CN112679431A

CN112679431A - Method for preparing isoquinolone compound

Info

Publication number: CN112679431A
Application number: CN201910996278.1A
Authority: CN
Inventors: 焦宁; 朱占群; 孙国峰; 宋彦彬; 邢贺; 吴欣超
Original assignee: Anlite Shanghai Pharmaceutical Technology Co ltd; Shanghai Acebright Pharmaceuticals Group Co ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Current assignee: Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date: 2019-10-18
Filing date: 2019-10-18
Publication date: 2021-04-20
Anticipated expiration: 2039-10-18
Also published as: CN112679431B

Abstract

The invention provides a method for preparing isoquinolone compounds. Specifically, the present invention provides a method for preparing a compound of formula 4, comprising the steps of: the compound of the formula 3 is subjected to active metal catalytic conversion to obtain a compound of a formula 4. The method has the excellent technical effects of reasonable route, convenience and feasibility, high yield and purity of preparation, suitability for industrial production and the like.

Description

Method for preparing isoquinolone compound

Technical Field

The application relates to the field of pharmaceutical chemistry, in particular to a method for preparing isoquinolinone compounds.

Background

Rosemastat, chemical name (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino]-acetic acid, of formula: c₁₉H₁₆N₂O₅The molecular weight is: 352.11, CAS number: 808118-40-3, the chemical structural formula is:

rosxastat, a disease developed by fabrogen (fibrigen) corporation for the treatment of renal anemia, was applied for sale at home in 2017 in 11 months. The medicine is the first developed medicine for treating renal anemia in the world, such as small molecule hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI). The physiological role of Hypoxia Inducible Factor (HIF) is to increase not only erythropoietin expression, but also erythropoietin receptor and protein expression which promotes iron absorption and circulation. Rosemastat inhibits the Prolyl Hydroxylase (PH) enzyme by simulating ketoglutarate, one of the substrates of PH, and influences the action of the PH enzyme in maintaining the balance of HIF generation and degradation rates, thereby achieving the aim of correcting anemia. The roxasistat provides a new treatment means for anemia patients caused by chronic kidney diseases.

However, in the existing preparation technology of the rasagiline, the reaction route is often required to be reacted under the conditions of low temperature, high temperature and closed pressurization, the reaction condition is severe, the requirement on the process is high, the reaction route is long, the number of side reactions is large, the subsequent purification is difficult, the yield and the purity of the synthesized rasagiline are low, and in addition, the existing synthesis method needs an expensive catalyst, so that the industrial production is not facilitated.

Therefore, a synthetic method of the isoquinolone compound of the roxasistat, which has a reasonable route, is convenient and easy to implement and is suitable for industrial production, needs to be developed.

Disclosure of Invention

The invention aims to provide a preparation method of the compound of the formula 4, which has the advantages of reasonable route, convenience, easiness, high yield and high purity and is suitable for industrial production.

In a first aspect of the present invention, there is provided a process for preparing a compound of formula 4, said process comprising the steps of:

the compound of the formula 3 is subjected to active metal catalytic conversion to obtain a compound of a formula 4;

wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

R¹and R²Independently is C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C10 alkyl-, or R¹And R²And the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, said 3-10 membered heterocycloalkyl group containing 1-2 (preferably 1 or 2) N atoms and 0-2 (preferably 0, 1 or 2) heteroatoms selected from O and S.

In another preferred embodiment, wherein R⁰Is H or C1-C6 alkyl.

In another preferred embodiment, wherein R⁰Is H or methyl.

In another preferred embodiment, R¹And R²Independently is methyl, benzyl, or R¹And R²And the nitrogen atom to which they are attached together form a piperidinyl or morpholinyl group.

In another preferred embodiment, R¹And R²Independently is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, or C6-C10 aryl-C1-C4 alkyl-, or R¹And R²And the nitrogen atom to which they are attached together form a 3-to 10-membered heterocycloalkyl group containing heteroatoms, which include oxygen, sulfur, and/or nitrogen atoms.

In another preferred embodiment, when R is⁰When not hydrogen, the process comprises steps 1-2):

1) the compound of the formula 3 reacts with active metal in acid or aqueous solution of acid or alcoholic solution of acid to obtain the compound of the formula 4';

2) reacting the compound of formula 4' with a base in a first inert solvent to obtain the compound of formula 4

In another preferred embodiment, when R is⁰When not hydrogen, the process comprises steps 1 '-2'):

1 ') reacting said compound of formula 3 with a base in a second inert solvent to obtain a compound of formula 3';

2 ') reacting the compound 3' with an active metal in acid or aqueous acid solution or alcoholic acid solution to obtain the compound 4;

in another preferred embodiment, when R is⁰In the case of hydrogen, the process comprises the steps of:

1') reacting the compound of formula 3 with an active metal in an acid or an aqueous acid solution or an alcoholic acid solution to obtain the compound of formula 4.

In another preferred example, in said step 1), said step 2') and/or said step 1 ″), said acid is an inorganic acid or an organic acid, wherein said inorganic acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof; the organic acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.

In another preferred example, in said step 1), said step 2') and/or said step 1 ″), the alcoholic solvent of said acid is selected from the group consisting of: methanol, ethanol, isopropanol, n-butanol, ethylene glycol, or combinations thereof.

In another preferred embodiment, in the step 1), the step 2') and/or the step 1 ″), the active metal is selected from the group consisting of: magnesium, aluminum, zinc, iron, or combinations thereof.

In another preferred embodiment, in the step 1), the molar ratio of the active metal to the compound of formula 3 is 2 to 20, preferably 2 to 10: 1.

in another preferred embodiment, in the step 2 '), the molar ratio of the active metal to the compound of formula 3' is 2 to 20, preferably 5 to 15.

