阅读说明：本技术 一种罗沙司他的制备方法 (Preparation method of Rosxastat ) 是由 陈庆财 陈祥峰 孙敏 贾剑敏 孙焕亮 解杰 于 2020-03-27 设计创作，主要内容包括：本发明属于药物制备领域,具体涉及一种罗沙司他的制备方法,包括：SM1与甘氨酸酯反应生成化合物B；化合物B与四R-3基甲烷二胺反应生成化合物C1；化合物C1反应生成化合物E1；化合物E1水解转化为目标化合物罗沙司他；优选的,化合物B还可以通过化合物A与醇酯化反应生成,或者通过SM1与甘氨酸或甘氨酸盐酰胺化反应生成化合物A,化合物A与醇酯化反应生成；化合物E1还可以通过化合物D1反应生成,或者通过化合物C1反应生成化合物D1,化合物D1反应生成。(The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of a roxarsone, which comprises the following steps: reacting SM1 with glycine ester to produce compound B; compounds B and tetra R 3 Reacting methyl diamine to generate a compound C1; compound C1 to compound E1; compound E1 is converted into the target compound of roxasistat through hydrolysis; preferably, the compound B can also be generated by the esterification reaction of the compound A and alcohol, or generated by the amidation reaction of SM1 and glycine or glycinate, and generated by the esterification reaction of the compound A and alcohol; compound E1 can also be produced by reacting compound D1, or by reacting compound C1 to produce compound D1 and compound D1.)

1. A process for the preparation of a rasagiline base comprising:

(1) reacting SM1 with glycine ester to produce compound B;

R₁、R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group;

(2) compounds B and tetra R₃Reacting methyl diamine to generate a compound C1;

each R₃Independently selected from C_1-6Alkyl radical, C_5-10Arylmethylene or C_5-10Aryl, or two R₃Together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

(3) compound C1 to compound E1;

(4) compound E1 is converted into the target compound of roxasistat through hydrolysis;

2. the process according to claim 1, wherein compound B is also obtainable by:

(1b) carrying out esterification reaction on the compound A and alcohol to generate a compound B;

alternatively, compound B can also be obtained by:

(1a) carrying out amidation reaction on SM1 and glycine or glycinate to generate a compound A;

(1b) carrying out esterification reaction on the compound A and alcohol to generate a compound B;

R₁、R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group.

3. The process according to claim 1, wherein compound E1 is also obtainable by:

(3b) compound D1 to give compound E1;

alternatively, compound E1 can also be obtained by:

(3a) compound C1 to give compound D1;

(3b) compound D1 to give compound E1;

R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group;

each R₃Independently selected from C_1-6Alkyl radical, C_5-10Arylmethylene or C_5-10Aryl, or two R₃Together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

R₄is selected from C_1-6Alkyl radical, C_5-10Aryl radical, C_5-10Heteroaryl and C_5-12A heterocyclic group.

4. The method of claim 1, wherein step (1) is selected from one or more of the following conditions:

the reaction is carried out under the alkaline condition, and the alkali is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate, sodium bicarbonate, sodium carbonate, N-diisopropylethylamine, triethylamine and the like;

the reaction solvent is selected from a single solvent or a mixed solvent of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, acetone, tetrahydrofuran, ethyl acetate, water and the like; the volume-to-mass ratio of the amount of the solvent to the SM1 is 2: 1-50: 1 ml/g;

the molar ratio of the alkali to the SM1 is 0.2: 1-10.0: 1;

the molar ratio of glycine ester to SM1 is 1: 1-10: 1;

the reaction temperature is from room temperature to reflux, and the reaction time is 4-48 h.

5. The method of claim 1, wherein step (2) is selected from one or more of the following conditions:

the reaction is carried out under acidic conditions, and the acid is selected from glacial acetic acid, propionic acid, formic acid, butyric acid and the like;

the mass ratio of the acid to the compound B is 1: 1-30: 1;

tetra R₃The molar ratio of the methyl enediamine to the compound B is 1: 1-10: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 4-48 h.

