml ice water, stirring for 6mins, separating, washing the organic phase with 5ml water for 3 times, combining the aqueous phases, extracting the aqueous phase with 5ml chloroform for 3 times, combining the organic phase and saturated carbonAdjusting the pH of the sodium acid aqueous solution to 7-8, separating liquid, carrying out 1 time on a 5ml water organic phase, drying by using anhydrous sodium sulfate, filtering, carrying out vacuum concentration, and recrystallizing ethylene glycol monomethyl ether to obtain 10.96g of a product with the yield of 76.48%. mp.203-205 ℃; purity by HPLC was 95.67%.1H- NMR(300MHz,CDCl3)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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding compound 1 (trimethoprim) (10.00g, 34.45mmol), acetic anhydride (17.03g, 166.80mmol) and 100ml dichloromethane into a 250ml reaction bottle, adding tin tetrachloride (8.00ml, 102.54mmol) under stirring, carrying out reflux reaction for 1h, cooling to room temperature, pouring the reaction liquid into 50ml ice water, stirring for 6mins, carrying out liquid separation, washing the organic phase for 3 times by 5ml water, combining the water phases, extracting the water phase for 3 times by 5ml chloroform, combining the organic phases, adjusting the pH value to 7-8 by saturated sodium carbonate aqueous solution, carrying out liquid separation, extracting the organic phase for 1 time by 5ml water, drying by anhydrous sodium sulfate, filtering, carrying out vacuum concentration, and recrystallizing ethylene glycol monomethyl ether to obtain 12.93g of a product with the yield of 90.23%. mp.203-205 ℃; purity was 95.72% by HPLC.1H- NMR(300MHz,CDCl3)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)
Figure BDA0002276982640000211
Adding compound 2(65.00g, 156.25mmol), potassium carbonate (15.090g, 109.35mmol) and 600ml methanol into a reaction bottle, stirring and refluxing for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly and precipitatingCrystallizing, filtering, washing with water, and drying to obtain 47.00g of white solid compound 3 with yield of 90.5% and mp.121-123 deg.C; purity by HPLC was 97.22%.1H-NMR(400MHz,CDCl3)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
Preparation of compound 3(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2,3, 4-trimethoxyphenyl) ethanone)
Adding the compound 2(65.01g, 156.49mmol), potassium carbonate (15.091g, 109.36mmol) and 600ml of ethanol into a reaction bottle, heating and refluxing for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly, crystallizing, filtering, washing with water, and drying to obtain 45.00g of a white solid compound 3, wherein the yield is 86.7 percent and the mp.121-123 ℃; purity was 97.32% by HPLC.1H-NMR(400MHz,CDCl3)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)
Figure BDA0002276982640000221
Adding the compound 3(30.00g, 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ in a ice salt bath, slowly dropwise adding 135.5ml of boron tribromide dichloromethane solution of 1mol/L, and raising the temperature to room temperature after the addition to react for 5 h. Cooling to 0 deg.C, quenching with 300ml methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 25.50g white solid compound 4 with yield 88.74%. mp.217 ℃; purity was 96.10% by HPLC.1H-NMR(300MHz, CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
A500 ml reaction flask was charged with compound 3(20.01g, 60.27mmol) and 200ml of 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 thereto, and after completion of the addition, the reaction was allowed to warm to room temperature for 5 hours. Cooling to 0 deg.c, quenching with methanol, stirring for 1 hr, vacuum concentrating the dried solvent, and re-crystallizing with ethanol to obtain 16.02g of white solid compound 4 in 83.58% yield. mp.217 ℃; the purity was 96.08% by HPLC.1H-NMR(400MHz,CDCl3) 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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
A250 ml reaction flask is added with the compound 3(10.02g, 30.18mmol) and 100ml chloroform, cooled to-6 ℃ by an ice salt bath, added with 45.3ml of 1mol/L boron trichloride dichloromethane solution, and heated to room temperature for reaction for 5 h. Cooling to 0 deg.c, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.88g of compound 4 as a white solid with a yield of 82.10%. mp.217 ℃; purity was 96.13% by HPLC.1H-NMR(400MHz,CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
The compound 3(10.11g, 30.45mmol) and 200ml of dichloromethane are added into a 500ml reaction bottle, the temperature of an ice salt bath is reduced to-6 ℃, 45.7ml of 1mol/L boron trichloride dichloromethane solution is added dropwise, and the temperature is raised to the room temperature for reaction for 5h after the addition is finished. Cooling to 0 deg.c, quenching with methanol, stirring for 1 hr, vacuum concentrating the dried solvent, and re-crystallizing with ethanol to obtain 7.96g of white solid compound 4 in 82.20% yield. mp.217 ℃;the purity was 96.09% by HPLC.1H-NMR(400MHz,CDCl3) 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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
Adding the compound 3(30.00g, 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ in a ice salt bath, slowly dropwise adding 108.5ml of boron tribromide dichloromethane solution of 1mol/L, and heating to room temperature after the addition is finished to react for 5 h. Cooling to 0 deg.c, quenching in 300ml methanol, stirring for 1 hr, vacuum concentrating the dry solvent, and re-crystallizing in ethanol to obtain 21.73g white solid compound 4 in 75.62% yield. mp.217 ℃; purity by HPLC was 96.19%.1H-NMR(300MHz, CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
Adding the compound 3(30.00g, 90.36mmol) and 600ml of dichloromethane into a 1L reaction bottle, cooling to-6 ℃ in a ice salt bath, slowly dropwise adding 153.5ml of boron tribromide dichloromethane solution of 1mol/L, and raising the temperature to room temperature after the addition to react for 5 h. Cooling to 0 deg.c, quenching in 300ml methanol, stirring for 1 hr, vacuum concentrating the dry solvent, and re-crystallizing in ethanol to obtain 24.73g white solid compound 4 in 86.06% yield. mp.217 ℃; purity was 96.10% by HPLC.1H-NMR(300MHz, CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
A250 ml reaction flask is added with the compound 3(10.00g, 30.12mmol) and 100ml chloroform, cooled to-6 ℃ by an ice salt bath, added with 51.5ml of 1mol/L boron trichloride dichloromethane solution, and heated to room temperature for reaction for 5 h. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.83g of compound 4 as a white solid with a yield of 81.75%. mp.217 ℃; purity by HPLC was 96.25%.1H-NMR(400MHz,CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