In another preferred embodiment, in the step 1 ″), the molar ratio of the active metal to the compound of formula 3 is 2 to 20, preferably 5 to 10.

In another preferred embodiment, in step 1), the temperature of the reaction is 60 to 140 ℃, preferably 60 to 100 ℃.

In another preferred embodiment, in the step 1), the reaction time is 0.5 to 12 hours, preferably 4 to 6 hours.

In another preferred embodiment, in step 2'), the temperature of the reaction is 60 to 140 ℃, preferably 60 to 100 ℃.

In another preferred embodiment, in step 2'), the reaction time is 0.5 to 12 hours, preferably 2 to 6 hours.

In another preferred embodiment, in step 1 ″), the temperature of the reaction is 60 to 140 ℃, preferably 70 to 120 ℃.

In another preferred embodiment, in the step 2), the first inert solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), or a combination thereof.

In another preferred embodiment, in the step 1'), the second inert solvent is selected from water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), Dimethylsulfoxide (DMSO), or a combination thereof.

In another preferred example, in said step 2) and/or said step 1'), said base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.

In another preferred embodiment, in the step 2), the reaction time is 2-8h, preferably 3-6 h.

In another preferred example, in the step 2), the reaction temperature is room temperature.

In another preferred embodiment, in step 1'), the reaction time is 2-8h, preferably 3-6 h.

In another preferred example, in the step 1'), the reaction temperature is room temperature.

In another preferred example, the step 1 ") includes the steps of: mixing the compound shown in the formula 3, the active metal and the acid or the aqueous solution or the alcoholic solution of the acid, filtering, washing a filter cake with acetic acid, concentrating the filtrate, and treating with methyl tert-ether to obtain the compound shown in the formula 4.

In another preferred example, the step 1) includes the steps of: and mixing the compound shown in the formula 3, the active metal and the acid or the aqueous solution of the acid or the alcoholic solution of the acid, reacting, after the reaction is finished, performing suction filtration, washing a filter cake with acetic acid, concentrating a filtrate, and treating with methyl tert-ether to obtain the compound shown in the formula 4'.

In another preferred embodiment, in the step 2), the compound of formula 4', the base and the first inert solvent are mixed and reacted, after the reaction is finished, the pH is adjusted to be acidic by using an acid, a solid is precipitated, and the solid is filtered to obtain the compound of formula 4.

In another preferred embodiment, in the step 1 '), the compound of formula 3, a base and a second inert solvent are mixed and reacted, after the reaction is finished, the pH is adjusted to be acidic by using an acid to precipitate a solid, and the solid is filtered to obtain the compound of formula 3'.

In another preferred embodiment, in the step 2 '), the compound of formula 3', the active metal and the acid or the aqueous solution of the acid or the alcoholic solution of the acid are mixed and reacted, after the reaction is finished, suction filtration is carried out, the filter cake is washed by acetic acid, the filtrate is concentrated and treated by methyl tertiary ether, so as to obtain the compound of formula 4.

In another preferred embodiment, the reaction is carried out under normal pressure.

In another preferred embodiment, in the step 1), the reaction is carried out under normal pressure.

In another preferred example, in the step 2), the reaction is carried out under normal pressure.

In another preferred embodiment, in step 1'), the reaction is carried out under normal pressure.

In another preferred embodiment, in the step 2'), the reaction is carried out under normal pressure.

In another preferred embodiment, in step 1 "), the reaction is carried out under normal pressure.

In another preferred embodiment, in said step 1), said step 2') or said step 1 ″), said acid is selected from the group consisting of: sulfuric acid, phosphoric acid, trifluoroacetic acid, acetic acid, or a combination thereof.

In another preferred example, in the step 1), the step 2') or the step 1 ″), the alcohol solvent of the acid alcohol solution is isopropanol.

In another preferred embodiment, in the step 1), the step 2') or the step 1 ″), the molar ratio of the active metal to the compound of formula 3 is 5 to 15.

In another preferred example, in said step 1), said step 2') or said step 1 ″), said reaction temperature is 80 to 130 ℃.

In another preferred example, in the step 2), the first inert solvent is methanol.

In another preferred embodiment, in step 1'), the second inert solvent is methanol.

In another preferred example, the alkali in step 2) is sodium hydroxide.

In another preferred example, in the step 1'), the alkali is sodium hydroxide.

In another preferred embodiment, the compound of formula 3 is prepared by the following method:

a) reacting the compound shown in the formula 1 with glycine or glycine ester to obtain a compound shown in a formula 2;

b) reacting the compound of formula 2 with aminal to obtain a compound of formula 3;

wherein the glycine ester is NH₂-CH₂-C(O)-O-R⁰Said aminal is (R)¹R²)N-CH₂-N(R¹R²)；

R⁰Selected from H, C1-C10 alkyl, C6-C10 aryl;

In another preferred embodiment, in the step a), the compound of formula 1 is reacted with glycine or glycine ester in the presence of a third inert solvent and an organic base to obtain the compound of formula 2.

In another preferred embodiment, in the step b), the compound of formula 2 is reacted with aminal in a fourth inert solvent under acid catalysis to obtain the compound of formula 3.

In another preferred embodiment, in step a), the third inert solvent is selected from the group consisting of: ethylene glycol methyl ether, methanol, ethanol, isopropanol, N-butanol, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, or a combination thereof.

In another preferred embodiment, in step a), the organic base is selected from the group consisting of: triethylamine (TEA), 1, 8-diazabicycloundec-7-ene (DBU), N-Diisopropylethylamine (DIEA), N-methylmorpholine, pyridine, or combinations thereof.