6. The method of claim 1, wherein step (3) is selected from one or more of the following conditions:

the reducing agent is zinc powder or magnesium powder; the molar ratio of the reducing agent to the C1 is 5: 1-40: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide, acetic acid, propionic acid and water; the volume-to-mass ratio of the amount of the solvent to the C1 is 2: 1-20: 1 ml/g;

adding acid in the reaction, wherein the acid is one or a mixture of several of formic acid, acetic acid, propionic acid, citric acid and hydrochloric acid; the molar ratio of the acid to the C1 is 5: 1-50: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 1-48 h.

7. The method of claim 1, wherein step (4) is selected from one or more of the following conditions:

the reaction is carried out under alkaline conditions, and the alkali is selected from lithium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate; the molar ratio of the alkali to the E1 is 1: 1-10: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide and water; the volume-to-mass ratio of the amount of the solvent to the E1 is 5: 1-30: 1 ml/g;

the reaction temperature is 0-100 ℃, and the reaction time is 0.5-24 h.

8. The method of claim 2, wherein:

step (1a) is selected from one or more of the following conditions:

the glycinate salt is selected from sodium glycinate, potassium glycinate, magnesium glycinate and lithium glycinate; the molar ratio of the glycine or glycine salt to the SM1 is 1: 1-6: 1;

the reaction solvent is one or a mixture of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide and water; the volume-to-mass ratio of the amount of the solvent to the SM1 is 4: 1-30: 1 ml/g;

the reaction temperature is from room temperature to reflux, and the reaction time is 1-48 h;

step (1b) is selected from one or more of the following conditions:

the reaction is carried out under the alkaline condition, and the alkali is selected from N, N-diisopropylethylamine, potassium carbonate, sodium carbonate, triethylamine and sodium bicarbonate; the molar ratio of the alkali to the A is 0.5: 1-5: 1;

the esterification reagent is thionyl chloride and oxalyl chloride, and the molar ratio of the esterification reagent to A is 1:1 to 5: 1;

the reaction temperature is from room temperature to reflux, and the reaction time is 2-24 h.

9. The method according to claim 3, wherein the step (3b) is selected from one or more of the following conditions:

the reducing agent is zinc powder or magnesium powder; the molar ratio of the reducing agent to the D1 is 5: 1-40: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide, acetic acid, propionic acid and water; the volume-to-mass ratio of the amount of the solvent to D1 is 4: 1-20: 1 ml/g;

adding acid in the reaction, wherein the acid is one or a mixture of several of formic acid, acetic acid, propionic acid, citric acid and hydrochloric acid; the molar ratio of the acid to the D1 is 5: 1-50: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 1-48 h.

10. The method according to claim 3, wherein the step (3a) is selected from one or more of the following conditions:

the reaction is carried out under acidity, the acid is acetic acid and propionic acid, and the molar ratio of the acid to C1 is 4: 1-20: 1;

the reaction reagent is R₄Acid anhydride, wherein the molar ratio of the reaction reagent to the C1 is 2: 1-10: 1;

the reaction solvent is one or more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetone, N-dimethylacetamide, dimethyl sulfoxide and acetic acid; the volume-mass ratio of the amount of the solvent to the C1 is 0.5: 1-15: 1 ml/g;

the reaction temperature is from room temperature to reflux, and the reaction time is 4-48 h.

Technical Field

The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of a roxasistat.

Background

Rosxastat, trade name:is the first new oral medicine approved to be on the market in China for treating renal anemia, and is prepared from AsriconThe medicine is developed in cooperation with the Fabry-Perot, is approved by the national drug administration (NMPA) on the market in 2018, 12 and 17 months, and is used for treating anemia of chronic kidney disease dialysis patients. The medicine has not yet been marketed in any other country before being approved for marketing in China. As the first hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) in the world, the rosomastat effectively promotes the erythropoiesis by promoting the production of endogenous erythropoietin, improving the absorption and utilization of iron, reducing hepcidin and being not influenced by the negative effect of inflammation on the production of hemoglobin and erythrocytes. Rosemastat has been shown to induce erythropoiesis. In multiple subpopulations of chronic kidney disease patients, rospastat maintains erythropoietin levels in or near the normal physiological range, thereby increasing red blood cell counts, while not being affected by inflammatory conditions and avoiding intravenous iron supplementation.