A250 ml reaction flask is added with the compound 3(10.00g, 30.12mmol) and 100ml chloroform, cooled to-6 ℃ by an ice salt bath, added with 46.5ml of 1mol/L boron trichloride dichloromethane solution, and heated to room temperature for reaction for 5 h. Cooling to 0 ℃, quenching with methanol, stirring for 1h, vacuum concentrating the dry solvent, and recrystallizing with ethanol to obtain 7.58g of compound 4 as a white solid with a yield of 79.14%. mp.217 ℃; purity was 96.21% by HPLC.1H-NMR(400MHz,CDCl3)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) diethylamide)
Figure BDA0002276982640000251
To the reaction flask were added compound 2(10.005g,24.050mmol) and 100ml dichloromethane and the ice salt bath was cooled to-8 ℃. A solution of boron tribromide in dichloromethane (36ml,36.000mmol) was slowly added dropwise, and after 1h of reaction, the temperature was raised to room temperature and the reaction was allowed to proceed for 19 h. The reaction solution was poured into 90ml of ice water and saturated sodium carbonate waterThe solution was adjusted to pH 6, filtered and the cake recrystallized from isopropanol to yield 8.730g of compound 8, 90.336%. mp 203-; purity was 97.53% by HPLC.1H-NMR(400MHz,CDCl3)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
Preparation of Compound 8(N, N' - (5- (2-acetyl-3-hydroxy-4, 5-dimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
To the reaction flask were added compound 2(10.000g,24.038mmol) and 100ml dichloromethane and the ice salt bath was cooled to-8 ℃. A solution of boron trichloride in methylene chloride (36ml,36.000mmol) was slowly added dropwise thereto, and after 1 hour of reaction, the temperature was raised to room temperature and the reaction was carried out for 15 hours. Pouring the reaction solution into 90ml of ice water, adjusting the pH value of the saturated sodium carbonate aqueous solution to about 6, and performing suction filtration. Recrystallization of the cake from isopropanol afforded 8.700g of compound 8, yield 90.023%. mp.203-205 ℃; purity by HPLC was 97.49%.1H-NMR(400MHz,CDCl3)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
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
Figure BDA0002276982640000261
Adding the compound 8(5.000g, 12.438mmol), potassium carbonate (0.172g, 1.244mmol) and 50ml of methanol into a reaction bottle, heating and refluxing for 1.5h, stopping heating, cooling to room temperature, placing in an ice bath, stirring slowly, crystallizing, filtering, washing with water, and drying to obtain 3.901g of a white solid compound 4, wherein the yield is 98.63%, and the temperature is mp.121-123 ℃. Purity by HPLC was 98.97%.1H-NMR(400MHz,CDCl3)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-dimethoxychroman-4-one)
Figure BDA0002276982640000262
A100 ml reaction flask was charged with compound 4(4.01g, 12.58mmol), cyclopropanecarboxaldehyde (1.07g, 15.29mmol) and 40ml acetonitrile, and pyrrolidine (1.34g, 18.87mol) and acetic acid (1.13g, 18.83 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered with suction and dried to give 4.57g of an acetate salt of compound 5 as a white-like solid with an yield of 84.28% and mp168-171 ℃.1H-NMR(400MHz,CDCl3)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]+).
Acetate salt of compound 5 (4.57g, 10.63mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.93g of off-white solid in 84.23% yield. mp.152-155 ℃; purity was 96.13% by HPLC.1H-NMR(400MHz,CDCl3)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
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 250ml reaction flask were added compound 4(11.00g, 34.59mmol), cyclopropanecarboxaldehyde (3.63g, 51.86mmol) and 110ml acetonitrile, and pyrrolidine (3.68g, 51.83mmol) and propionic acid (2.557g, 34.56mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, and dried to give the propionate salt of compound 5, which was stirred in a saturated sodium carbonate solution for 1h and dried to give 11.11g of compound 5, yield 86.81%. mp.152-155 ℃; purity by HPLC was 96.15%.
Example 27
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 100ml reaction flask, compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00mmol) and 40ml acetonitrile were added, and piperidine (1.55g, 18.22mmol) and acetic acid (1.12g, 18.67 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered with suction, and dried to give 4.68g of an acetate salt of compound 5 as a white-like solid with an yield of 86.52%.
Acetate salt of compound 5 (4.68g, 10.88mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 4.02g of off-white solid with a yield of 86.38%. mp.152-155 ℃; purity by HPLC was 96.17%.
Example 28
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 100ml reaction flask were added compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.08g, 15.429mmol) and 40ml acetonitrile, and while stirring, piperidine (1.57g, 18.44mmol) and propionic acid (1.38g, 18.67 mmol) were slowly added dropwise, stirred at room temperature for 36h, filtered to give the propionate salt of compound 5, which was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.98g of an off-white solid with a yield of 85.52%. mp.152-155 ℃; the purity was 96.11% by HPLC.
Example 29
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00mmol) and 40ml acetonitrile were added to a 100ml reaction flask, and pyrrolidine (1.35g, 19.01mol) and acetic acid (1.51g, 25.17 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered with suction, and dried to give 4.57g of acetate as a white-like solid compound 5 with an yield of 84.28%.
Acetate salt of compound 5 (4.54g, 10.56mmol) was stirred in saturated sodium carbonate solution for 1h, filtered and dried to give 3.91g off-white solid in 84.01% yield. mp.152-155 ℃; purity was 96.11% by HPLC.
Example 30
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 100ml reaction flask were added compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00mmol) and 40ml acetonitrile, and pyrrolidine (1.36g, 19.15mol) and acetic acid (0.75g, 12.50 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered with suction, stirred in saturated sodium carbonate solution for 1h, filtered, and dried to give 3.23 g of an off-white solid in a total yield of 78.5% (based on compound 4, 12.58 mmol). mp.152-155 ℃; purity by HPLC was 96.25%.
Example 31
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 100ml reaction flask were added compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00mmol) and 40ml acetonitrile, and pyrrolidine (1.34g, 18.87mol) and acetic acid (0.38g, 6.33 mmol) were slowly added dropwise with stirring, stirred at room temperature for 36h, filtered, dried, stirred in saturated sodium carbonate solution for 1h, filtered, dried, and recrystallized from ethanol to give 2.82g of an off-white solid with a yield of 60.59%. mp.152-155 ℃; purity was 96.01% by HPLC.