In another preferred embodiment, in step a), the glycine ester is selected from the group consisting of: glycine methyl ester, glycine ethyl ester, glycine benzyl ester, or combinations thereof.

In another preferred embodiment, in said step a), the molar ratio of said glycine or glycine ester to said compound of formula 1 is from 1 to 4.

In another preferred embodiment, in the step a), the molar ratio of the organic base to the compound of formula 1 is 1 to 5.

In another preferred embodiment, in the step a), the reaction temperature is 50 ℃ to 100 ℃.

In another preferred embodiment, in the step a), the reaction time is 4-10 h.

In another preferred embodiment, in the step b), the fourth inert solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, 1, 4-dioxane, acetic acid, or a combination thereof.

In another preferred embodiment, in step b), the acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

In another preferred embodiment, in step b), the aminal is selected from the group consisting of: tetramethylethylenediamine, tetrabenzylethylenediamine, bispiperazinylmethane, bismorphinylmethane, dipiperidinomethane, or combinations thereof.

In another preferred embodiment, in said step b), the molar ratio of said aminal to said compound of formula 2 is from 1 to 10.

In another preferred embodiment, in the step b), the reaction temperature is 70-120 ℃.

In another preferred embodiment, in the step b), the reaction time is 3-10 h.

In another preferred embodiment, in step a), the compound of formula 1, the organic base, glycine or glycine ester and the third inert solvent are mixed and reacted, then filtered, the filtrate is diluted with water, the pH is adjusted to acidity, and crystallization is performed to obtain the compound of formula 2.

In another preferred embodiment, in the step b), after the compound of formula 2, the acid, the aminal and the fourth inert solvent are mixed and reacted, the reaction solution is extracted with water and ethyl acetate to obtain the compound of formula 3.

In another preferred embodiment, in the step a), the third inert solvent is acetonitrile.

In another preferred embodiment, in step a), the organic base is 1, 8-diazabicycloundecen-7-ene (DBU).

In another preferred example, in the step a), the glycine ester is glycine methyl ester.

In another preferred embodiment, in said step a), the molar ratio of said glycine or glycine ester to said compound of formula 1 is from 1.3 to 2.5.

In another preferred embodiment, in the step a), the molar ratio of the organic base to the compound of formula 1 is 2 to 4.

In another preferred embodiment, in the step a), the reaction temperature is 65 ℃ to 90 ℃.

In another preferred embodiment, in the step b), the fourth inert solvent is selected from the group consisting of: water, acetic acid, or a combination thereof.

In another preferred embodiment, in step b), the acid is selected from the group consisting of: trifluoroacetic acid, sulfuric acid, phosphoric acid, or a combination thereof.

In another preferred embodiment, in the step b), the aminal is tetramethylethylenediamine.

In another preferred embodiment, in said step b), the molar ratio of said aminal to said compound of formula 2 is from 1.5 to 5.

In another preferred embodiment, in the step b), the reaction temperature is 80 ℃ to 110 ℃.

In another preferred embodiment, in the step b), the reaction is carried out under normal pressure.

In another preferred embodiment, in the step a), the reaction is carried out under normal pressure.

In another preferred embodiment, the reaction is carried out at normal pressure

In another preferred embodiment, the mixture containing the compound of formula 3 obtained in step b) is subjected to the subsequent reaction according to said step 1), step 1') or step 1 ") without work-up.

In another preferred embodiment, the reaction does not need to be carried out under a closed environment condition.

In another preferred embodiment, the reaction is carried out under closed and open conditions.

In a second aspect of the present invention, an isoquinolinone compound intermediate is provided, and the structure of the isoquinolinone compound intermediate is shown in formula 3.

Wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

In another preferred embodiment, the intermediate is

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have made extensive and intensive studies and have unexpectedly found a process for preparing a compound having the structure of formula 4. The preparation method of the compound with the structure of the formula 4 has the advantages of reasonable route, convenience, easiness, high yield and purity of preparation, suitability for industrial production and the like. On this basis, the inventors have completed the present invention.

Term(s) for

As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".

As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-C10 alkyl) means that the alkyl group contains 1-10 carbon atoms, representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system radical having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C3-C10), meaning that the cycloalkyl group has 3-10 carbon atoms, representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, and the like.

The term "aryl" refers to aromatic cyclic hydrocarbon groups, e.g. having 1, or 2 rings, especially to monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). When an aryl group is preceded by a carbon number limitation, that number is a ring carbon atom of the aryl group, e.g., C6-C10 aryl refers to an aryl group having 6-10 ring carbon atoms, representative examples include, but are not limited to, phenyl, biphenyl, or naphthyl.

The term "heterocycloalkyl", also known as "heterocyclyl", refers to a fully saturated or partially unsaturated cyclic group in which at least one heteroatom is present in the ring of at least one carbon atom. When a heterocycloalkyl group is preceded by a number of members, it refers to the number of ring atoms of the heterocycloalkyl group, for example, a 3-10 membered heterocycloalkyl group refers to a heterocycloalkyl group having 3-10 ring atoms, representative examples include, but are not limited to, piperidinyl or morpholinyl.

In the present invention, all substituents are unsubstituted substituents unless otherwise specified.

The abbreviated forms used in the present invention and their meanings are described in the following table:

abbreviations	Means of
		DMF	N, N-dimethylformamide
NMP	N-methyl pyrrolidone
		DMSO	Dimethyl sulfoxide
TEA	Triethylamine
		DBU	1, 8-diazabicycloundec-7-enes
DIEA	N, N-diisopropylethylamine
		DMF	N, N-dimethylformamide
TLC	Thin layer chromatography

As used herein, "inert solvent" refers to a solvent that does not react with other materials in the reaction (e.g., starting materials, catalysts, etc.).