It has the following structure:

CAS number 808118-40-3, Chinese academy name: [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid.

At present, more methods for preparing the roxasipid are involved.

The compound patent WO2004108681 of the original research FibroGen application discloses the following synthetic route:

the original ZL201310302822.0(CN103435546B) filed by the gazette corporation limited discloses a preparation method of the roxasistat as follows:

the zhejiang beida medical patent WO2013013609 discloses the following route:

the suzhou mingrui patent CN104892509B discloses the following route:

JOC,83(24), 15415-15425; 2018 discloses the following route:

shanghai gazan and medicine CN106478504A disclose the following routes:

the applicant has developed a new synthesis method for rosxastat:

disclosure of Invention

Specifically, the invention discloses a preparation method of a roxburgh rose sauce, which is characterized by comprising the following steps:

(1) reacting SM1 with glycine ester to produce compound B;

R₁、R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group;

(2) compounds B and tetra R₃Reacting methyl diamine to generate a compound C1;

each R₃Independently selected from C_1-6Alkyl radical, C_5-10Arylmethylene or C_5-10Aryl, or two R₃Together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

(3) compound C1 to compound E1;

(4) compound E1 is converted into the target compound of roxasistat through hydrolysis;

R₁、R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group.

Preferably, compound E1 can also be obtained by the following method:

(3b) compound D1 to give compound E1;

alternatively, compound E1 can also be obtained by:

(3a) compound C1 to give compound D1;

(3b) compound D1 to give compound E1;

R₂selected from hydrogen and unsubstituted or independently selected from C_3-8Cycloalkyl radical, C_5-12Heterocyclic group, C_5-10Aryl and C_5-10C substituted by one or more substituents in heteroaryl_1-6An alkyl group;

each R₃Independently selected from C_1-6Alkyl radical, C_5-10Arylmethylene or C_5-10Aryl, or two R₃Together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

R₄is selected from C_1-6Alkyl radical, C_5-10Aryl radical, C_5-10Heteroaryl and C_5-12A heterocyclic group.

Preferably, step (1) is selected from one or more of the following conditions:

the reaction is carried out under the alkaline condition, and the alkali is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate, sodium bicarbonate, sodium carbonate, N-diisopropylethylamine, triethylamine and the like;

the reaction solvent is selected from a single solvent or a mixed solvent of N, N-dimethylformamide, N-dimethylacetamide, methanol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, acetone, tetrahydrofuran, ethyl acetate, water and the like; the volume-to-mass ratio of the amount of the solvent to the SM1 is 2: 1-50: 1 ml/g;

the molar ratio of the alkali to the SM1 is 0.2: 1-10.0: 1;

the molar ratio of glycine ester to SM1 is 1: 1-10: 1;

the reaction temperature is from room temperature to reflux, and the reaction time is 4-48 h.

Preferably, the volume-to-mass ratio of the solvent to the SM1 is further preferably 2:1 to 45: 1; 5: 1-40: 1; 10: 1-35: 1; 15: 1-30: 1; 20:1 to 25: 1.

Preferably, the molar ratio of the base to SM1 may be further preferably 0.5:1 to 8: 1; 1: 1-6: 1; 2: 1-5: 1; 3:1 to 4: 1.

Preferably, the reaction time is further preferably 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Preferably, step (2) is selected from one or more of the following conditions:

the reaction is carried out under acidic conditions, and the acid is selected from glacial acetic acid, propionic acid, formic acid, butyric acid and the like;

the mass ratio of the acid to the compound B is 1: 1-30: 1;

tetra R₃The molar ratio of the methyl enediamine to the compound B is 1: 1-10: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 4-48 h.

Preferably, the mass ratio of the acid to the compound B is further preferably 2:1 to 25: 1; 5: 1-20: 1; 8: 1-15: 1; 10: 1-12: 1.

Tetra R₃The molar ratio of the methyl enediamine to the compound B is more preferably 1.2:1 to 8: 1; 1.5: 1-6: 1; 2: 1-5: 1; 3:1 to 4: 1.