Example 32
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Figure BDA0002276982640000291
Adding compound 5(4.00g, 10.81mmol) and 80ml methanol into a reaction bottle, cooling to 4 deg.C in ice bath, adding sodium borohydride (0.21g, 5.56mmol), reacting at room temperature for 2.5h, evaporating methanol, adding 40ml water, stirring for 10mins, filtering, adding A into filter cakeThe alcohol was refluxed for 3h, concentrated in vacuo, and recrystallized from ethanol and water (ethanol to water volume ratio 5:1) to give 3.88g of compound 6 as a white solid with a yield of 96.48%. mp.211-213 deg.C; the purity of the product is 99.23% by HPLC detection;1H- 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
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding the compound 5(4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.40g, 10.58mmol), reacting at room temperature for 2.5h, evaporating the methanol to dryness, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, and recrystallizing with ethanol and water to obtain 3.90g of a white solid compound 6 with the yield of 96.98%. mp.211-213 deg.C; the purity was 99.21% by HPLC.
Example 34
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding the compound 5(4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.29g, 7.67mmol), reacting at room temperature for 2.5h, evaporating the methanol to dryness, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, vacuum-concentrating, and recrystallizing ethanol and water to obtain 3.89g of a white solid compound 6 with the yield of 96.73%. mp.211-213 deg.C; the purity was 99.25% by HPLC.
Example 35
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Figure BDA0002276982640000301
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.53g, 14.02mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing with ethanol and water to obtain 3.18g of a white solid compound 6 with the yield of 91.90%. mp.211-213 deg.C; the purity was 99.19% by HPLC.
Example 36
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.70g, 18.52mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 3.20g of a white solid compound 6 with the yield of 92.47%. mp.211-213 deg.C; the purity was 99.23% by HPLC.
Example 37
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding acetate (4.00g, 9.30mmol) of the compound 5 and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.60g, 15.87mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing with ethanol and water to obtain 3.17g of a white solid compound 6 with the yield of 91.61%. mp.211-213 deg.C; the purity was 99.27% by HPLC.
Example 38
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding the compound 5(7.85g, 18.26mmol) and 150ml of ethanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding sodium borohydride (0.69g, 26.46mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 70ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 6.71g of a white solid compound 6 with the yield of 85.02%. mp.211-213 deg.C; the purity was 99.24% by HPLC.
Example 39
Preparation of compound 6 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-ol)
Adding the compound 5(4.00g, 10.81mmol) and 80ml of methanol into a reaction bottle, cooling to 4 ℃ in an ice bath, adding potassium borohydride (0.76g, 14.09mmol), reacting at room temperature for 2.5h, concentrating in vacuum, adding 40ml of water, stirring for 10mins, filtering, adding methanol into a filter cake, refluxing for 3h, concentrating in vacuum, and recrystallizing ethanol and water to obtain 3.78g of a white solid compound 6 with the yield of 93.99%. mp.211-213 deg.C; 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)
Figure BDA0002276982640000311
Adding compound 6(2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml tetrahydrofuran into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.54g, 8.10mmol) under stirring, heating and refluxing for 1h, detecting by TLC that no raw material is remained, cooling to room temperature, precipitating a large amount of white solid, filtering, and drying to obtain 2.54g of p-toluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 89.27%, and mp.208 ℃; the purity of the product is 99.91% by HPLC detection;1H- NMR(400MHz,CDCl3).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 (2.54g, 4.83mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to give 1.71g of the compound 7 as a white solid in a total yield of 89.40%. mp.215 ℃; HPLC detection thereofThe purity is 99.96%;1H-NMR(400MHz,CDCl3).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
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding a compound 6(2.00g, 5.38mmol, HPLC purity of 99.23%) and 8ml of dimethyl sulfoxide into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.54g, 8.10mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that basically no raw material is left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, precipitating a large amount of white solid from a dichloromethane layer, filtering, and drying to obtain 2.53g of p-toluenesulfonic acid salt of a white solid compound 7, wherein the yield is 89.36%, and mp.208 ℃; HPLC purity 99.92%.
P-toluenesulfonate (2.53g, 4.81mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to obtain 1.70g of a white solid compound 7 with a total yield of 89.32%. mp.215 ℃; the purity was 99.95% by HPLC.
Example 42
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding a compound 6(2.00g, 5.38mmol, HPLC purity of 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.55g, 8.15mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, performing dichloromethane chromatography to obtain a large amount of white solid, filtering, and drying to obtain 2.50g of p-toluenesulfonic acid salt of a white solid compound 7, wherein the yield is 88.30%, and mp.208 ℃; HPLC purity 99.94%.
P-toluenesulfonate of compound 7 (2.50g, 4.75mmol) was stirred in a saturated sodium carbonate solution for 1h, filtered off with suction 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
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of acetone into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.53g, 8.04mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, precipitating a large amount of white solid from a dichloromethane layer, filtering, and drying to obtain 2.52g of p-toluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 89.01%, and mp.208 ℃; HPLC purity 99.95%.
P-toluenesulfonate (2.52g, 4.79mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to obtain 1.70g of a white solid compound 7 with a total yield of 89.32%. mp.215 ℃; the purity was 99.97% by HPLC.
Example 44
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction bottle, adding p-toluenesulfonic acid monohydrate (1.53g, 8.04mmol) under stirring, reacting at 80 ℃ for 1h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, washing a dichloromethane phase for 5 times, performing dichloromethane chromatography to obtain a large amount of white solid, filtering, and drying to obtain 2.49g of p-toluenesulfonic acid salt of compound 7 as a white solid, wherein the yield is 87.51%, and mp.208 ℃; HPLC purity 99.96%.
P-toluenesulfonate (2.49g, 4.73mmol) of the compound 7 was stirred in a saturated sodium carbonate solution for 1 hour, suction filtered, and dried to give 1.67g of a white solid compound 7 with a total yield of 87.30%. mp.215 ℃; the purity was 99.96% by HPLC.
Comparative example 1
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Compound 1a (2.576g, 6.888mmol), acetic anhydride (3.510g, 34.438mmol) and 20ml of chloroform were charged into a 50ml reaction flask, and aluminum trichloride (2.230g, 16.724mmol) was slowly added thereto under stirring, followed by reaction under reflux for 10 hours, whereby the desired product was not produced.