As used herein, as used herein

And

the structures may be used interchangeably.

Preparation method

Preparation method of isoquinolone compound with structure of formula 4

The invention provides a preparation method of a compound with a structure shown in a formula 3, which comprises the following steps:

wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

In another preferred embodiment, wherein R⁰Is H or methyl.

In another preferred embodiment, R1 and R2 are independently methyl, benzyl, or R1 and R2 together with the nitrogen atom to which they are attached form a piperidinyl or morpholinyl group.

In a preferred embodiment of the invention, when R is⁰When not hydrogen, the process comprises steps 1-2):

2) reacting the compound of formula 4' with a base in a first inert solvent to obtain a compound of formula 4;

in a preferred embodiment of the invention, when R is⁰When not hydrogen, the process comprises steps 1 '-2'):

in a preferred embodiment of the invention, when R is⁰In the case of hydrogen, the process comprises the steps of:

In a preferred embodiment of the present invention, in the step 1), the step 2') and/or the step 1 ″), the acid is an inorganic acid or an organic acid, wherein the inorganic acid includes (but is not limited to): hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof; such organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof.

In another preferred example, in the step 1), the step 2') and/or the step 1 ″), the alcoholic solvent of the acid comprises (but is not limited to): methanol, ethanol, isopropanol, n-butanol, ethylene glycol, or combinations thereof.

In another preferred example, in the step 1), the step 2') and/or the step 1 ″), the active metal includes (but is not limited to): magnesium, aluminum, zinc, iron, or combinations thereof.

In another preferred example, in the step 2), the first inert solvent includes (but is not limited to): water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), or a combination thereof.

In another preferred embodiment, in the step 1'), the second inert solvent is selected from water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), Dimethylsulfoxide (DMSO), or a combination thereof. And/or

In said step 2) and/or said step 1'), said base includes (but is not limited to): sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.

In another preferred embodiment of the present invention, the compound of formula 3 is prepared by the following method:

R⁰Selected from H, C1-C10 alkyl, C6-C10 aryl;

In another preferred embodiment, wherein R⁰Is H or C1-C6 alkyl.

In another preferred embodiment, wherein R⁰Is H or methyl.

In a preferred embodiment of the present invention, in the step a), the compound of formula 1 is reacted with glycine or a glycine ester in the presence of a third inert solvent and an organic base to obtain the compound of formula 2.

In another preferred embodiment of the present invention, in the step b), the compound of formula 2 is reacted with aminal in a fourth inert solvent under acid catalysis to obtain the compound of formula 3.

In another preferred example, in the step a), the third inert solvent includes (but is not limited to): ethylene glycol methyl ether, methanol, ethanol, isopropanol, N-butanol, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, or a combination thereof.

In another preferred example, in the step a), the organic base includes (but is not limited to): triethylamine (TEA), 1, 8-diazabicycloundec-7-ene (DBU), N-Diisopropylethylamine (DIEA), N-methylmorpholine, pyridine, or combinations thereof.

In another preferred example, in the step a), the glycine ester includes (but is not limited to): glycine methyl ester, glycine ethyl ester, glycine benzyl ester, or combinations thereof.

In another preferred example, in the step b), the fourth inert solvent includes (but is not limited to): water, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, 1, 4-dioxane, acetic acid, or a combination thereof.

In another preferred embodiment, in step b), the acid includes (but is not limited to): formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

In another preferred embodiment, in step b), the aminal includes (but is not limited to): tetramethylethylenediamine, tetrabenzylethylenediamine, bispiperazinylmethane, bismorphinylmethane, dipiperidinomethane, or combinations thereof.

In the step b), the reaction time is 3-10 h.

Isoquinolinone compound intermediate

The invention provides an isoquinolone compound intermediate, and the structure of the isoquinolone compound intermediate is shown in a formula 3.

Wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

In another preferred embodiment, wherein R⁰Is H or C1-C6 alkyl.

In another preferred embodiment, wherein R⁰Is H or methyl.

In another preferred embodiment, the intermediate is

The main advantages of the invention include:

1) the compound shown in the formula 1 is firstly subjected to aminolysis reaction with glycine, and a glycine group is preferentially introduced to an isoquinoline parent nucleus. The step can be completed only by heating under normal pressure without using closed environments such as a sealed tube and the like, so that the requirements of a preparation process on equipment are reduced, the operation steps are simplified, and potential safety hazards are reduced.

2) In the invention, because the solvent or reagent used in the preparation process of the compound of the formula 4 can be the same as that used in the preparation of the compound of the formula 3, the one-pot method continuous feeding of the compound of the formula 2 to the isoquinolinone compound can be realized without any post-treatment, thereby greatly shortening the generation period, improving the production efficiency and being more beneficial to industrial scale-up production.

3) The preparation method of the isoquinolone compound has short reaction route, does not need to use noble metals such as palladium and the like as catalysts, can reduce the content of heavy metals in the final product, is convenient for post-treatment, improves the product quality and reduces the production cost.

4) Compared with the prior art, the preparation process of the isoquinolone compound has the advantages of simple preparation process, short reaction time, high yield, less by-products, good amplification production result and better industrial prospect.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Examples

In examples 1-7, all reactions were carried out under normal pressure (standard atmospheric pressure) at room temperature, which means a temperature of 25. + -. 5 ℃.