The reaction temperature may be more preferably 40 to 90 ℃; 50-80 ℃; 60-70 ℃;

the reaction time can be further optimized to be 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Preferably, step (3) is selected from one or more of the following conditions:

the reducing agent is zinc powder or magnesium powder; the molar ratio of the reducing agent to the C1 is 5: 1-40: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide, acetic acid, propionic acid and water; the volume-to-mass ratio of the amount of the solvent to the C1 is 2: 1-20: 1 ml/g;

adding acid in the reaction, wherein the acid is one or a mixture of several of formic acid, acetic acid, propionic acid, citric acid and hydrochloric acid; the molar ratio of the acid to the C1 is 5: 1-50: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 1-48 h.

Preferably, the molar ratio of the reducing agent to the C1 may be further preferably 8:1 to 35: 1; 10: 1-32: 1; 12: 1-30: 1; 15: 1-25: 1; 18: 1-20: 1.

The volume-to-mass ratio of the amount of the solvent to the C1 is further preferably 2: 1-18: 1; 4: 1-15: 1; 6: 1-12: 1; 8: 1-10: 1.

The molar ratio of the acid to the C1 may be further preferably 8:1 to 45: 1; 10: 1-40: 1; 12: 1-35: 1; 15: 1-30: 1; 18: 1-25: 1; 20:1 to 22: 1.

The reaction temperature may be more preferably 40 to 90 ℃; 50-80 ℃; 60-70 ℃;

the reaction time is further preferably 2-48 h; 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Preferably, step (4) is selected from one or more of the following conditions:

the reaction is carried out under alkaline conditions, and the alkali is selected from lithium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate; the molar ratio of the alkali to the E1 is 1: 1-10: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide and water; the volume-to-mass ratio of the amount of the solvent to the E1 is 5: 1-30: 1 ml/g;

the reaction temperature is 0-100 ℃, and the reaction time is 0.5-24 h.

Preferably, the molar ratio of the base to the E1 may be further preferably 1.5:1 to 8: 1; 2: 1-6: 1; 3: 1-5: 1.

The volume-to-mass ratio of the amount of the solvent to the E1 is further preferably 8:1 to 25: 1; 10: 1-20: 1; 12: 1-15: 1 ml/g.

The reaction temperature is further preferably 5-90 ℃; 10-80 ℃; 15-70 ℃; 20-60 ℃; 25-50 ℃; 30-40 ℃;

the reaction time can be further optimized to be 1-20 h; 2-18 h; 4-16 h; 6-12 h; 8-10 h.

Preferably, step (1a) is selected from one or more of the following conditions:

the glycinate salt is selected from sodium glycinate, potassium glycinate, magnesium glycinate and lithium glycinate; the molar ratio of the glycine or glycine salt to the SM1 is 1: 1-6: 1;

the reaction solvent is one or a mixture of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide and water; the volume-to-mass ratio of the amount of the solvent to the SM1 is 4: 1-30: 1 ml/g;

the reaction temperature is from room temperature to reflux, and the reaction time is 1-48 h;

preferably, the molar ratio of glycine or glycine salt to SM1 may be further preferably 1.5:1 to 5: 1; 2: 1-4: 1; 2.5-3: 1.

The volume-to-mass ratio of the amount of the solvent to the SM1 may be more preferably 5:1 to 25:1, 6:1 to 20:1, 8:1 to 15:1, 10:1 to 12:1 ml/g.

The reaction time is further preferably 2-48 h; 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Preferably, step (1b) is selected from one or more of the following conditions:

the reaction is carried out under the alkaline condition, and the alkali is selected from N, N-diisopropylethylamine, potassium carbonate, sodium carbonate, triethylamine and sodium bicarbonate; the molar ratio of the alkali to the A is 0.5: 1-5: 1;

the esterification reagent is thionyl chloride and oxalyl chloride, and the molar ratio of the esterification reagent to A is 1: 1-5: 1;

the reaction temperature is from room temperature to reflux, and the reaction time is 2-24 h.

Preferably, the molar ratio of the base to a may be further preferably 1:1 to 4: 1; 1.5: 1-3: 1; 2: 1-2.5: 1.

The molar ratio of the esterification reagent to A may be more preferably 1.5:1 to 4:1, 2:1 to 3.5:1, or 2.5:1 to 3: 1.

The reaction time is further preferably 4-18 h; 6-12 h; 8-10 h.

