WO2024212883A1 - Preparation method for aryl methoxy isoindoline derivative - Google Patents

Abstract

The present invention relates to a preparation method for an aryl methoxy isoindoline derivative, and belongs to the field of pharmaceutical chemical industry. Specifically, in the presence of a reducing agent, a compound of formula III and a compound of formula II react in an organic solvent to generate a compound of formula I. Provided is a new preparation route for the aryl methoxy isoindoline derivative, and the preparation route has a high yield and a high product purity.

Description

A method for preparing arylmethoxyisoindoline derivatives

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority and benefits of Chinese invention patent application No. 202310387486.8 filed with the State Intellectual Property Office of China on April 11, 2023, and all the contents disclosed in the application are incorporated herein by reference in their entirety.

Technical Field

The invention relates to the field of medical technology, and in particular to a method for preparing an arylmethoxyisoindoline derivative.

Background Art

Systemic lupus erythematosus (SLE) is an autoimmune disease that is formed by antibodies and immune complexes and mediates organ and tissue damage. Clinically, multiple system involvement is often present. There are a large number of antibodies in the patient's serum, and immune complexes are deposited in small blood vessels, causing pathological damage to vasculitis and resulting in multiple organ dysfunction. Systemic lupus erythematosus is more common in women, of which 90% of patients are often women of childbearing age between 20 and 40 years old.

The compound of formula I-1 is a novel oral cereblon E3 ubiquitin ligase immunomodulator, the chemical name of which is (s)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione, and clinically shows good efficacy in the treatment of SLE. It has the following structure:

WO200627788 and US201446058 disclose methods for preparing compounds of formula I-1, but they still face problems such as poor yield or lengthy routes. Therefore, a new method for synthesizing compounds of formula I-1 is urgently needed.

SUMMARY OF THE INVENTION

The invention provides a novel preparation method of arylmethoxyisoindoline derivatives. The product prepared by the preparation route has good yield and purity.

In addition, the present invention also provides a compound of formula III or a salt thereof, which can be used to prepare an arylmethoxyisoindoline derivative or a salt thereof.

Furthermore, the present invention also provides a method for preparing the compound of formula III or its salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for preparing a compound of formula I, characterized in that: a compound of formula III or a salt thereof and a compound of formula II or a salt thereof are reacted in an organic solvent A in the presence of a reducing agent to generate a compound of formula I or a salt thereof,

in,

^R1 is H or an amino protecting group;

^R2 is OH or _C1 - _C6 alkoxy.

In some typical embodiments, R ¹ is H, tert-butyloxycarbonyl, benzyloxycarbonyl, tert-methoxycarbonyl or benzyl; in some more typical embodiments, R ¹ is H.

In some embodiments of the present invention, R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy; in some typical embodiments, R ² is methoxy or ethoxy; in some more typical embodiments, R ² is methoxy.

In some embodiments of the present invention, more than 80% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and more than 80% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt; in some typical embodiments, more than 90% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and more than 90% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt; in some more typical embodiments, 100% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and 100% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt; in some most typical embodiments, the compound of formula II-S or its salt exists in the form of the compound of formula II-1 or its salt, and the compound of formula IS or its salt exists in the form of the compound of formula I-1 or its salt;

In some particular embodiments of the present invention, the compound of formula III or its salt is a compound of formula III-1 or its salt, the compound of formula II or its salt is a compound of formula II-1 or its salt, and the compound of formula I or its salt is a compound of formula I-1 or its salt,

In some embodiments of the present invention, the organic solvent A is selected from one or more of C ₁ -C ₆ alkyl alcohols, 6-10 aromatic hydrocarbons, C ₆ -C ₁₀ aliphatic hydrocarbons, halogenated C ₁ -C ₇ alkanes, amides, ketones, esters, ethers, and nitriles. In some typical embodiments, the organic solvent A is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, ethylene glycol monomethyl ether, tetrahydrofuran, N,N-dimethylacetamide, acetonitrile, one or a mixed solvent of two or more thereof; in some more typical embodiments, the organic solvent A is selected from methanol, ethanol, isopropyl alcohol, tetrahydrofuran, N,N-dimethylacetamide, acetonitrile, one or a mixed solvent of two or more thereof; in some more typical embodiments, the organic solvent A is selected from methanol, ethanol, tetrahydrofuran, acetonitrile, one or a mixed solvent of two or more thereof; in some most typical embodiments, the organic solvent A is one of methanol, ethanol, tetrahydrofuran or a mixed solvent consisting of ethanol and tetrahydrofuran.

In some embodiments of the present invention, the reducing agent is one or more of alkali metal borohydride, palladium carbon/hydrogen, Raney nickel/hydrogen, diisobutylaluminum hydride; in some embodiments, the reducing agent is one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, palladium carbon/hydrogen, Raney nickel/hydrogen, diisobutylaluminum hydride; in some more typical embodiments, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon/hydrogen, diisobutylaluminum hydride; in some more typical embodiments, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride; in some more typical embodiments, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon/hydrogen; in some more typical embodiments, the reducing agent is sodium borohydride.

In some embodiments of the present invention, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.2-22; in some embodiments of the present invention, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4-20; in some typical embodiments, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.2-0.8; in more typical embodiments, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4, 1:0.5, 1:0.6, 1:0.7 or any range between the ratios; in the most typical embodiment, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4, 1:0.5, 1:0.6.

In some typical embodiments, the reducing agent is palladium carbon/hydrogen, and the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:15-24, calculated on the basis of palladium; in a more typical embodiment, the reducing agent is palladium carbon/hydrogen, and the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:18, 1:19, 1:20, 1:21, 1:22 or a range between any ratios thereof, calculated on the basis of palladium; in the most typical embodiment, the reducing agent is palladium carbon/hydrogen, and the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:19-20, calculated on the basis of palladium.