Example 1

1) Adding 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (20g, 68mmol) into acetonitrile, slowly adding DBU (20.7g,136mmol) dropwise, then adding glycine (7.66g,102mmol), heating to 50 ℃ for 6h, detecting the completion of the reaction by TLC plate, and cooling to roomWarmed and filtered. Diluting the filtrate with water, adjusting pH to weak acidity, stirring for crystallization, filtering and drying to obtain 22g of (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid with yield 95.6% and purity 98.4% by HPLC.¹H-NMR(400MHz,CDCl₃)：δ12.85(s,1H),8.48–8.37(m,2H),8.34(d,J＝9.0Hz,1H),7.52–7.37(m,3H),7.23(d,J＝7.4Hz,1H),7.15–7.08(m,2H),4.28(d,J＝5.8Hz,2H)；MSm/z(ESI)：339(M+1)。

2) Mixing (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid (2.2g, 6.5mmol) with acetic acid, slowly adding tetramethylmethanediamine (13mmol), performing argon replacement on a reaction system, heating to 70 ℃ for reaction for 3h, completing TLC detection reaction, and directly performing the next step without treatment on the obtained reaction system. Taking a small amount of mixed liquor after reaction, adding water to precipitate solid to obtain the compound shown as the formula 3a, wherein the purity of the compound is 99% by HPLC (high performance liquid chromatography) determination. 1H NMR (400MHz, DMSO) δ 13.60(s,1H),10.01(s,1H),8.21(d, J ═ 9.1Hz,1H),7.70(d, J ═ 2.0Hz,1H), 7.56-7.44 (m,3H),7.28(t, J ═ 7.4Hz,1H),7.19(d, J ═ 7.7Hz,2H),4.56(s,2H),4.00(d, J ═ 6.1Hz,2H),2.68(s, 6H); MS m/z (ESI): 396(M + 1).

3) Adding zinc powder (4.2g, 32.5mmol) into the reaction system obtained in the previous step at room temperature, reacting for 5h at 70 ℃, detecting by TLC to finish the reaction, cooling to room temperature, performing suction filtration, leaching a filter cake with acetic acid, concentrating the filtrate, and treating with methyl tertiary ether to obtain [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -methyl]2.28g of-acetic acid, 99.1% yield and 99.5% purity by HPLC.¹H NMR(400MHz,DMSO)δ13.07(d,J＝196.2Hz,2H),9.10(t,J＝5.9Hz,1H),8.30(d,J＝9.0Hz,1H),7.62(d,J＝2.3Hz,1H),7.51(ddd,J＝15.9,8.6,5.0Hz,3H),7.26(t,J＝7.4Hz,1H),7.19(d,J＝7.7Hz,2H),4.06(d,J＝6.1Hz,2H),2.71(s,3H)；MS m/z(ESI)：353(M+1)。

Example 2

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to DMSO, TEA (13.7g, 136mmol) was slowly added dropwise, followed by glycine (10.2g, 136mmol), warmed to 65 ℃ for 6h, checked by TLC plate for completion, cooled to room temperature, and filtered. Diluting the filtrate with water, adjusting pH to weak acidity, stirring for crystallization, filtering and drying to obtain (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid 21.5g with yield 93.5% and purity of 97.9% by HPLC.

2) Mixing (2.2g, 6.5mmol) of (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid with trifluoroacetic acid, slowly adding tetrabenzyl methane diamine (26mmol), replacing with argon, heating to 100 ℃ for reaction for 3h, completing the TLC detection reaction, and directly carrying out the next step without processing the obtained reaction system. Taking a small amount of mixed solution after reaction, adding water to precipitate solid to obtain the compound shown as the formula 3b, wherein the purity of the compound is 99% by HPLC (high performance liquid chromatography) determination. MS m/z (ESI): 548(M + 1).¹H NMR(400MHz,DMSO)δ13.62(s,1H),10.21(s,1H),8.36(d,J＝9.1Hz,1H),7.80(d,J＝2.0Hz,1H),7.60–7.50(m,3H),7.36–7.24(m,11H),7.12(d,J＝7.7Hz,2H),4.56(s,2H),4.00(s,4H),3.72(d,J＝6.1Hz,2H)。

3) Adding zinc powder (8.4g, 65mmol) into the reaction system obtained in the last step at room temperature, reacting for 5h at 120 ℃, detecting by TLC to finish the reaction, cooling to room temperature, performing suction filtration, leaching a filter cake with acetic acid, concentrating a filtrate, and treating with methyl tert-ether to obtain [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid 2.25g, wherein the total yield is 98.7%, and the purity is 98.8% by HPLC. The profile data for the remaining materials were the same as in example 1.

Example 3

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to acetonitrile, pyridine (10.8g, 136mmol) was slowly added dropwise, followed by glycine (7.66g,102mmol), warmed to 100 ℃ for 6h, checked by TLC plates for completion, cooled to room temperature, and filtered. Diluting the filtrate with water, adjusting pH to weak acidity, stirring for crystallization, filtering and drying to obtain 21g of (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid with yield of 91.3% and purity of 98% by HPLC.