Preferably, step (3b) is selected from one or more of the following conditions:

the reducing agent is zinc powder or magnesium powder; the molar ratio of the reducing agent to the D1 is 5: 1-40: 1;

the solvent is one or a mixture of more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetone, N-dimethylacetamide, dimethyl sulfoxide, acetic acid, propionic acid and water; the volume-to-mass ratio of the amount of the solvent to D1 is 4: 1-20: 1 ml/g;

adding acid in the reaction, wherein the acid is one or a mixture of several of formic acid, acetic acid, propionic acid, citric acid and hydrochloric acid; the molar ratio of the acid to the D1 is 5: 1-50: 1;

the reaction temperature is 30-100 ℃, and the reaction time is 1-48 h.

Preferably, the molar ratio of the reducing agent to the D1 is 8: 1-35: 1; 10: 1-32: 1; 12: 1-30: 1; 15: 1-25: 1; 18: 1-20: 1.

The volume-to-mass ratio of the amount of the solvent to D1 may be more preferably 4:1 to 18:1, 4:1 to 15:1, 6:1 to 12:1, 8:1 to 10:1 ml/g.

The molar ratio of the acid to D1 may be further preferably 8:1 to 45: 1; 10: 1-40: 1; 12: 1-35: 1; 15: 1-30: 1; 18: 1-25: 1; 20:1 to 22: 1.

The reaction temperature may be more preferably 40 to 90 ℃; 50-80 ℃; 60-70 ℃;

the reaction time is further preferably 2-48 h; 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Preferably, step (3a) is selected from one or more of the following conditions:

the reaction is carried out under acidity, the acid is acetic acid and propionic acid, and the molar ratio of the acid to C1 is 4: 1-20: 1;

the reaction reagent is R₄The molar ratio of the acid anhydride to the reactants to C1 is 2:1 ℃10:1；

The reaction solvent is one or more of N, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetone, N-dimethylacetamide, dimethyl sulfoxide and acetic acid; the volume-mass ratio of the amount of the solvent to the C1 is 0.5: 1-15: 1 ml/g;

the reaction temperature is from room temperature to reflux, and the reaction time is 4-48 h.

Preferably, the molar ratio of the acid to the C1 may be further preferably 5:1 to 18:1, 8:1 to 15:1, or 10:1 to 12: 1.

The molar ratio of the reaction reagent to the C1 is more preferably 2.5:1 to 8: 1; 3: 1-6: 1; 4: 1-5: 1.

The volume-to-mass ratio of the amount of the solvent to the C1 is more preferably 1: 1-12: 1, 1: 1-10: 1, 1.5: 1-8: 1, 2: 1-6: 1, 4: 1-5: 1 ml/g.

The reaction time can be further optimized to be 4-36 h; 6-24 h; 8-18 h; 10-12 h.

Detailed Description

The term "alkyl" refers to saturated monovalent hydrocarbon radicals having from 1 to 6 carbon atoms, more specifically from 1 to 4 carbon atoms and even more specifically from 1 to 3 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and the like.

The term "cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group having 3 to 8 or 3 to 6 carbon atoms, which has a single ring or multiple rings, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, cyclohexenyl, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. As used herein, the term refers to a saturated or unsaturated (but not aromatic) group having a single ring or multiple fused rings, having 5 to 12 carbon atoms, and having 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the rings, wherein in the fused ring system one or more of the rings can be aryl or heteroaryl, provided that the point of attachment is on a heterocyclic ring. The nitrogen and/or sulfur ring atoms may optionally be oxidized to provide N-oxide or sulfoxide and sulfone derivatives. Examples of heterocyclyl groups include, but are not limited to: piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, pyrrolidinyl, morpholino, thiomorpholino and the like.

The term "aryl" refers to a monovalent aromatic 5-10 carbon atom carbocyclic group having a single ring or multiple fused rings, with preferred aryl groups including phenyl and naphthyl.

The term "heteroaryl" refers to an aromatic ring of 5 to 10 carbon atoms with 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups may have a single ring or multiple fused rings, provided that the point of attachment is through the ring containing the heteroatom, and the ring is aromatic. The nitrogen and/or sulfur ring atoms may optionally be oxidized to provide N-oxide or sulfoxide and sulfone derivatives. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, indolyl, thiophenyl, thienyl and furanyl.