In some embodiments of the present invention, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is 1:0.5-10; in some typical embodiments, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is 1:1-8; in some more typical embodiments, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is 1:1-5; in some more typical embodiments, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is The molar ratio is 1:1-2; in some more typical embodiments, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is 1:1.3-1.7; in some most typical embodiments, the molar ratio of the compound of formula II or its salt to the compound of formula III or its salt is 1:1, 1:1.1, 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, or 1:1.8 or any range between the ratios.

In some embodiments of the present invention, the reaction temperature of the route I reaction is -20°C to 30°C; in some typical embodiments, the reaction temperature of the route I reaction is -10°C to 25°C; in some typical embodiments, the reaction temperature of the route I reaction is 0°C to 25°C; in some more typical embodiments, the reaction temperature of the route I reaction is -20°C to 5°C; in some more typical embodiments, the reaction temperature of the route I reaction is 0°C to 5°C; in some most typical embodiments, the reaction temperature of the route I reaction is -15°C, -12°C, -10°C, -7°C, -5°C, -3°C, 0°C, 1°C, 2°C, 3°C, 4°C or 5°C or any range therein; in some more typical embodiments, the reaction temperature of the route I reaction is 20°C to 30°C; in some most typical embodiments, the reaction temperature of the route I reaction is 22°C, 23°C, 24°C, 25°C, 26°C or 27°C or any range therein.

In some embodiments of the present invention, the reaction time of the route I reaction is 0.5h to 24h; in some typical embodiments, the reaction time of the route I reaction is 2h to 12h; in some most typical embodiments, the reaction time of the route I reaction is 3h, 4h, 5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h or 12h or any range therein.

In some embodiments of the present invention, the reaction of route I is carried out in the presence of an alkaline reagent A; in some typical embodiments, the alkaline reagent A is selected from one or a mixture of two of an organic alkaline reagent and an inorganic alkaline reagent; in some typical embodiments, the alkaline reagent A is selected from one or a mixture of two or more of an alkali metal carbonate, DBU, tetra(C ₁ -C ₄ alkyl)ammonium halide, and C ₆ -C ₁₀ alkylamine; in some more typical embodiments, the alkaline reagent A is selected from one or a mixture of two or more of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylamine, and diisopropylethylamine; in some more typical embodiments, the alkaline reagent A is selected from one or a mixture of two or more of potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium iodide, triethylamine, and diisopropylethylamine; in some more typical embodiments, the alkaline reagent A is selected from One or a mixture of two or more selected from potassium carbonate, sodium carbonate, tetrabutylammonium iodide, diisopropylethylamine, and DBU; in some more typical embodiments, the alkaline agent A is selected from potassium carbonate, triethylamine, and diisopropylethylamine, or a mixture of two or more selected from diisopropylethylamine; in some more typical embodiments, the alkaline agent A is selected from a mixture of tetrabutylammonium iodide and DBU, potassium carbonate, diisopropylethylamine, sodium carbonate, tetrabutylammonium iodide, or triethylamine; in some most typical embodiments, the alkaline agent A is selected from potassium carbonate or triethylamine; in some most typical embodiments, the alkaline agent A is selected from diisopropylethylamine.

In some embodiments of the present invention, the molar feed ratio of the alkaline reagent A to the compound of formula III or its salt is 0-5:1; in some typical embodiments, the molar feed ratio of the alkaline reagent A to the compound of formula III or its salt is 0-4:1; in a more typical embodiment, the molar feed ratio of the alkaline reagent A to the compound of formula III or its salt is 0-3:1; in the most typical embodiment, the molar feed ratio of the alkaline reagent A to the compound of formula III or its salt is 0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.7:1, 1.9:1, 2:1, 2.5:1, 2.6:1, 2.7:1 or 2.8:1 or any range therein.

In some embodiments of the present invention, the reaction of Route I is optionally carried out under nitrogen protection; in some typical embodiments, the reaction of Route I is carried out under nitrogen protection.

In some embodiments of the present invention, the reaction of route I optionally further comprises, at the end of the reaction, adjusting the pH value to 5.5-8.0, filtering and removing the solution to obtain a crude compound of formula I or a salt thereof; in some typical embodiments, the reaction of route I optionally further comprises, at the end of the reaction, adjusting the pH value to 6.0-7.5, filtering and removing the solution to obtain a crude compound of formula I or a salt thereof; in more typical embodiments, the reaction of route I optionally further comprises, at the end of the reaction, adjusting the pH value to 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4 or 7.5 or any range between them, filtering and removing the solution to obtain a crude compound of formula I or a salt thereof; in the most typical embodiment, the reaction of route I further comprises adjusting the pH value to 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4 or 7.5 or any range between them with dilute hydrochloric acid, sodium acetate or sodium hydroxide at the reaction end, filtering and removing the solution to obtain a crude compound of formula I or a salt thereof.

In some embodiments of the present invention, the reaction of route I optionally further comprises recrystallization of the crude compound of formula I or its salt; in some typical embodiments, the reaction of route I optionally further comprises recrystallization of the crude compound of formula I or its salt using _C1 - _C6 alcohol, 6-10 aromatic hydrocarbons, C3 _{- C7} esters and/or nitriles as good solvents and n-heptane as poor solvents; in some more typical embodiments, the reaction of route I optionally further comprises recrystallization of the crude compound of formula I or its salt using methanol, ethanol, toluene, acetonitrile or isopropyl acetate as good solvents and n-heptane or water as poor solvents.

In some typical embodiments, the reaction of route I optionally further comprises recrystallizing the crude compound of formula I or its salt using toluene, ethanol, acetonitrile or isopropyl acetate as a recrystallization solvent; in some more typical embodiments, the reaction of route I optionally further comprises recrystallizing the crude compound of formula I or its salt using toluene, ethanol, acetonitrile or isopropyl acetate as a recrystallization solvent.

The present invention also provides a compound of formula III or a salt thereof,

Wherein, ^R2 is OH or _C1 - _C6 alkoxy.

In some embodiments of the present invention, R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy; in some typical embodiments, R ² is methoxy or ethoxy; in some more typical embodiments, R ² is methoxy.

The present invention also provides use of a compound of formula III or a salt thereof in preparing a compound of formula I or a salt thereof; in particular, use of a compound of formula III or a salt thereof in preparing a compound of formula I-S or a salt thereof; more particularly, use of a compound of formula III-1 or a salt thereof in preparing a compound of formula I-1 or a salt thereof.

The present invention also provides a method for preparing a compound of formula III or a salt thereof, characterized in that: a compound of formula V or a salt thereof and a compound of formula IV or a salt thereof are reacted in an organic solvent B to obtain a compound of formula III or a salt thereof,

in,

R ² is OH or C ₁ -C ₆ alkoxy;

R ³ is OH, optionally substituted C ₁ -C ₆ alkylsulfonyloxy, optionally substituted benzenesulfonyloxy or halogen;

^R4 is OH or halogen;

Furthermore, R ³ and R ⁴ are not halogen at the same time.

In some embodiments of the present invention, R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy; in some typical embodiments, R ² is methoxy or ethoxy; in some more typical embodiments, R ² is methoxy.

In some embodiments of the present invention, R ³ is OH, OTs, OMs, OTf, ONs, F, Cl, Br or I; in some typical embodiments, R ³ is F, Cl, Br or I; in some more typical embodiments, R ³ is Cl.

In some embodiments of the present invention, R ⁴ is OH, F, Cl, Br or I; in some typical embodiments, R ⁴ is OH; in some more typical embodiments, R ⁴ is OH and R ³ is Cl.

In some embodiments of the present invention, the organic solvent B is selected from C ₁ -C ₆ alkyl alcohols, 6-10 aromatic hydrocarbons, C ₆ -C ₁₀ aliphatic hydrocarbons, halogenated C ₁ -C ₇ alkanes, amides, ketones, esters, ethers, nitriles, water, one or more mixed solvents, in some typical embodiments, the organic solvent B is selected from methanol, ethanol, n-propanol, isopropanol, acetone, N, N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, water, one or more mixed solvents; in some more typical embodiments, the organic solvent B is selected from isopropanol, acetone, N, N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, water, one or more mixed solvents; in some more typical embodiments, the organic solvent B is selected from isopropanol, tert-butanol, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, water, one or two mixed solvents; in some more typical embodiments, the organic solvent B is selected from isopropanol, N, N-dimethylformamide, tetrahydrofuran, acetonitrile or a mixed solvent mixed with water; in some most typical embodiments, the organic solvent B is selected from a mixed solvent of tetrahydrofuran and water, isopropanol or N, N-dimethylformamide.

In some embodiments of the present invention, the reaction of route II is carried out in the presence of a basic reagent B; in some typical embodiments, the basic reagent B is selected from alkali metal carbonates, DBU, tetra(C ₁ -C ₆ alkyl) ammonium halide, alkali metal hydride or a mixture of two or more thereof; in some more typical embodiments, the alkaline agent B is selected from lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, DBU, sodium hydrogen or a mixture of two or more thereof; in some more typical embodiments, the alkaline agent B is selected from potassium carbonate, cesium carbonate, DBU, tetrabutylammonium iodide, sodium hydrogen or a mixture of two or more thereof; in some more typical embodiments, the alkaline agent B is selected from potassium carbonate, cesium carbonate, DBU, sodium hydrogen or tetrabutylammonium iodide; in some more typical embodiments, the alkaline agent B is selected from cesium carbonate, DBU, sodium hydrogen or potassium carbonate; in some most typical embodiments, the alkaline agent B is selected from cesium carbonate, or potassium carbonate, or a mixture of potassium carbonate and tetrabutylammonium iodide; in some most typical embodiments, the alkaline agent B is selected from cesium carbonate or potassium carbonate.

In some embodiments of the present invention, the route II reaction is carried out in the presence of an alkaline reagent B and a phase transfer catalyst. In some typical embodiments, the phase transfer catalyst is selected from one or a mixture of more than one of linear polyethylene glycol, linear polyethylene glycol dialkyl ether, 18-crown ether-6, and 15-crown ether-5; in some more typical embodiments, the phase transfer catalyst is selected from one or a mixture of more than one of linear polyethylene glycol dialkyl ether, 18-crown ether-6, and 15-crown ether-5; in some most typical embodiments, the phase transfer catalyst is selected from 18-crown ether-6.

In some embodiments of the present invention, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:0.5-10; in some typical embodiments, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:1-8; in some more typical embodiments, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:1-5; in some more typical embodiments, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:1-2; in some more typical embodiments, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:1-1.8; in some most typical embodiments, the molar ratio of the compound of formula V or its salt to the compound of formula IV or its salt is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.8 or any range between the values therein.

In some embodiments of the present invention, the molar ratio of the compound of formula V or its salt to the alkaline agent B is 1:0.1-5; in some typical embodiments, the molar ratio of the compound of formula V or its salt to the alkaline agent B is 1:0.1-3; in some typical embodiments, the molar ratio of the compound of formula V or its salt to the alkaline agent B is 1:0.3-3; in some typical embodiments, the molar ratio of the compound of formula V or its salt to the alkaline agent B is 1:0.4-3; in some typical embodiments, the molar ratio of the compound of formula V or its salt to the alkaline agent B is 1:0.5-1. The molar ratio of reagent B is 1:0.5-3; in some of the most typical embodiments, the molar ratio of the compound of formula V or its salt to the basic reagent B is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3 or any range therein.

In some embodiments of the present invention, the reaction temperature of the route II reaction is 0°C to 85°C; in some typical embodiments, the reaction temperature of the route II reaction is 0°C to 10°C; in some more typical embodiments, the reaction temperature of the route II reaction is 0°C to 5°C; in some typical embodiments, the reaction temperature of the route II reaction is 50°C to 80°C; in some more typical embodiments, the reaction temperature of the route II reaction is 55°C to 70°C; in some more typical embodiments, the reaction temperature of the route II reaction is 60°C to 70°C; in some typical embodiments, the reaction temperature of the route II reaction is 80°C to 85°C; in some most typical embodiments, the reaction temperature of the route II reaction is 60°C, 63°C, 65°C, 66°C or 68°C or any range therein.

In some embodiments of the present invention, the reaction time of the route II reaction is 0 to 48 hours; in some typical embodiments, the reaction time of the route II reaction is 4 hours to 32 hours; in some more typical embodiments, the reaction time of the route II reaction is 2 hours to 24 hours; in some most typical embodiments, the reaction time of the route II reaction is 3h, 4h, 5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 24h or any range therein.

In some embodiments of the present invention, the reaction of Route II is optionally carried out under nitrogen protection; in some typical embodiments, the reaction of Route II is carried out under nitrogen protection.

In some embodiments of the present invention, the reaction of Route II optionally further comprises a post-treatment step, which includes but is not limited to cooling, filtering, and concentrating the filtrate in sequence to obtain a solid at the end of the reaction.

The present invention also provides a method for preparing the compound of formula I or a salt thereof, characterized in that it comprises the following reaction steps:

(1) reacting a compound of formula V or a salt thereof with a compound of formula IV or a salt thereof in the presence of a basic agent B in an organic solvent B to obtain a compound of formula III or a salt thereof;

(2) reacting the compound of formula III or its salt with the compound of formula II or its salt in the presence of an alkaline agent A and a reducing agent in an organic solvent A to produce a compound of formula I or its salt;

in,

^R1 and ^R2 are as defined in Scheme I;

The definitions of the compounds of formula I and formula II are the same as those in route I;

R ³ and R ⁴ are as defined in Scheme II;

The definitions of alkaline reagent A, organic solvent A and reducing agent are the same as those in route I;

The definitions of alkaline reagent B and organic solvent B are the same as those in Scheme II.

In some embodiments of the present invention, the reaction conditions of step (1) are as shown in the aforementioned route II and the reaction conditions of step (2) are as shown in the aforementioned route I.

In some embodiments of the present invention, ^R1 in the compound of formula I is an amino protecting group, and route I or route III further comprises removing the amino protecting group from the compound of formula I or a salt thereof to generate a compound of formula I-2 or a salt thereof,

In some embodiments of the present invention, R ¹ in the compound of formula IS or its salt is an amino protecting group, and route I or route III optionally further comprises removing the amino protecting group from the compound of formula IS or its salt to generate a compound of formula I-1 or its salt.

The present invention also provides a method for preparing a compound of formula I-1 or a salt thereof, characterized in that it comprises the reaction steps as described above: a compound of formula V or a salt thereof and a compound of formula IV or a salt thereof react in an organic solvent B in the presence of an alkaline reagent B to obtain a compound of formula III or a salt thereof.

The present invention also provides a method for preparing a compound of formula I-1 or a salt thereof, characterized in that it comprises the reaction steps as described above: a compound of formula III or a salt thereof and a compound of formula II or a salt thereof react in an organic solvent A in the presence of an alkaline reagent A and a reducing agent to generate a compound of formula I or a salt thereof.

The compound of formula V of the present invention can be purchased or prepared according to the prior art, and the prior art includes but is not limited to WO2013163244A1 and WO2014153055A2; the compound of formula IV of the present invention can be purchased or prepared according to the prior art, and the prior art includes but is not limited to WO2003047570A1, WO2014025978A1, and IN2012CH00514A.

In the present invention, the hydrogen spectrum data of the compound was measured by Bruker 400MHz.

In the present invention, the infrared chromatographic data of the compound was measured by Bruker nanoIR3.

In the present invention, the compound LC-MS was measured by Agilent 6410B QQQ LC/MS.

In the present invention, the purity of the compound was measured by HPLC, and the specific chromatographic conditions were as follows:

Chromatographic column: SHIMADZU AQ-C18 150*4.6mm, 3μm;

Mobile phase A: 1.0 mL trifluoroacetic acid was dissolved in 1000 mL purified water, shaken, filtered, sonicated, and set aside;

Mobile phase B: 1.0 mL trifluoroacetic acid was dissolved in 1000 mL acetonitrile, shaken, filtered, sonicated, and set aside;

Detection wavelength: 230nm, Peakwidth>0.1min(2s response time)(2.5Hz);

Flow rate: 1.0 mL/min;

Injection volume: 10 μL;

Column temperature: 30°C;

Collection time: 36min;

Needle washing solution: acetonitrile;

Elution was performed according to the following gradient elution program: 0-31 min, elution was performed according to 95% mobile phase A, 5% mobile phase B, 31 min-36.1 min, elution was performed according to 2% mobile phase A, 98% mobile phase B, 36.1 min-45 min, elution was performed according to 95% mobile phase A, 5% mobile phase B.

The invention provides a novel preparation route of arylmethoxyisoindoline derivatives, and the product prepared by the preparation route has good yield and purity.

It is easy for those skilled in the art to understand that the error range of the parameters listed in the present invention also belongs to the protection scope of the present invention, and the error range includes but is not limited to the expected experimental error, technical error and instrument error of a given technology for measuring the value.

It is easy for a person skilled in the art to understand that when the same R substituent appears in the reactants and products of the same reaction, unless otherwise specified, it should be the same variable; for example, in route I, when ^R1 in the compound of formula II is H, ^R1 in the compound of formula I should also be H.

It is easy for those skilled in the art to understand that the determination of the reaction endpoint can be achieved based on their experience, experimental phenomena, technical means monitoring, etc.; the "technical means monitoring" includes but is not limited to thin layer chromatography, high performance liquid chromatography, ultraviolet spectrophotometer, etc.; the "at the reaction endpoint" only represents a program node, and does not mean that it must be continuous in time. For example, "at the reaction endpoint, adjust the pH value" only means that a procedure for adjusting the pH value needs to be performed after the reaction endpoint, and does not mean that the reaction endpoint and the adjustment of the pH value must be continuous in time. The two can be performed continuously or there can be a time interval.

Reaction time refers to the time from adding the first material to the end of the reaction.

In the present invention, unless otherwise specified, the following terms have the following meanings:

“N” stands for Mol/L.

"Amino protecting group" refers to a functional group that can reversibly convert an amino group into an inert group, thereby preventing the amino group from participating in the reaction during the subsequent reaction. Amino protecting groups include, but are not limited to, tert-butyloxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, benzyl, allyloxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), p-methoxybenzyl (Pmb), allyloxycarbonyl (Alloc), 2,4-dimethoxybenzyl (Dmb), p-Nitrobenzenesulfonyl (Ns), trifluoroacetyl (Tfa), 2,2,2-trichloroethoxycarbonyl (Troc), (trimethylsilyl)ethanesulfonyl (SES), tert-butyldimethyl (TCP), pivaloyl (PiV), allyl (Allyl), N-bromosuccinimide (Nbs), o-N-bromosuccinimide (oNbs), p-N-bromosuccinimide (pNbs), (trimethylsilyl)ethoxymethyl (SEM), tert-butyl (t-Bu) or 2,2,2-trichloroethoxycarbonyl (Troc), etc.

"OTs" refers to p-toluenesulfonyloxy; "OMs" refers to sulfonyloxy; "OTf" refers to trifluoromethanesulfonyloxy; "ONs" refers to nitrobenzenesulfonyloxy; "OH" refers to hydroxyl; "h" refers to hour; "min" refers to minute; "g" refers to gram; “DBU” refers to 1,8-diazabicyclo[5.4.0]-undec-7-ene; “DMAC” refers to N,N-dimethylacetamide; “dilute hydrochloric acid” refers to hydrochloric acid with a mass fraction of less than 20%; “HPLC” refers to high performance liquid chromatography; and “pH” refers to the acidity or alkalinity of a solution.

C ₁ -C ₆ alkyl alcohol refers to alkyl alcohols with carbon number ranging from 1 to 6, including but not limited to one or a mixed solvent of two or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol or glycerol.

6-10 membered aromatic hydrocarbons are aromatic hydrocarbons with carbon number ranging from 6 to 10, including but not limited to one or a mixed solvent of two or more of benzene, xylene, toluene, ethylbenzene, n-propylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, isopropylbenzene, diethylbenzene or isobutylbenzene.

The C ₆ -C ₁₀ aliphatic hydrocarbons are aliphatic hydrocarbons with carbon atoms ranging from 6 to 10, including but not limited to one or a mixed solvent of two or more of n-pentane, isopentane, n-hexane, isohexane, n-heptane, isoheptane, cyclohexane, pentane or methylcyclohexane.

Halogenated C ₁ -C ₇ alkanes refer to halogenated alkanes with carbon number ranging from 1 to 7, including but not limited to one or a mixed solvent of methyl iodide, ethyl bromide, isopropyl bromide, benzyl chloride, bromobenzene, p-methoxyiodobenzene, p-fluoroiodobenzene or m-methylbromobenzene; amides such as one or a mixed solvent of two or more of acetamide, dimethylacetamide, hexamethylphosphoramide or dimethylformamide (DMF).

C ₆ -C ₁₀ alkylamine refers to alkylamines with carbon atoms ranging from 6 to 10, including but not limited to one or a mixed solvent of two or more of triethylamine, diisopropylethylamine, dipropylamine, and tripropylamine.

Ketones refer to compounds in which a carbonyl group is connected to two hydrocarbon groups, including but not limited to one or a mixed solvent of two or more of acetone, methyl ethyl ketone, methyl n-propyl ketone, methyl n-butyl ketone, diethyl ketone, trimethyl nonanone, cyclohexanone, cyclopentanone, methylcyclohexanone, 2,4-pentanedione, acetonylacetone, acetophenone or fenchone.

Esters such as diethyl carbonate, methyl acetate, ethyl acetate, γ-butyrolactone, γ-valerolactone, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-butyl propionate, methyl lactate, ethyl lactate (EL), γ-butyrolactone, n-butyl lactate, n-pentyl lactate, diethyl malonate, dimethyl phthalate, diethyl phthalate, one or a mixed solvent of two or more thereof.

Ethers refer to products in which the hydrogen in the hydroxyl group of an alcohol or phenol is replaced by a hydrocarbon group, including but not limited to ethyl ether, isopropyl ether, n-butyl ether, n-hexyl ether, 2-ethylhexyl ether, dimethyl dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-n-hexyl ether, ethylene glycol monophenyl ether, ethylene glycol mono-2-ethyl butyl ether, ethylene glycol dibutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol mono-n-butyl ether, diethylene glycol di-n-butyl ether, diethylene glycol mono-n-hexyl ether, propylene glycol monomethyl ether (PGME), propylene glycol monoethyl ether, propylene glycol monopropyl ether, propylene glycol monobutyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, tripropylene glycol monomethyl ether, tetrahydrofuran Or one or a mixed solvent of two or more of 2-methyltetrahydrofuran.

Nitriles refer to organic compounds formed by connecting carbon atoms containing a hydrocarbon group and a cyano group, including but not limited to one or a mixed solvent of two or more of acetonitrile, propionitrile, butyronitrile, or benzonitrile.

The ratio of mobile phase in HPLC is volume ratio.

“10% palladium on carbon” means that the mass fraction of palladium in palladium on carbon accounts for 10% of the total mass of palladium on carbon.

"0.5%-10% palladium on carbon/hydrogen" refers to a combination of 0.5%-10% palladium on carbon and hydrogen.

"Raney nickel/hydrogen" refers to a combination of Raney nickel and hydrogen.

"Room temperature" refers to 20°C-25°C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the liquid phase spectrum of the hydrochloride of the compound of formula I-1 prepared in Example 6 measured by LC-MS.

FIG2 shows the ¹ H-NMR (DMSO-d ₆ ) spectrum of the hydrochloride salt of the compound of formula I-1 prepared in Example 6.

FIG3 shows the HPLC spectrum of the hydrochloride salt of the compound of formula I-1 prepared in Example 6.

FIG4 shows the infrared chromatogram of the hydrochloride of the compound of formula I-1 prepared in Example 6.

FIG5 shows the liquid phase spectrum measured by LC-MS of the compound of formula III-1 prepared in Example 3.

FIG6 shows the ¹ H-NMR (DMSO-d ₆ ) spectrum of the compound of formula III-1 prepared in Example 3.

DETAILED DESCRIPTION

For the sake of clarity, the present invention is further described in detail below in conjunction with the implementation examples, but it should be understood that the examples do not limit the scope of the present application. All reagents used in this application are commercially available and can be used without further purification.

Example 1 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction bottle and dissolved in 200 mL of isopropanol. 1.34 g of solid tetrabutylammonium iodide and 30.56 g of solid potassium carbonate were added under stirring at room temperature, and then 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine was added. The temperature was raised to reflux and the reaction was carried out for 10 h. The reaction solution was cooled, filtered and concentrated to obtain 36.34 g of a solid (i.e., the title compound).

Example 2 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

Under nitrogen protection, add 20 g of methyl 2-formyl-3-hydroxybenzoate to the reaction bottle and dissolve it in 200 mL of acetonitrile. Add 50 g of DBU and 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine under stirring at room temperature. Raise the temperature to 30-40°C and react for 24 hours. The reaction solution is cooled, filtered and concentrated to obtain 35.23 g of a solid (i.e., the title compound).

Example 3 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction bottle and dissolved in 200 mL of DMF. 19.26 g of cesium carbonate powder was added under stirring at room temperature, and then 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine was added. The temperature was raised to 60°C. The reaction was continued for 4 h, and the reaction solution was cooled, filtered and concentrated to obtain 37.10 g of a solid (ie, the title compound).

Example 4 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction bottle, dissolved in 200 mL of DMF, cooled to 0°C, 4 g of commercially available sodium hydrogen sulfide (of which the mass fraction of sodium hydrogen was 60%) was added in three batches, and then a solution containing 60 mL of DMF and 40 g of 4-(4-(chloromethyl)benzyl)morpholine was added dropwise. The reaction was carried out at 0-5°C for 24 hours. The reaction solution was cooled, filtered and concentrated to obtain 30.74 g of a solid (i.e., the title compound).

Example 5 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction bottle and dissolved in 200 mL of tetrahydrofuran and 50 mL of water. 30.56 g of solid potassium carbonate and 1.2 g of 18-crown-6, a phase transfer catalyst, were added under stirring at room temperature. Then, 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine were added. The temperature was raised to reflux and the reaction was allowed to react for 10 h. The reaction solution was cooled, filtered and concentrated to obtain 36.75 g of a solid (i.e., the title compound).

Example 6 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione hydrochloride (hydrochloride of the compound of formula I-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinemethyl)benzyl)oxy)benzoate prepared in Example 5 was added to the reaction bottle and dissolved in 155 mL of methanol. 9.96 g of potassium carbonate solid was added and cooled to 0°C. 4.62 g of (S)-3-aminopiperidine-2,6-dione was dissolved in 45 mL of methanol and stirred for 2 h. TLC showed that most of it was converted into Schiff base. 5.0 g of sodium borohydride was added in 10 batches. , control the temperature not exceeding 5°C, react for 8 hours, quench the reaction with 20mL 2N dilute hydrochloric acid, concentrate to remove most of the solvent, add 100mL saturated brine, extract three times with 50mL isopropyl acetate, concentrate the organic phase to obtain 15.9g of solid, dissolve the solid in 40mL isopropyl acetate, heat to reflux, add 15mL n-heptane after dissolving, cool to 10°C for 15 hours, filter to obtain 14.5g of solid (i.e., the title compound) with a purity of 99.87%.

Example 7 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (compound of formula I-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinemethyl)benzyl)oxy)benzoate prepared in Example 2 was added to the reaction bottle, dissolved in 260 mL of tetrahydrofuran, and cooled to 0°C. 4.62 g of (S)-3-aminopiperidine-2,6-dione was dissolved in 45 mL of ethanol, 20 mL of triethylamine was added, and then stirred for 2 h. 20 g of sodium triacetoxyborohydride was added in batches, the temperature was controlled not to exceed 5°C, and the reaction was carried out for 8 h. Add 50 mL of 2N dilute hydrochloric acid to quench the reaction, filter, concentrate the filtrate to about 150 mL, adjust the pH to 6-8 with sodium acetate, extract three times with 50 mL of isopropyl acetate, combine the organic phases, and concentrate to obtain 17.2 g of solid. Dissolve the solid in 75 mL of ethanol, raise the temperature to reflux, add 20 mL of water dropwise after it becomes clear, cool to 10°C for 15 h, and filter to obtain 12.32 g of solid (i.e., the title compound) with a purity of 97.85%.

Example 8 (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (compound of formula I-1) Preparation of

Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinemethyl)benzyl)oxy)benzoate prepared in Example 3 was added to a reaction bottle and dissolved in 200 mL of ethanol. 10 mL of diisopropylethylamine was added and the mixture was cooled to 0°C. 4.62 g of (S)-3-aminopiperidine-2,6-dione was dissolved in 45 mL of ethanol and stirred for 1 h. 3 g of 10% palladium carbon (50% water) was added and hydrogen was replaced three times. The mixture was pressurized to 75 psi and reacted at room temperature for 8 h. The mixture was filtered and the filter cake was rinsed twice with an appropriate amount of ethanol/water. The combined filtrate was concentrated to obtain 16.5 g of a solid. The solid was dissolved in 45 mL of acetonitrile and the temperature was raised to reflux. After the solid was dissolved, 15 mL of n-heptane was added and the temperature was lowered to 10°C for 15 h. The solid (i.e., the title compound) was filtered to obtain 15.06 g of the solid with a purity of 94.91%.

Example 9 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (compound of formula I-1)

Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinemethyl)benzyl)oxy)benzoate prepared in Example 5 was added to a reaction bottle and dissolved in 180 mL of tetrahydrofuran. The mixture was cooled to 0°C, and 4.62 g of (S)-3-aminopiperidine-2,6-dione was dissolved in 45 mL of tetrahydrofuran. The mixture was stirred for 1 h, cooled to -50°C, and 90 mL of 1N diisobutylaluminum hydride toluene solution was added dropwise. The temperature was controlled not to exceed -45°C, and then the mixture was reacted at -10°C for 3 h. The reaction was quenched with 200 mL of 0.5 N sodium hydroxide solution, filtered, and the filtrate was extracted 3 times with 100 mL of toluene. The organic phase was washed twice with saturated brine. The organic phase was concentrated to obtain 18.98 g of a solid. The solid was mixed with 70 mL of toluene, heated to reflux, cooled to 25°C after the solution was cleared, and filtered to obtain 13.45 g of a solid (i.e., the title compound) with a purity of 98.79%.

The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims (10)