Comparative example 2
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Adding the compound 1a (100.0g, 267.1mmol), acetic anhydride (55.4g, 544.3mmol) and 1000ml of dichloromethane into a reaction bottle, slowly adding tin tetrachloride (62ml, 537.8mmol) under stirring, heating for reflux reaction for 3h, cooling to room temperature, pouring the reaction liquid into 600ml of ice water, stirring for 20mins, separating, washing the organic phase twice with 50ml of water, combining the aqueous phases, washing the organic phase 4 times with 50ml of dichloromethane, combining the organic phases, washing the organic phase with saturated sodium carbonate solution to pH of about 7, washing the organic phase 1 time with 50ml of water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing 200ml of ethylene glycol monomethyl ether to obtain 60.2g of the compound 2, wherein the yield is 54.2%. mp.204-206 ℃; the purity of the product is 96.05 percent by HPLC detection;1H-NMR (400MHz,CDCl3).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
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
A50 ml reaction vessel was charged with trimethoprim (2.000g, 6.889mmol), acetic anhydride (3.516g, 34.440mmol) and 20ml chloroform, and aluminum trichloride (2.235g, 16.762mmol) was slowly added thereto under stirring, and the reaction was refluxed for 10 hours until no target product was produced.
Comparative example 4
Preparation of compound 2(N, N' - (5- (2-acetyl-3, 4, 5-trimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
A50 ml reaction flask is added with the compound 1 trimethoprim (2.000g, 6.889mmol), acetic anhydride (3.502g, 34.303mmol) and 20ml chloroform, stirred and slowly added with ferric trichloride (2.234g, 13.773mmol), heated for reflux reaction for 12h, cooled to room temperature, and no target product is generated.
Comparative example 5
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
Compound 3(3.000g, 9.036mmol) and 60ml of methylene chloride were added to a 100ml reaction flask, and aluminum trichloride (2.410g, 18.077mmol) was slowly added with stirring, and the mixture was heated under reflux for 10 hours, whereby the desired compound was not produced.
Comparative example 6
Preparation of compound 4(1- (6- ((2, 4-diaminopyrimidin-5-yl) methyl) -2-hydroxy-3, 4-dimethoxyphenyl) ethanone)
A100 ml reaction flask was charged with Compound 3(4.000g, 12.048mmol), 20ml acetic acid and 10ml 48% hydrobromic acid, heated at reflux for 1h, and TLC checked that the starting material was substantially reacted completely but no target compound was formed.
Comparative example 7
Preparation of Compound 8(N, N' - (5- (2-acetyl-3-hydroxy-4, 5-dimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
Compound 2(4.000g, 9.615mmol), 60ml of methylene chloride and aluminum trichloride (2.412g, 18.089mmol) were charged into a 100ml reaction flask, and the mixture was heated under reflux for 10 hours to react, whereby the desired compound was not produced.
Comparative example 8
Preparation of Compound 8(N, N' - (5- (2-acetyl-3-hydroxy-4, 5-dimethoxybenzyl) pyrimidine-2, 4-diyl) diethylamide)
A100 ml reaction flask was charged with Compound 2(4.000g, 9.615mmol), 20ml acetic acid and 10ml 48% hydrobromic acid, and heated under reflux for 2h, and TLC checked that the starting material was substantially reacted completely but no target compound was formed.
Comparative example 9
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Into a 100ml reaction flaskCompound 4(4.000g, 12.579mmol), cyclopropanecarboxaldehyde (1.071g, 15.300mmol) and 40ml acetonitrile were added, pyrrolidine (1.38g, 19.437mmol) 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, 3.9% yield. mp.152-155 deg.C.1H-NMR(400 MHz,CDCl3)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
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Compound 4(4.011g, 12.613mmol), cyclopropanecarboxaldehyde (1.072g, 15.314mmol) and 40ml acetonitrile were added to a 100ml reaction flask, piperidine (1.607g, 18.875 mmol) was slowly added dropwise, stirred at room temperature for 48h, the dry solvent was concentrated in vacuo, and purified by thin layer column chromatography to give 0.105g of compound 5 with 2.25% yield. mp.152-155 deg.C.1H-NMR(400MHz,CDCl3)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
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Compound 4(4.000g, 12.579mmol), cyclopropanecarboxaldehyde (1.082g, 15.457mmol) and 40ml acetonitrile were added to a 100ml reaction flask, pyrrolidine (1.377g, 18.841mol) was slowly added dropwise, stirred at room temperature for 50h, concentrated in vacuo, and purified by thin layer column chromatography to give 0.175g of compound 5, 3.76% yield. mp.152-155 deg.C.1H-NMR(400 MHz,CDCl3)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
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Compound 4(4.000g, 12.579mmol), cyclopropanecarboxaldehyde (1.070g, 15.286mmol), 40ml of methanol and potassium hydroxide (1.060g, 18.687mol) were charged into a 100ml reaction flask, and the mixture was heated under reflux for 10 hours, whereby the objective compound 5 was not produced.
Comparative example 13
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
A100 ml reaction flask was charged with compound 4(4.001g, 12.582mmol), cyclopropanecarbaldehyde (1.072g, 15.314mmol), 40ml tetrahydrofuran and potassium tert-butoxide (2.090g, 18.629mol), and the reaction was heated under reflux for 8 hours, whereby the objective compound 5 was not produced.
Comparative example 14
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
Compound 4(4.018g, 12.635mmol), cyclopropanecarboxaldehyde (1.082g, 15.457mmol) and 40ml of isopropanol were added to a 100ml reaction flask, pyrrolidine (1.347g, 18.972 mmol) was slowly added dropwise, stirred at room temperature for 36h, the dry solvent was concentrated in vacuo, and purified by thin layer column chromatography to give 0.598g of compound 5 with a yield of 15.0%. mp.152-155 deg.C.1H-NMR(400MHz,CDCl3)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
Preparation of compound 5 (2-cyclopropyl-5- ((2, 4-diaminopyrimidin-5-yl) methyl) -7, 8-dimethoxychroman-4-one)
To a 100ml reaction flask were added compound 4(4.00g, 12.58mmol), cyclopropanecarboxaldehyde (1.05g, 15.00mmol) and 40ml acetonitrile, and pyrrolidine (1.35g, 19.0 mmol) was slowly added dropwise with stirring1mol) of the raw materials are stirred for 36 hours at room temperature, filtered, dried and recrystallized by ethanol to obtain 2.15g of off-white solid with the yield of 46.20 percent. mp.152-155 ℃; purity was 96.63% by HPLC.1H-NMR(400MHz,CDCl3)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-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Compound 6(2.00g, 5.38mmol, HPLC purity 99.23%), 20ml of methanol and p-toluenesulfonic acid monohydrate (1.53g, 8.04mmol) were added to a reaction flask, and after stirring the reaction at room temperature for 0.5h, the starting material was substantially disappeared by TLC, but no target compound was produced. Methanol was concentrated off in vacuo, 20ml of saturated aqueous sodium carbonate solution was added to adjust the pH to 9, 10ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, dichloromethane was concentrated off in vacuo, and the crude product was recrystallized from a solvent in which isopropanol was mixed with water (isopropanol: water ═ 2:1) to give 1.75g of the alcoholic hydroxymethylated compound of compound 6 (5- ((2-cyclopropyl-4, 7, 8-trimethoxychromen-5-yl) methyl) pyrimidine-2, 4-diamine) in 84.3% yield.