Detailed Description

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.

EXAMPLE 1 preparation of Compound A

Weighing 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (SM 1-1, 20g, 68mmol) and sodium glycinate (19.8g, 200mmol) and adding into a reaction bottle, then adding DMF 110ml, introducing nitrogen, stirring at 110 ℃ for reaction, after the reaction is finished (the system is turbid), cooling to less than 20 ℃, then slowly dripping water to obtain the turbid system, finally dripping AcOH to adjust the pH to about 5-6, separating out a solid, crystallizing at less than 10 ℃ for 1-2 hours, then carrying out suction filtration, washing with water to obtain a white solid, and drying to obtain a compound A20.93 g, with the yield of 91% and the purity of 99.4%.

EXAMPLE 2 preparation of Compound B-1

(1) Preparation of Compound B-1 from Compound A

Adding compound A (40g, 118mmol) into a reaction flask, adding ethanol (400ml) and DIPEA (16.8g, 130mmol), cooling with a cold trap under protection of N2 (5 deg.C, and adding SOCl dropwise when the internal temperature is less than 5 deg.C₂(16.9g, 142mmol), the system is in a turbid state, the system is viscous and is not easy to stir after the dropwise addition (the internal temperature is less than 15 ℃), the refrigeration and the heating are stopped, the reaction is carried out at the external 60 ℃, the reaction is finished after the internal temperature is more than 50 ℃ and the reaction is about 2 hours, the temperature is reduced after the reaction is finished, part of water is dropwise added after the internal temperature is less than 40 ℃, then the temperature is reduced, 0.8N sodium hydroxide aqueous solution is dropwise added after the internal temperature is controlled to be less than 15 ℃, the pH value is adjusted to be 5-6, the crystallization is carried out for 1 hour (the internal temperature is less than 15 ℃), the suction filtration is carried out, the filter cake is obtained by water washing, the filter cake is completely added into a reaction bottle, then 170mL of DMF is added, the heating and the dissolution is carried out at 60 ℃, the temperature is reduced after the dissolution, 680mL of water is dropwise added when the internal temperature is less than 10 ℃, the crystallization is carried out for 30 minutes after the dropwise addition, the suction filtration and the water washing is carried out, the filter cake is obtained, the drying, the compound B-141.38 g is obtained, the yield is 95.4%, and the HPLC is 99.5%.

(2) Preparation of Compound B-1 from SM1-1

Weighing 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (10g, 34mmol), glycine ethyl ester hydrochloride (14.2g, 102mmol) and sodium methoxide (6.43g, 119mmol), adding the mixture into a reaction bottle, adding DMF (100ml), introducing nitrogen, stirring at 110 ℃ for reaction, cooling to less than 20 ℃ until the system is turbid after the reaction is finished, slowly dropwise adding water to the system to obtain a turbid system, dropwise adding AcOH to adjust the pH to about 5-6, separating out solids, crystallizing at the temperature of less than 10 ℃ for 1-2 hours, performing suction filtration, washing with water to obtain white solids, and drying to obtain a compound B-111.6 g with the yield of 93%.

Example 3 preparation of C1-1

Weighing a compound B-1(20g, 54.6mmol), adding glacial acetic acid (44g, 732.7mmol) into a reaction bottle, controlling the temperature to be less than 25 ℃, slowly dropwise adding tetramethylmethanediamine (7.24g, 70.9mmol), stirring for 30min (protected by N2) after dropwise adding is finished, heating, externally arranging 60 ℃, stirring overnight, after TLC detection reaction is finished, cooling, dropwise adding 200ml of purified water when the temperature is controlled to be less than 20 ℃, cooling again after dropwise adding is finished, dropwise adding prepared 2N NaOH aqueous solution when the temperature is controlled to be less than 10 ℃ to regulate the pH to be 8-9, performing timed crystallization for 1h after dropwise adding is finished, performing suction filtration to obtain a filter cake, and drying to obtain a compound C1-120.97g, the yield is 89.71%, and the HPLC is 99.06%.