2) Adding (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid (2.2g, 6.5mmol) into 10ml of acetic acid and 10ml of isopropanol, slowly adding dipiperidinomethane (30mmol), heating to 90 ℃ for reaction for 3h after argon replacement, completing TLC detection reaction, and directly carrying out the next step without processing the obtained reaction system. Taking a small amount of mixed liquor after reaction, adding water to precipitate solid to obtain a compound shown as a formula 3c, wherein the purity is 99% by HPLC (high performance liquid chromatography) determination. MS m/z (ESI): 436(M + 1).¹H NMR(400MHz,DMSO)δ13.60(s,1H),10.03(s,1H),8.23(d,J＝9.1Hz,1H),7.70(d,J＝2.0Hz,1H),7.56–7.44(m,3H),7.28(t,J＝7.4Hz,1H),7.19(d,J＝7.7Hz,2H),4.26(s,2H),3.68(d,J＝6.1Hz,2H),2.84–2.44(m,4H),1.66–1.50(m,4H),1.46–1.38(m,2H)。

3) Adding zinc powder (16.8g, 130mmol) into the reaction system obtained in the last step at room temperature, reacting for 5h at 60 ℃, detecting by TLC to finish the reaction, cooling to room temperature, performing suction filtration, leaching a filter cake with acetic acid, concentrating a filtrate, and treating with methyl tert-ether to obtain [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid 2.1g, wherein the yield is 92.1% and the purity is 99.3% by HPLC. The profile data for the remaining materials were the same as in example 1.

Example 4

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to acetonitrile, DBU (27.4g, 272mmol) was slowly added dropwise, followed by glycine (7.66g,102mmol), warmed to 100 ℃ for 6h, checked by TLC plate for completion, cooled to room temperature, and filtered. Diluting the filtrate with water, adjusting pH to weak acidity, stirring for crystallization, filtering and drying to obtain 21g of (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid with yield of 91.3% and purity of 98.3% by HPLC.

2) Adding (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid (2.2g, 6.5mmol) into a mixed solution of 10ml of water and 1ml of concentrated sulfuric acid, slowly adding dipiperidine methane (13mmol) while stirring, heating to 90 ℃ after argon displacement for reaction for 5 hours, completing TLC detection reaction, directly taking a small amount of mixed solution after reaction in the next step without treatment of the obtained reaction system, adding water to precipitate solid, and obtaining the compound shown in the formula 3c, wherein the purity is 99% by HPLC (high performance liquid chromatography).

3) Adding zinc powder (4.2g, 32.5mmol) and a proper amount of sulfuric acid into the reaction system obtained in the last step at room temperature, reacting for 5h at 90 ℃, completing TLC detection reaction, cooling to room temperature, performing suction filtration, and drying a filter cake to obtain 2.25g of [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid with the yield of 98.7 percent and the purity of 99.2 percent determined by HPLC. The profile data for the material was the same as in example 3.

Example 5

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to acetonitrile, DBU (27.4g, 272mmol) was slowly added dropwise, followed by glycine (7.66g,102mmol), warmed to 100 ℃ for 6h, checked by TLC plate for completion, cooled to room temperature, and filtered. Diluting the filtrate with water, adjusting pH to weak acidity, stirring for crystallization, filtering and drying to obtain 21g of (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid with yield of 91.3% and purity of 98.1% by HPLC.

2) Adding (4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid (2.2g, 6.5mmol) into a mixed solution of 15ml of propionic acid and 5ml of 1, 4-dioxane, slowly adding dimorpholinomethane (6.5mmol), replacing with argon, heating to 90 ℃ for reaction for 3h, completing TLC detection reaction, and directly carrying out the next step without treatment on the obtained reaction system. Taking a small amount of mixed liquor after reaction, adding water to precipitate solid to obtain a compound shown as a formula 3d, wherein the purity of the compound is 99% by HPLC (high performance liquid chromatography) determination. MS m/z (ESI): 438(M + 1).¹H NMR(400MHz,DMSO)δ13.61(s,1H),10.02(s,1H),8.22(d,J＝9.1Hz,1H),7.70(d,J＝2.0Hz,1H),7.56–7.44(m,3H),7.28(t,J＝7.4Hz,1H),7.19(d,J＝7.7Hz,2H),4.28(s,2H),3.70(d,J＝6.1Hz,2H),3.44–3.34(m,4H),2.87–2.42(m,4H)。

3) Adding iron powder (4.2g, 32.5mmol) and a proper amount of phosphoric acid into the reaction system obtained in the last step at room temperature, reacting for 5h at 130 ℃, detecting by TLC that the reaction is finished, cooling to room temperature, performing suction filtration, leaching a filter cake with acetic acid, concentrating a filtrate, and treating with methyl tert-ether to obtain 2.15g of [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid with the yield of 93% and the purity of 99.6% by HPLC. The profile data for the remaining materials were the same as in example 1.

Example 6

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to acetonitrile, DBU (20.7g,136mmol) was slowly added dropwise, followed by glycine methyl ester (9.09g,102mmol), warmed to 50 ℃ for 6h, checked by TLC plate for completion, cooled to room temperature, and filtered. The filtrate was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to give 21.6g of methyl (4-hydroxy-7-phenoxyisoquinoline-3-carboxamido) acetate in a yield of 90% and a purity of 98.2% by HPLC. MS m/z (ESI): 353(M + 1). 1H NMR (400MHz, CDCl3) δ 12.85(s,1H), 8.48-8.37 (m,2H),8.34(d, J ═ 9.0Hz,1H), 7.52-7.37 (m,3H),7.23(d, J ═ 7.4Hz,1H), 7.15-7.08 (m,2H),4.28(d, J ═ 5.8Hz,2H),3.81(s, 3H).

2) Mixing (4-hydroxy-7-phenoxyisoquinoline-3-formamido) methyl acetate (2.2g, 6.5mmol) with acetic acid, slowly adding tetramethylmethanediamine (13mmol), performing argon replacement on a reaction system, heating to 80 ℃ for reaction for 3 hours, completing TLC detection reaction, and directly performing the next step without treatment on the obtained reaction system. Taking a small amount of mixed liquor after reaction, adding water to precipitate solid to obtain a compound shown as a formula 3e, wherein the purity of the compound is 99% by HPLC (high performance liquid chromatography). MS m/z (ESI): 410(M + 1). 1H NMR (400MHz, DMSO) δ 13.35(s,1H),9.22(s,1H),8.29(d, J ═ 9.1Hz,1H),7.93(d, J ═ 2.1Hz,1H),7.53(m, J ═ 19.4,13.4,8.1Hz,3H),7.28(t, J ═ 7.4Hz,1H),7.21(d, J ═ 7.7Hz,2H),4.15(d, J ═ 6.1Hz,2H),3.79(s,2H),3.69(s,3H),2.12(s, 6H).