Figure BDA0002276982640000381
mp.237-240℃；1H-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
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
After compound 6(2.00g, 5.38mmol, HPLC purity 99.23%), 20ml of toluene and 3.07g, 26.9mmol of trifluoroacetic acid were added to the reaction flask, and the reaction was stirred under reflux for 2 hours, the starting material was almost disappeared by TLC, but no target compound was produced.
Comparative example 18
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
After compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of dilute sulfuric acid (2mol/L) were added to the reaction flask and stirred at room temperature for 2h, the starting material was substantially disappeared by TLC, but no target product was formed.
Comparative example 19
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Compound 6(2.00g, 5.38mmol, HPLC purity 99.23%), 20ml of methanol and p-toluenesulfonic acid monohydrate (1.54g, 8.10mmol) were charged into a reaction flask, and after heating under reflux and stirring for 0.5h, the starting material was substantially disappeared by TLC, but no target compound was produced. Methanol was concentrated off in vacuo, 20ml of saturated aqueous sodium carbonate solution was added to adjust the pH to 9, 10ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, dichloromethane was concentrated off in vacuo, and the crude product was recrystallized from a solvent in which isopropanol was mixed with water (isopropanol: water ═ 2:1) to give 1.80g of an alcoholic hydroxymethylated compound of compound 6 (5- ((2-cyclopropyl-4, 7, 8-trimethoxychromen-5-yl) methyl) pyrimidine-2, 4-diamine) in 86.7% yield.
Figure BDA0002276982640000391
mp.237-240℃；1H-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
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
After compound 6(2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dilute sulfuric acid (2mol/L) were added to the reaction flask and the reaction was stirred under reflux for 1 hour, the starting material was substantially disappeared by TLC, but no target product was formed.
Comparative example 21
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(1.70g, 4.57mmol, HPLC purity 99.23%) and 7ml of dimethyl sulfoxide into a reaction bottle, adding trifluoroacetic acid (1.56g, 13.68mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase for 5 times with water, drying with anhydrous sodium sulfate, concentrating in vacuum, recrystallizing with ethanol, and drying to obtain 1.39g of compound 7, wherein the yield is 85.92%. mp.215 ℃; purity by HPLC was 98.96%.
Comparative example 22
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding trifluoroacetic acid (1.84g, 16.14mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase for 5 times with water, drying with anhydrous sodium sulfate, concentrating in vacuum, recrystallizing with ethanol, and drying to obtain 1.65g of compound 7, wherein the yield is 86.17%. mp.215 ℃; purity by HPLC was 98.95%.
Comparative example 23
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of acetone into a reaction bottle, adding trifluoroacetic acid (1.83g, 16.05mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase for 5 times, drying with anhydrous sodium sulfate, concentrating under vacuum, recrystallizing with ethanol, and drying to obtain 1.67g of compound 7 with yield of 87.5%. mp.215 ℃; purity by HPLC was 98.97%.
Comparative example 24
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.01g, 5.40mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction bottle, adding trifluoroacetic acid (1.84g, 16.14mmol) under stirring, reacting at 80 ℃ for 5h, detecting by TLC that no raw material is basically left, cooling to room temperature, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, washing the organic phase for 5 times with water, drying with anhydrous sodium sulfate, concentrating in vacuum, recrystallizing with ethanol, and drying to obtain 1.69g of compound 7, wherein the yield is 88.8%. mp.215 ℃; purity was 98.99% by HPLC.
Comparative example 25
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(1.69g, 4.54mmol, HPLC purity 99.23%) and 20ml of tetrahydrofuran into a reaction bottle, adding trifluoroacetic acid (1.56g, 13.68mmol) under stirring, heating and refluxing for 15h, detecting by TLC that no raw material is basically left, adding dichloromethane after evaporating tetrahydrofuran, adjusting the pH of an organic phase to 9 by using a saturated sodium carbonate solution, separating, extracting an aqueous phase by using dichloromethane for 3 times, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating in vacuum, recrystallizing by using ethanol, and drying to obtain 1.43g of compound 7, wherein the yield is 88.44%. mp.215 ℃; purity was 98.89% by HPLC.
Comparative example 26
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding a mixed solution of compound 6(2.21g, 5.94mmol, HPLC purity of 99.23%) and 12ml of tetrahydrofuran and 4ml of dimethyl sulfoxide into a reaction flask, adding methanesulfonic acid (0.856g, 8.91mmol) under stirring, heating and refluxing for 3h, reducing the temperature to room temperature when TLC has no raw material, vacuum-concentrating to remove tetrahydrofuran, adding dichloromethane, adjusting pH to 9 with saturated sodium carbonate solution, demixing, washing dichloromethane phase for 3 times, evaporating to remove solvent, recrystallizing with ethanol, vacuum-filtering, and vacuum-concentrating to obtain 1.52g of white solid compound 7 with yield of 72.28%. mp.215 ℃; purity was 98.93% by HPLC.
Comparative example 27
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml tetrahydrofuran into a reaction bottle, adding concentrated sulfuric acid (0.53g, 5.41mmol) under stirring, heating and refluxing for 3h, cooling to room temperature, performing suction filtration, drying to obtain sulfate of compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1h, performing suction filtration, and drying to obtain 1.72g of white solid compound 7 with the total yield of 90.37%. mp.215 ℃; purity by HPLC was 98.90%.