EXAMPLE 4 preparation of Compound D1-1

Compound C1-1(5.0g, 11.8mmol), acetic acid (5.0g, 83.3mmol) and DMF (4ml) were weighed into a reaction flask, heated to 40 deg.C, acetic anhydride (4.82g, 47.2mmol) was added dropwise, after the addition was complete, heated to 100 deg.C and reacted overnight. After cooling to room temperature, 35ml of water was added dropwise, and the mixture was washed with water by filtration. The solid was dissolved in a mixed solution of 60ml DCM and 20ml water, morpholine (2.06g, 23.6mmol) was added at room temperature, the organic phase was separated, the aqueous phase was extracted twice with DCM, then the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulphate, concentrated to dryness and polish dried with THF/water to give compound D1-13.89 g, yield 75%.

EXAMPLE 5 preparation of Compound E1-1

(1) Preparation of compound E1-1 from compound D1-1;

compound D1-1(3.0g,6.8mmol), zinc powder (2.30g, 35.2mmol) and 30ml of ethyl acetate were weighed into a reaction flask. Acetic acid (4.24g, 70.6mmol) was added dropwise at room temperature, reaction was carried out overnight at 50 ℃ and incomplete reaction was detected by TLC, and zinc powder (2.30g, 35.2mmol) and acetic acid (4.24g, 70.6mmol) were added, reaction was carried out to completion at 50 ℃, filtration was carried out, washing was carried out with 12ml of DMF, ethyl acetate was removed by concentration under reduced pressure, then 48ml of water was added dropwise, and filtration was carried out to obtain 2.43g of Compound E1-1.

(2) Preparation of Compound E1-1 from Compound C1-1

Adding a compound C1-1(10g, 23.6mmol) and zinc powder (30.73g, 472.8mmol) into a reaction bottle, then adding 30ml of DMF into the system, heating to 40-50 ℃, stirring and dissolving, cooling to room temperature, then dropwise adding propionic acid (70g, 945.9mmol), stirring for 10min after dropwise adding is finished, heating to 45 ℃ for overnight reaction, detecting that the raw material C1 is completely reacted by TLC, cooling the reaction system to room temperature, adding 40ml of EA into the system, stirring for 30min, then carrying out suction filtration, eluting a filter cake with THF until no product exists in the washing filtrate, filtering the obtained filtrate with diatomite until turbid solid exists, allowing the filtrate to be slightly turbid, concentrating the filtrate at 45 ℃ until almost no liquid drops overflow, dropwise adding 250ml of water into the obtained filtrate, crystallizing for 1.5h at 10 ℃, carrying out suction filtration to obtain the filter cake, drying the filter cake to obtain 7.76g of crude E1-1, and obtaining the yield: 86.4%, purity: 98.589.

(3) preparation of Compound E1-1 from Compound C1-1

Adding a compound C1-1(5.0g, 11.8mmol) and zinc powder (15.3g, 235mmol) into a reaction bottle, adding DMF (40ml) into the system, stirring (40-50 ℃) to dissolve, cooling to room temperature, adding citric acid monohydrate (49g, 233mmol), heating to 45 ℃ to react for 2 hours, detecting that the raw materials are completely reacted by TLC, cooling the reaction system to room temperature, adding EA (40ml) into the system, stirring for 30 minutes, performing suction filtration, leaching a filter cake with ethyl acetate until no product exists in the washing filtrate, concentrating the filtrate until no liquid drops overflow, adding 250ml of water into the obtained filtrate dropwise, crystallizing at 10 ℃ for 1.5 hours, performing suction filtration to obtain a filter cake, and drying the filter cake to obtain E1-13.84 g (yield: 86.0%, purity: 99.6%).

EXAMPLE 6 Synthesis of the object Compound

Adding a compound E1-1(7.0g,18.4mmol), DMF (80ml) and triethylamine (2ml) into a reaction bottle, dropwise adding an aqueous solution (18ml) of lithium hydroxide (1.73g,72.2mmol), heating to 50 ℃ for reaction, dropwise adding 400ml of water after the reaction is completed, heating to 60 ℃, adjusting the pH value to 4-5 with acetic acid, cooling for crystallization, filtering, and washing with water to obtain a finished product 5.57 g.