A method for preparing a compound of formula I or a salt thereof, characterized in that: a compound of formula III or a salt thereof and a compound of formula II or a salt thereof react in an organic solvent A in the presence of a reducing agent to generate a compound of formula I or a salt thereof,
in, ^R1 is H or an amino protecting group; ^R2 is OH or _C1 - _C6 alkoxy. The method according to claim 1, characterized in that ^R1 is H, tert-butyloxycarbonyl, benzyloxycarbonyl, tert-methoxycarbonyl or benzyl, preferably, ^R1 is H; R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy, preferably, R ² is methoxy or ethoxy, more preferably, R ² is methoxy; Preferably, more than 80% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and more than 80% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt. Preferably, more than 90% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and more than 90% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt. Preferably, 100% by weight of the compound of formula II or its salt exists in the form of the compound of formula II-S or its salt, and 100% by weight of the compound of formula I or its salt exists in the form of the compound of formula IS or its salt. More preferably, the compound of formula II-S or its salt exists in the form of the compound of formula II-1 or its salt, and the compound of formula IS or its salt exists in the form of the compound of formula I-1 or its salt.
The method according to claim 1, characterized in that the reducing agent is one or more of alkali metal borohydride, palladium carbon/hydrogen, Raney nickel/hydrogen, diisobutylaluminum hydride. Preferably, the reducing agent is sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, palladium carbon/hydrogen, Raney nickel/hydrogen, diisobutylaluminum hydride. One or more of the mixed reagents, preferably, the reducing agent is sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon/hydrogen, diisobutylaluminum hydride. One or two mixed reagents, preferably, the reducing agent is sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride. Preferably, the reducing agent is a mixed reagent of one or two of sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride. Preferably, the reducing agent is a mixed reagent of one or two of sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon/hydrogen, more preferably, the reducing agent is sodium borohydride; The molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.2-22, preferably, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4-20, preferably, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.2-0.8, preferably, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4, 1:0.5, 1:0.6, 1:0.7 or any ratio range therein, Preferably, the molar feed ratio of the reducing agent to the compound of formula III or its salt is 1:0.4, 1:0.5, 1:0.6; If the reducing agent is palladium carbon/hydrogen, the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:15-24, calculated on the basis of palladium. Preferably, the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:18, 1:19, 1:20, 1:21, 1:22 or any range between the ratios. More preferably, the molar feed ratio of palladium carbon to the compound of formula III or its salt is 1:19-20. The method according to claim 1, characterized in that The organic solvent A is selected from one or more of C ₁ -C ₆ alkyl alcohols, 6-10 aromatic hydrocarbons, C ₆ -C ₁₀ aliphatic hydrocarbons, halogenated C ₁ -C ₇ alkanes, amides, ketones, esters, ethers, and nitriles. Preferably, the organic solvent A is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol monomethyl ether, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile. Preferably, the organic solvent A is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile. Preferably, the organic solvent A is selected from one or more of methanol, ethanol, tetrahydrofuran, and acetonitrile. Preferably, the organic solvent A is one of methanol, ethanol, and tetrahydrofuran, or a mixed solvent consisting of ethanol and tetrahydrofuran. The reaction of route I is carried out in the presence of an alkaline reagent A, wherein the alkaline reagent A is selected from one or a mixture of organic alkaline reagents and inorganic alkaline reagents. Preferably, the alkaline reagent A is selected from one or a mixture of two or more of alkali metal carbonates, DBU, tetra(C ₁ -C ₄ alkyl)ammonium halides, and C ₆ -C ₁₀ alkylamines. Preferably, the alkaline reagent A is selected from one or a mixture of two or more of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylamine, and diisopropylethylamine. Preferably, the alkaline reagent A is selected from one or a mixture of two or more of potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium iodide, triethylamine, and diisopropylethylamine. Reagent A is selected from potassium carbonate, sodium carbonate, tetrabutylammonium iodide, diisopropylethylamine, DBU or a mixture of two or more thereof. Preferably, the alkaline reagent A is selected from potassium carbonate, triethylamine, diisopropylethylamine or a mixture of two or more thereof. Preferably, the alkaline reagent A is selected from a mixture of tetrabutylammonium iodide and DBU, potassium carbonate, diisopropylethylamine, sodium carbonate, tetrabutylammonium iodide or triethylamine. Preferably, the alkaline reagent A is selected from potassium carbonate or triethylamine. Preferably, the alkaline reagent A is selected from diisopropylethylamine. The use of the compound of formula I according to claim 1 in the preparation of ipomide or its salt, preferably, more than 80% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, preferably, more than 90% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, preferably, 100% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, more preferably, the compound of formula I-S or its salt exists in the form of a compound of formula I-1 or its salt. A compound of formula III or a salt thereof,
Wherein, R ² is OH or C ₁ -C ₆ alkoxy, preferably, R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy, preferably, R ² is methoxy or ethoxy, more preferably, R ² is methoxy. The use of the compound of claim 6 in the preparation of a compound of formula I or a salt thereof, preferably, more than 80% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, preferably, more than 90% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, preferably, 100% by weight of the compound of formula I or its salt exists in the form of a compound of formula I-S or its salt, more preferably, the compound of formula I-S or its salt exists in the form of a compound of formula I-1 or its salt. A method for preparing the compound according to claim 6, characterized in that the compound of formula V or its salt and the compound of formula IV or its salt are reacted in an organic solvent B to obtain a compound of formula III,
in, R ² is OH or C ₁ -C ₆ alkoxy; R ³ is OH, optionally substituted C ₁ -C ₆ alkylsulfonyloxy, optionally substituted benzenesulfonyloxy or halogen; ^R4 is OH or halogen; Furthermore, R ³ and R ⁴ are not halogen at the same time. The method according to claim 8, characterized in that R ² is OH, methoxy, ethoxy, n-propoxy or isopropoxy, preferably, R ² is methoxy or ethoxy, more preferably, R ² is methoxy; R ³ is OH, OTs, OMs, OTf, ONs, F, Cl, Br or I, preferably, R ³ is F, Cl, Br or I, more preferably, R ³ is Cl; R ⁴ is OH, F, Cl, Br or I, preferably, R ⁴ is OH, more preferably, R ⁴ is OH and R ³ is Cl. The method according to claim 8, characterized in that route II is reacted in the presence of an alkaline reagent B and a phase transfer catalyst, and reacted in an organic solvent B, The organic solvent B is selected from one or more of C ₁ -C ₆ alkyl alcohols, 6-10 aromatic hydrocarbons, C ₆ -C ₁₀ aliphatic hydrocarbons, halogenated C ₁ -C ₇ alkanes, amides, ketones, esters, ethers, nitriles, and water. Preferably, the organic solvent B is selected from one or more of methanol, ethanol, n-propanol, isopropanol, acetone, N,N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, and water. Preferably, the organic solvent B is selected from one or more of isopropanol, acetone, N,N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, and water. Preferably, the organic solvent B is selected from one or more of isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and water. Preferably, the organic solvent B is selected from one or more of isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, and water. Preferably, the organic solvent B is selected from one of isopropanol, N,N-dimethylformamide, tetrahydrofuran, acetonitrile or a mixed solvent mixed with water. Preferably, the organic solvent B is selected from a mixed solvent of tetrahydrofuran and water, isopropanol or N,N-dimethylformamide; The alkaline reagent B is selected from one or a mixture of two or more of alkali metal carbonates, DBU, tetra(C ₁ -C ₆ alkyl)ammonium halides, and alkali metal hydrides. Preferably, the alkaline reagent B is selected from one or a mixture of two or more of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, DBU, and sodium hydrogen. Preferably, the alkaline reagent B is selected from one or a mixture of two or more of potassium carbonate, cesium carbonate, DBU, tetrabutylammonium iodide, and sodium hydrogen. Preferably, the alkaline reagent B is selected from potassium carbonate, cesium carbonate, DBU, sodium hydrogen, or tetrabutylammonium iodide. Preferably, the alkaline reagent B is selected from cesium carbonate, DBU, sodium hydrogen, or potassium carbonate. Preferably, the alkaline reagent B is selected from cesium carbonate, or potassium carbonate, or a mixture of potassium carbonate and tetrabutylammonium iodide. Preferably, the alkaline reagent B is selected from cesium carbonate or potassium carbonate. The phase transfer catalyst is selected from one or a mixture of linear polyethylene glycol, linear polyethylene glycol dialkyl ether, 18-crown ether-6, 15-crown ether-5, preferably, the phase transfer catalyst is selected from one or a mixture of two or more of linear polyethylene glycol dialkyl ether, 18-crown ether-6, 15-crown ether-5, preferably, the phase transfer catalyst is selected from 18-crown ether-6.