Comparative example 28
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 8ml of dimethyl sulfoxide into a reaction bottle, adding concentrated sulfuric acid (0.54g, 5.50mmol) under stirring, heating and refluxing for 3 hours, reducing the temperature to room temperature when TLC basically has no raw materials, adding dichloromethane, adjusting the pH of an organic phase to 9 by using a saturated sodium carbonate solution, separating, extracting dichloromethane from an aqueous phase for 3 times, combining the organic phases, washing the organic phase for 5 times by using water, drying by using anhydrous sodium sulfate, filtering, vacuum concentrating, recrystallizing by using ethanol, carrying out suction filtration, and drying to obtain 1.75g of compound 7, wherein the yield is 91.95%. mp.215 ℃; purity was 98.98% by HPLC.
Comparative example 29
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml of methyltetrahydrofuran into a reaction bottle, adding concentrated sulfuric acid (0.54g, 5.51mmol) under stirring, heating and refluxing for reaction for 3h, cooling to room temperature, performing suction filtration and drying to obtain sulfate of compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1h, performing suction filtration and drying to obtain 1.71g of white solid compound 7, wherein the total yield is 89.85%. mp.215 ℃; purity by HPLC was 98.92%.
Comparative example 30
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(2.00g, 5.38mmol, HPLC purity 99.23%) and 20ml acetone into a reaction bottle, adding concentrated sulfuric acid (0.55g, 5.61mmol) while stirring, heating and refluxing for reaction for 3h, cooling to room temperature, performing suction filtration and drying to obtain sulfate of compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1h, performing suction filtration and drying to obtain 1.72g of white solid compound 7, wherein the total yield is 90.37%. mp.215 ℃; purity by HPLC was 98.95%.
Comparative example 31
Preparation of compound 7(5- [ (2-cyclopropyl-7, 8-dimethoxy-2H-1-benzopyran-5-yl) methyl ] -2, 4-pyrimidine-diamine)
Adding compound 6(1.71g, 4.60mmol, HPLC purity 99.23%) and 20ml of dimethylformamide into a reaction bottle, adding concentrated sulfuric acid (0.48g, 4.90mmol) under stirring, heating and refluxing for reaction for 3h, cooling to room temperature, performing suction filtration and drying to obtain sulfate of compound 7, stirring a filter cake in a saturated sodium carbonate solution for 1h, performing suction filtration and drying to obtain 1.46g of white solid compound 7, wherein the total yield is 89.72%. mp.215 ℃; purity by HPLC was 98.97%.
Comparative example 32
Under nitrogen protection, compound 1b (2.000g, 4.646mmol), 10ml of DCM and acetic anhydride (1.513g, 14.818mmol) were added to a reaction flask, followed by slow dropwise addition (2.7ml, 23.072mmol) of stannic chloride under ice bath. After stirring at room temperature for 18 hours, no compound 2a was formed.
On the basis of the failure to obtain the compound 2a, the target compound cannot be prepared by continuously referring to the reaction route of the invention.

Claims (18)

1. An elaprine p-toluenesulfonate salt as shown in formula 7a,
Figure FDA0002276982630000011
2. a preparation method of elaprine p-toluenesulfonate shown in a formula 7a is characterized by comprising the following steps of: in an aprotic solvent, under the action of p-toluenesulfonic acid, carrying out elimination reaction on a chroman compound shown as a formula 6 to obtain elaprine p-toluenesulfonic acid shown as a formula 7 a;
the aprotic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide and dimethyl sulfoxide;
Figure FDA0002276982630000012
3. the method according to claim 2, wherein the aprotic solvent is a mixed solvent of tetrahydrofuran and dimethylsulfoxide, tetrahydrofuran, methyltetrahydrofuran, acetone, dimethylformamide or dimethylsulfoxide;
and/or in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the dosage range of the volume-mass ratio of the aprotic solvent to the chroman compound shown in the formula 6 is 4-15 ml/g;
and/or in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the molar ratio of the p-toluenesulfonic acid to the chroman compound shown in the formula 6 is (0.5-3) to 1, preferably (1-3) to 1;
and/or in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the temperature of the elimination reaction is 60-100 ℃;
and/or, in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the elimination reaction time is 0.5 to 15 hours;
and/or, in the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a, the elimination reaction further comprises a post-treatment operation, and the post-treatment operation comprises any one of the following two operations: (i) cooling to separate out solid, filtering and drying; (ii) adding halogenated hydrocarbon solvent, washing the organic phase with water, separating out solid, filtering and drying.
4. The method for preparing the elaprine p-toluenesulfonate shown in the formula 7a according to claim 2 or 3, wherein the method for preparing the elaprine p-toluenesulfonate shown in the formula 7a further comprises the following steps: in an organic solvent, under the action of a reducing reagent, carrying out a reduction reaction on a chromanone compound shown in a formula 5 and/or a salt of the chromanone compound shown in the formula 5 to obtain a chromane compound shown in a formula 6;
the reducing reagent is sodium borohydride and/or potassium borohydride;
Figure FDA0002276982630000021
5. the method for preparing elaprine p-toluenesulfonate shown in claim 4, which is characterized in that in the method for preparing the chromane compound shown in formula 6, the salt of the chromanone compound shown in formula 5 is formed by the chromanone compound shown in formula 5 and an acid in a molar ratio of 1:1, wherein the acid is preferably acetic acid and/or propionic acid, and is further preferably acetic acid;
and/or in the preparation method of the chroman compound shown in the formula 6, the organic solvent is methanol and/or ethanol, preferably methanol;
and/or in the preparation method of the chromane compound shown in the formula 6, the volume-mass ratio dosage range of the organic solvent and the chromanone compound shown in the formula 5 and/or the salt of the chromanone compound shown in the formula 5 is 5-25 ml/g;
and/or in the preparation method of the chromane compound shown in the formula 6, the molar ratio of the reducing reagent to the chromanone compound shown in the formula 5 is (0.5-2):1, the molar ratio of the reducing reagent to the salt of the chromanone compound shown in the formula 5 is (1.5-2): 1;
and/or in the preparation method of the chroman compound shown in the formula 6, the temperature of the reduction reaction is-15-30 ℃, preferably 20-30 ℃;
and/or in the preparation method of the chroman compound shown in the formula 6, the reduction reaction time is 0.5-3 hours;
and/or in the preparation method of the chroman compound shown in the formula 6, the reduction reaction further comprises the following post-treatment steps: removing the solvent, washing, filtering and recrystallizing to obtain the product; wherein, the filtering step further comprises the following steps: adding an alcohol solvent into the filter cake for refluxing, and removing the solvent after refluxing; the recrystallization is preferably carried out in a mixture of an alcoholic solvent and water.
6. The method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a according to claim 4, wherein the method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a further comprises the following steps: step (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 cyclopropanecarboxaldehyde as shown in the specification to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown as a formula 5 and the acid;
Figure FDA0002276982630000031
7. the method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a according to claim 6, wherein the method for preparing the salt of elaprine p-toluene sulfonic acid shown in the formula 7a further comprises the following steps: step (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 cyclopropanecarboxaldehyde as shown in the specification to obtain a tetrahydropyranone substance; the tetrahydropyranone substance comprises a chromanone compound shown as a formula 5 and the acid;
step (2): carrying out neutralization reaction on the tetrahydropyranone substance obtained in the step (1) and alkali as shown in the specification to obtain a chromanone compound shown in a formula 5;
Figure FDA0002276982630000032
8. the method for preparing elaprine p-toluenesulfonate shown in formula 7a according to claim 6 or 7, wherein in the method for preparing the chromanone compound shown in formula 5, in step (1), the organic solvent is a nitrile solvent;
and/or in the preparation method of the chromanone compound shown in the formula 5, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 4 can be 8-20 ml/g;
and/or in the preparation method of the chromanone compound shown in the formula 5, the alkali is pyrrolidine and/or piperidine, preferably pyrrolidine;
and/or in the preparation method of the chromanone compound shown in the formula 5, the molar ratio of the alkali to the phenol compound shown in the formula 4 is (1-2): 1;
and/or in the preparation method of the chromanone compound shown in the formula 5, the acid is acetic acid and/or propionic acid, preferably acetic acid;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the acid to the phenol compound shown in the formula 4 is (0.5-2): 1;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the molar ratio of the cyclopropane formaldehyde to the phenol compound shown in the formula 4 is (1-2): 1;
and/or in the preparation method of the chromanone compound shown as the formula 5, in the step (1), the temperature of the aldol condensation-ring closure reaction is 0-50 ℃;
and/or in the preparation method of the chromanone compound shown in the formula 5, in the step (1), the time of the aldol condensation-ring closure reaction is 20-40 hours;
and/or in the preparation method of the chromanone compound shown in the formula 5, the tetrahydropyranone substance consists of the chromanone compound shown in the formula 5 and the acid;
and/or in the preparation method of the chromanone compound shown as the formula 5, in the step (2), the alkali is alkali metal carbonate and/or alkali metal bicarbonate;
and/or in the preparation method of the chromanone compound shown in the formula 5, the aldol condensation-ring closure reaction further comprises post-treatment, and 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 in the preparation method of the chromanone compound shown in the formula 5, the neutralization reaction further comprises post-treatment, and the post-treatment comprises the following steps: and after the neutralization reaction is finished, filtering and drying the reaction system to obtain the chromanone compound shown as the formula 5.
9. The method for preparing elaprine p-toluenesulfonate shown in formula 7a according to claim 6 or 7, wherein the method for preparing elaprine p-toluenesulfonate shown in formula 7a further comprises the following scheme 1 or scheme 2:
scheme 1 includes the following steps: in an organic solvent, in the presence of alkali, performing an acetamido hydrolysis reaction on a phenol compound shown as a formula 8 to obtain the phenol compound shown as a formula 4;
Figure FDA0002276982630000051
scheme 2 includes the following steps: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetophenone compound shown in the formula 3 as shown in the specification to obtain a phenol compound shown in the formula 4;
10. the method for preparing elaprine p-toluenesulfonate shown in claim 9, wherein in scheme 1, the organic solvent is an alcohol solvent, preferably one or more of methanol, ethanol and isopropanol, and further preferably methanol;
and/or, in the scheme 1, the volume-mass ratio of the organic solvent to the phenol compound shown in the formula 8 is 5-20 ml/g;
and/or, in the scheme 1, the base is alkali metal carbonate, preferably 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): 1;
and/or, in the scheme 1, the temperature of the acetamido hydrolysis reaction is 60-82 ℃;
and/or, in the scheme 1, the time of the hydrolysis reaction of the acetamido is 0.5 to 2 hours;
and/or, in the scheme 1, the preparation method further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylamino hydrolysis reaction is finished, crystallizing a reaction system, filtering, washing with water and drying to obtain the phenol compound shown as the formula 4;
and/or, in the scheme 2, the organic solvent is a halogenated hydrocarbon solvent, preferably 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 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 (1-2): 1;
and/or, in the scheme 2, the temperature of the selective demethylation reaction is-15 ℃ to 35 ℃, and is preferably-6 ℃ to 30 ℃;
and/or, in the scheme 2, the lewis acid is dropwise added into the acetyl compound shown in the formula 2 and the organic solvent;
and/or, in the case of scheme 2, the time of the selective demethylation reaction is 2 to 5 hours;
and/or, in the scheme 2, the preparation method further comprises post-treatment, and the post-treatment comprises the following steps: and after the selective demethylation reaction is finished, carrying out extraction and extinction, concentration and recrystallization on the reaction system to obtain the phenol compound shown in the formula 4.
11. The method of claim 9, wherein when the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme 1, the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme a, wherein scheme a comprises the steps of: in an organic solvent, in the presence of Lewis acid, performing selective demethylation reaction on the acetyl compound shown as the formula 2 as shown in the specification to obtain the phenol compound shown as the formula 8;
when the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a further comprises the scheme 2, the preparation method of the elaprine p-toluenesulfonate shown in the formula 7a further comprises a scheme B, and the scheme B comprises the following steps; in an organic solvent, in the presence of alkali, performing the following acetylamino hydrolysis reaction on an acetyl compound shown as a formula 2 to obtain an acetophenone compound shown as a formula 3;
12. the method for preparing elaprine p-toluenesulfonate according to claim 11, wherein in scheme a, the organic solvent is a halogenated hydrocarbon solvent, preferably 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 8-20 ml/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 (1-2): 1;
and/or, in the scheme A, the temperature of the selective demethylation reaction is-15-35 ℃, preferably-8-30 ℃;
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 time of the selective demethylation reaction is 10-20 hours;
and/or, the scheme A further comprises post-treatment, and the post-treatment comprises the following steps: after the selective demethylation reaction is finished, performing extraction and extinction, adjusting the pH value to 6, filtering and recrystallizing on a reaction system to obtain the phenol compound shown as the formula 8;
and/or, in the scheme B, the organic solvent is an alcohol solvent, preferably one or more of methanol, ethanol and isopropanol, and further preferably methanol;
and/or in the scheme B, the volume-mass ratio of the organic solvent to the acetyl compound shown in the formula 2 is 5-15 ml/g;
and/or, in the scheme B, the base is alkali metal carbonate, preferably 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): 1;
and/or, in the scheme B, the temperature of the acetamido hydrolysis reaction is 60-82 ℃, preferably 65-70 ℃;
and/or, in the scheme B, the time of the hydrolysis reaction of the acetamido is 0.5-2 hours;
and/or, the scheme B further comprises post-treatment, and the post-treatment comprises the following steps: after the hydrolysis reaction of the acetamido, crystallizing, filtering, washing and drying a reaction system to obtain the acetophenone compound shown in the formula 3.
13. The method of claim 11, wherein the method for preparing the salt of eplerenone p-toluene sulfonic acid represented by formula 7a further comprises the following scheme a or scheme b:
the scheme a comprises the following steps: in an organic solvent, under the existence of Lewis acid, carrying out acetylation reaction on trimethoprim shown in a formula 1 and an acetylation reagent shown in the following formula to obtain an acetyl compound shown in a formula 2;
Figure FDA0002276982630000081
the scheme b comprises the following steps: in an organic solvent, in the presence of Lewis acid, performing acetylation reaction on an acetamide compound shown in a formula 1a and an acetylation reagent as shown in the specification to obtain an acetyl compound shown in a formula 2;
Figure FDA0002276982630000082
14. the method for preparing elaprine p-toluenesulfonate according to claim 13, wherein in scheme a, the organic solvent is a halogenated hydrocarbon solvent, preferably one or more of chloroform, dichloromethane and dichloroethane, and more preferably chloroform;
and/or in the scheme a, the volume-mass ratio of the organic solvent to the trimethoprim shown in the formula 1 is 5-15 ml/g;
and/or, in the scheme a, the acetylation reagent is acetyl chloride and/or acetic anhydride, preferably acetic anhydride;
and/or in the scheme a, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is (3-6):1, preferably (4-5): 1;
and/or, in the scheme a, the Lewis acid is stannic chloride;
and/or in the scheme a, the molar ratio of the Lewis acid to the trimethoprim shown in the formula 1 is (1-3) to 1, preferably (2-3): 1;
and/or, in the scheme a, the temperature of the acetylation reaction is 25-85 ℃, preferably 60-65 ℃;
and/or, in the scheme a, the time of acetylation reaction is 1-5 hours;
and/or, the scheme a further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylation reaction is finished, carrying out extraction and sterilization on a 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, adjusting the pH value of the combined organic phase to 7-8, separating liquid to obtain an organic phase, drying, filtering, concentrating and recrystallizing the washed organic phase and the organic phase to obtain the acetyl compound shown in the formula 2;
and/or, in the scheme b, the organic solvent is a halogenated hydrocarbon solvent, preferably one or more of chloroform, dichloromethane and dichloroethane, and further preferably chloroform;
and/or, in the scheme b, the volume mass ratio of the organic solvent to the acetamide compound shown in the formula 1a is 5-15 ml/g;
and/or, in the scheme b, the acetylation reagent is acetyl chloride and/or acetic anhydride, preferably acetic anhydride;
and/or, in the scheme b, the molar ratio of the acetylation reagent to the acetamide compound shown in the formula 1a is (1.5-4) to 1, preferably 2: 1;
and/or, in the scheme b, the Lewis acid is stannic chloride;
and/or, in the scheme b, the molar ratio of the Lewis acid to the acetamide compound shown in the formula 1a is (1-3) to 1, preferably (2-3): 1;
and/or, in the scheme b, the temperature of the acetylation reaction is 25-85 ℃, preferably 60-65 ℃;
and/or, in the scheme b, the time of acetylation reaction is 1-5 hours;
and/or, the scheme b further comprises post-treatment, and the post-treatment comprises the following steps: after the acetylation reaction is finished, carrying out extraction and sterilization on a 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, adjusting the pH value of the combined organic phase to 7-8, separating liquid to obtain an organic phase, washing the organic phase with water, drying, filtering, concentrating, and recrystallizing to obtain the acetyl compound shown in the formula 2.
15. The method of claim 13, wherein when the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme b, the method of preparing the salt of eplerenone p-toluene sulfonic acid of formula 7a further comprises scheme c, and wherein scheme c comprises the steps of: in an organic solvent, under the action of an acetylation reagent, carrying out acetylation reaction on trimethoprim shown in a formula 1 to obtain an acetamide compound shown in a formula 1 a;
Figure FDA0002276982630000101
16. the process for preparing elaprine p-toluenesulfonate according to claim 15, wherein in scheme c, the organic solvent is toluene;
and/or in the scheme c, the dosage range of the volume mass ratio of the organic solvent to the trimethoprim shown in the formula 1 is 5-20 ml/g;
and/or, in the scheme c, the acetylation reagent is acetic anhydride and/or acetyl chloride;
and/or, in the scheme c, the molar ratio of the acetylation reagent to the trimethoprim shown in the formula 1 is (2-5): 1;
and/or, in the scheme c, the temperature of the acetylation reaction is 100-110 ℃;
and/or, in the scheme c, the time of the acetylation reaction is 1-3 hours;
and/or, in the scheme c, the acetylation reaction further comprises the operation of post-treatment, and the post-treatment comprises the following post-treatment steps: crystallizing, filtering and drying.
17. A preparation method of elaprine shown in formula 7 is characterized by comprising the following steps: under the action of alkali, performing neutralization reaction on the tosylate by the elaprine shown in the formula 7a to obtain the elaprine shown in the formula 7;
Figure FDA0002276982630000102
18. the method for preparing elaprine as shown in the formula 7, according to claim 17, wherein the base is one or more of sodium carbonate, sodium bicarbonate and potassium carbonate, preferably sodium carbonate, and more preferably saturated sodium carbonate aqueous solution;
and/or, the neutralization reaction further comprises the operation of post-treatment, and the operation of post-treatment comprises the following steps: filtering and drying to obtain the product.
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