3) Adding zinc powder (4.2g, 32.5mmol) into the reaction system obtained in the last step at room temperature, reacting for 5h at 80 ℃, detecting by TLC that the reaction is finished, cooling to room temperature, performing suction filtration, leaching a filter cake with acetic acid, concentrating a filtrate, and treating with methyl tert-ether to obtain [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid methyl ester 2.28g, wherein the yield is 99.1% and the purity is 98.5% by HPLC. MS m/z (ESI): 367(M + 1). 1H NMR (400MHz, DMSO) δ 13.22(s,1H),9.24(t, J ═ 6.2Hz,1H),8.30(d, J ═ 9.0Hz,1H),7.63(d, J ═ 2.3Hz,1H),7.51(m, J ═ 9.9,4.2,2.3Hz,3H),7.27(dd, J ═ 9.3,5.5Hz,1H),7.18(m, J ═ 10.1,5.2Hz,2H),4.15(d, J ═ 6.2Hz,2H),3.69(s,3H),2.72(s, 3H).

4) [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid methyl ester (2g, 5.46mmol) and sodium hydroxide (0.328g, 8.19mmol) were added to 20mL of methanol, stirred at room temperature for 4h, TLC detected the reaction was complete, pH was adjusted to weak acidity with 2N hydrochloric acid to precipitate a solid, and filtration gave [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ] -acetic acid 1.88g, yield 98%, purity by HPLC 98.6%. The profile data were the same as in example 1.

Example 7

1) Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20g, 68mmol) was added to acetonitrile, DBU (20.7g,136mmol) was slowly added dropwise, followed by glycine methyl ester (9.09g,102mmol), warmed to 50 ℃ for 6h, checked by TLC plate for completion, cooled to room temperature, and filtered. The filtrate was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure to give 21.6g of methyl (4-hydroxy-7-phenoxyisoquinoline-3-carboxamido) acetate in a yield of 90% and a purity of 98.7% by HPLC.

2) Mixing (4-hydroxy-7-phenoxyisoquinoline-3-formamido) methyl acetate (2.2g, 6.5mmol) with acetic acid, slowly adding tetramethylmethanediamine (13mmol), replacing the reaction system with argon, heating to 80 ℃ for reaction for 3h, and detecting the completion of the reaction by TLC. The reaction solution was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness to give 2.53g of methyl (1- ((dimethylamino) methyl) 4-hydroxy-7-phenoxyisoquinoline-3-carboxamido) acetate (3e), yield 95%, purity 98.3% by HPLC.

3) Adding (1- ((dimethylamino) methyl) 4-hydroxy-7-phenoxyisoquinoline-3-formamido) methyl acetate (2.5g, 6.1mmol) and sodium hydroxide (0.366g, 9.15mmol) into 25mL methanol, stirring at room temperature for reaction for 4h, after TLC detection reaction is finished, adjusting pH to weak acidity with 2N hydrochloric acid to precipitate a solid, and filtering to obtain (1- ((dimethylamino) methyl) 4-hydroxy-7-phenoxyisoquinoline-3-formamido) acetic acid 2.36g, wherein the yield is 98%, and the purity is 98.1% by HPLC (high performance liquid chromatography).

4) Adding (1- ((dimethylamino) methyl) 4-hydroxy-7-phenoxyisoquinoline-3-carboxamido) acetic acid (2g, 5.06mmol) to 20mL of acetic acid, adding zinc powder (3.3g, 50.6mmol), reacting at 80 ℃ for 5h, detecting by TLC that the reaction is complete, cooling to room temperature, carrying out suction filtration, leaching the filter cake with acetic acid, concentrating the filtrate, and treating with methyl tert-ether to obtain [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) -amino ] -acetic acid methyl ester 1.73g, with a yield of 97%, and a purity of 98.3% by HPLC. The respective material profile data are the same as in example 1 or example 6.

Comparative example 1

According to CN103435546, a synthesis method of roxasistat is disclosed, and the specific route is as follows (step d-g in example 3):

the total yield of the route is 62.1%, and the steps of palladium-carbon catalysis and ammonolysis need pressurization, so that the process has high requirements on equipment in industrial production, a pipe sealing device or other pressure-resistant equipment needs to be used, and potential safety hazards exist to a certain extent.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A process for preparing a compound of formula 4, said process comprising the steps of:

wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

2. The method of claim 1,

when R is⁰When not hydrogen, the process comprises steps 1-2) or steps 1 '-2'):

or the like, or, alternatively,

when R is⁰In the case of hydrogen, the process comprises the steps of:

3. The method of claim 2, wherein the method comprises one or more features selected from the group consisting of:

in said step 1), said step 2') and/or said step 1 ″), said acid is an inorganic acid or an organic acid, wherein said inorganic acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof; the organic acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof;

in said step 1), said step 2') and/or said step 1 ″), the alcoholic solvent of said acid is selected from the group consisting of: methanol, ethanol, isopropanol, n-butanol, ethylene glycol, or combinations thereof;

in said step 1), said step 2') and/or said step 1 ″), said active metal is selected from the group consisting of: magnesium, aluminum, zinc, iron, or combinations thereof;

in the step 1), the molar ratio of the active metal to the compound of formula 3 is 2-20, preferably 2-10: 1;

in the step 2 '), the molar ratio of the active metal to the compound of formula 3' is 2 to 20, preferably 5 to 15;

in the step 1 "), the molar ratio of the active metal to the compound of the formula 3 is 2 to 20, preferably 5 to 10;

in the step 1), the reaction temperature is 60-140 ℃, preferably 60-100 ℃;

in the step 1), the reaction time is 0.5-12h, preferably 4-6 h;

in step 2'), the temperature of the reaction is 60 to 140 ℃, preferably 60 to 100 ℃;

in the step 2'), the reaction time is 0.5 to 12 hours, preferably 2 to 6 hours;

in step 1 "), the temperature of the reaction is 60-140 ℃, preferably 70-120 ℃;

in the step 2), the first inert solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), or a combination thereof;

said step 1'), wherein said second inert solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), or a combination thereof; and/or

In said step 2) and/or said step 1'), said base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof.

4. The method of claim 2, wherein the method comprises one or more features selected from the group consisting of:

in said step 1), said step 2') or said step 1 ″), said acid is selected from the group consisting of: sulfuric acid, phosphoric acid, trifluoroacetic acid, acetic acid, or a combination thereof;

in said step 1), said step 2') or said step 1 ″), the alcoholic solvent of said acid is isopropanol;

in said step 1), said step 2') or said step 1 ″), the molar ratio of said active metal to the compound of formula 3 is 5 to 15;

said step 1), said step 2') or said step 1 ″), said reaction temperature is 80 to 130 ℃;

in the step 2), the first inert solvent is methanol;

or in step 1'), the second inert solvent is methanol;

the alkali in the step 2) is sodium hydroxide; and/or

In step 1'), the base is sodium hydroxide.

5. The method of claim 1, wherein the compound of formula 3 is prepared by:

wherein the glycine ester is NH₂-CH₂-C(O)-O-R⁰Said aminal is (R)¹ R²)N-CH₂-N(R¹ R²)；

R⁰Selected from H, C1-C10 alkyl, C6-C10 aryl;

6. The method of claim 5,

in the step a), the compound shown in the formula 1 is reacted with glycine or glycine ester in the presence of a third inert solvent and an organic base to obtain the compound shown in the formula 2; and/or

In the step b), reacting the compound of formula 2 with aminal in a fourth inert solvent under acid catalysis to obtain the compound of formula 3.

7. The method of claim 6, wherein the method includes one or more features from the group consisting of:

in the step a), the third inert solvent is selected from the group consisting of: ethylene glycol methyl ether, methanol, ethanol, isopropanol, N-butanol, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, or a combination thereof;

in step a), the organic base is selected from the group consisting of: triethylamine (TEA), 1, 8-diazabicycloundecen-7-ene (DBU), N-Diisopropylethylamine (DIEA), N-methylmorpholine, pyridine, or combinations thereof;

in step a), the glycine ester is selected from the group consisting of: glycine methyl ester, glycine ethyl ester, glycine benzyl ester, or combinations thereof;

in said step a), the molar ratio of said glycine or glycine ester to said compound of formula 1 is from 1 to 4;

in the step a), the molar ratio of the organic base to the compound of formula 1 is 1-5;

in the step a), the reaction temperature is 50-100 ℃;

in the step a), the reaction time is 4-10 h;

in the step b), the fourth inert solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, 1, 4-dioxane, acetic acid, or a combination thereof;

in step b), the acid is selected from the group consisting of: formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof;

in step b), the aminal is selected from the group consisting of: tetramethylethylenediamine, tetrabenzylethylenediamine, bispiperazinylmethane, bismorphinylmethane, dipiperidinylmethane, or a combination thereof;

in said step b), the molar ratio of said aminal to said compound of formula 2 is from 1 to 10;

in the step b), the reaction temperature is 70-120 ℃; and/or

In the step b), the reaction time is 3-10 h.

8. The method of claim 6, wherein the method includes one or more features from the group consisting of:

in the step a), the third inert solvent is acetonitrile;

in said step a), said organic base is 1, 8-diazabicycloundec-7-ene (DBU);

in the step a), the glycine ester is glycine methyl ester;

in said step a), the molar ratio of said glycine or glycine ester to said compound of formula 1 is from 1.3 to 2.5;

in the step a), the molar ratio of the organic base to the compound of formula 1 is 2-4;

in the step a), the reaction temperature is 65-90 ℃;

in the step b), the fourth inert solvent is selected from the group consisting of: water, acetic acid, or a combination thereof;

in step b), the acid is selected from the group consisting of: trifluoroacetic acid, sulfuric acid, phosphoric acid, or a combination thereof;

in the step b), the aminal is tetramethylmethane diamine;

in said step b), the molar ratio of said aminal to said compound of formula 2 is from 1.5 to 5; and/or

In the step b), the reaction temperature is 80-110 ℃.

9. The process according to claim 5, wherein the mixture comprising the compound of formula 3 obtained in step b) is subjected to the subsequent reaction according to step 1), step 1') or step 1 ") without work-up.

10. An isoquinolone compound intermediate is characterized in that the structure of the isoquinolone compound intermediate is shown as a formula 3:

wherein R is⁰Is H, C1-C10 alkyl or C6-C10 aryl;

R¹and R²Independently is C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C10 alkyl-, or R¹And R²And the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl group, said 3-10 membered heterocycloalkyl group containing 1-2 (preferably 1 or 2) N atoms and 0-2 (preferably 0, 1 or 2) heteroatoms selected from O and S;

preferably, the intermediate is: