A process for the preparation of arylmethoxyisoindoline derivatives

Abstract

The application relates to a preparation method of an arylmethoxy isoindoline derivative and belongs to the field of pharmaceutical chemical industry. Specifically, a compound of formula III and a compound of formula II are reacted in an organic solvent in the presence of a reducing agent to generate a compound of formula I. A new preparation route of the arylmethoxy isoindoline derivative is provided, and the preparation route has high yield and high product purity.

Description

A preparation method of arylmethoxyisoindoline derivatives

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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 said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the field of medical technology, in particular to a method for preparing an arylmethoxyisoindoline derivative. Background Art

[0004] Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of antibodies and immune complexes that mediate organ and tissue damage, often manifesting clinically in multiple systemic manifestations. Patients present with high levels of antibodies in their serum, which deposit immune complexes in small blood vessels, causing vasculitis and resulting in multi-organ dysfunction. SLE is more common in women, with 90% of patients being women of childbearing age, aged 20 to 40.

[0005] The compound of formula I-1 is a novel oral cereblon E3 ubiquitin ligase immunomodulator, whose chemical name is (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione. It has shown good efficacy in the treatment of SLE clinically and has the following structure:

[0006] WO200627788 and US201446058 disclose methods for preparing compounds of formula I-1, but these methods still suffer from problems such as poor yield or lengthy routes. Therefore, a new method for synthesizing compounds of formula I-1 is urgently needed.

[0007] SUMMARY OF THE INVENTION

[0008] The invention provides a novel preparation method of arylmethoxyisoindoline derivatives. The product prepared by this preparation route has good yield and purity.

[0009] In addition, the present invention also provides a compound of formula III or a salt thereof, which can be used to prepare arylmethoxyisoindoline derivatives or salts thereof.

[0010] Furthermore, the present invention also provides a method for preparing the compound of formula III or a salt thereof.

[0011] Detailed Description of the Invention

[0012] 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 react in an organic solvent A in the presence of a reducing agent to produce a compound of formula I or a salt thereof,

[0013] in,

[0014] R 1 is H or an amino protecting group;

[0015] R 2 is OH or C1-C6 alkoxy.

[0016] In some typical embodiments, R 1 is H, tert-butyloxycarbonyl, benzyloxycarbonyl, tert-methoxycarbonyl or benzyl; in some more typical embodiments, R 1 For H.

[0017] 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 It is a methoxy group.

[0018] 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;

[0019] 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,

[0020] In some embodiments of the present invention, the organic solvent A is selected from C1-C6 alkyl alcohols, 6-10 aromatic hydrocarbons, C6-C 10 a mixed solvent of one or more of aliphatic hydrocarbons, halogenated C1-C7 alkanes, amides, ketones, esters, ethers, and nitriles; in some typical embodiments, the organic solvent A is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol monomethyl ether, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile; in some more typical embodiments, the organic solvent A is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile; in some more typical embodiments, the organic solvent A is selected from the group consisting of methanol, ethanol, tetrahydrofuran, and acetonitrile; in some most typical embodiments, the organic solvent A is one of methanol, ethanol, tetrahydrofuran, or a mixed solvent consisting of ethanol and tetrahydrofuran.

[0021] In some embodiments of the present invention, the reducing agent is an alkali metal borohydride, palladium carbon / hydrogen, Raney nickel / hydrogen, diisobutylaluminum hydride, or a mixture of two or more thereof; in some embodiments, the reducing agent is sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, palladium carbon / hydrogen, Raney nickel / hydrogen, or diisobutylaluminum hydride, or a mixture of two or more thereof; in some more typical embodiments, the reducing agent is a mixture of one or two of sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon / hydrogen, or diisobutylaluminum hydride; in some more typical embodiments, the reducing agent is a mixture of one or two of sodium borohydride, sodium triacetoxyborohydride, or diisobutylaluminum hydride; in some more typical embodiments, the reducing agent is sodium borohydride.

[0022] 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 therein; 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.

[0023] 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 therein; 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.

[0024] 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 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 a range between any ratios therein.

[0025] In some embodiments of the present invention, the reaction temperature of the reaction of Route I is -20°C to 30°C; in some typical embodiments, the reaction temperature of the reaction of Route I is -10°C to 25°C; in some typical embodiments, the reaction temperature of the reaction of Route I is 0°C to 25°C; in some more typical embodiments, the reaction temperature of the reaction of Route I is -20°C to 5°C; in some more typical embodiments, the reaction temperature of the reaction of Route I is 0°C to 5°C; in some most typical embodiments, the reaction temperature of the reaction of Route I 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 reaction of Route I is 20°C to 30°C; in some most typical embodiments, the reaction temperature of the reaction of Route I is 22°C, 23°C, 24°C, 25°C, 26°C or 27°C, or any range therein.

[0026] In some embodiments of the present invention, the reaction time of the reaction of Route I is 0.5 h to 24 h; in some typical embodiments, the reaction time of the reaction of Route I is 2 h to 12 h; in some most typical embodiments, the reaction time of the reaction of Route I is 3 h, 4 h, 5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 9.5 h, 10 h, 10.5 h, 11 h, 11.5 h or 12 h or any range therein.

[0027] 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 organic alkaline reagents and inorganic alkaline reagents; in some typical embodiments, the alkaline reagent A is selected from alkali metal carbonates, DBU, tetra (C1-C4 alkyl) ammonium halides, C6-C 10In some more typical embodiments, the alkaline reagent A is selected from one or more mixtures of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylamine, diisopropylethylamine; In some more typical embodiments, the alkaline reagent A is selected from one or more mixtures of potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium iodide, triethylamine, diisopropylethylamine; In some more typical embodiments, the alkaline reagent A is selected from one or more mixtures of carbon In some more typical embodiments, the alkaline agent A is selected from one or more of potassium carbonate, triethylamine, and 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.

[0028] 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.

[0029] 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.

[0030] In some embodiments of the present invention, the reaction of route I optionally further comprises adjusting the pH value to 5.5-8.0 at the end of the reaction, 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 adjusting the pH value to 6.0-7.5 at the end of the reaction, 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 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, 7.10, 7.11, 7.12, 7.13, 7.14, 7.15, 7.16, 7.17, 7.18, 7.19, 7.20, 7.21, 7.22, 7.23, 7.24, 7.25, 7.26, 7.27, 7.28, 7.29, 7.30, 7.31, 7.32, 7.33, 7.34, 7.35, 7.36, 7.37, 7.38, 7.39, 7.40, 7.50, 7.51, 7.52, 7.53, 7.54, 7.55, 7.56, 7.57, 7.58, 7.69, 7.70, 7.71, 7.72, 7.73, 7.74, 7.75 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4 or 7.5 or any range thereof, 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 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 thereof with dilute hydrochloric acid, sodium acetate or sodium hydroxide at the end of the reaction, filtering and removing the solution to obtain a crude compound of Formula I or a salt thereof.

[0031] In some embodiments of the present invention, the reaction of Route I optionally further comprises recrystallizing the crude compound of Formula I or its salt; in some typical embodiments, the reaction of Route I optionally further comprises recrystallizing the crude compound of Formula I or its salt using C1-C6 alcohols, 6-10 membered 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 recrystallizing 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.

[0032] 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.

[0033] The present invention also provides a compound of formula III or a salt thereof,

[0034] Among them, R 2 is OH or C1-C6 alkoxy.

[0035] In some embodiments of the present invention, R 2 is OH, methoxy, ethoxy, n-propoxy or isopropoxy; in some typical embodiments, R2 is methoxy or ethoxy; in some more typical embodiments, R 2 It is a methoxy group.

[0036] The present invention also provides the use of a compound of formula III or a salt thereof in preparing a compound of formula I or a salt thereof; in particular, the use of a compound of formula III or a salt thereof in preparing a compound of formula IS or a salt thereof; more particularly, the use of a compound of formula III-1 or a salt thereof in preparing a compound of formula I-1 or a salt thereof.

[0037] 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,

[0038] in,

[0039] R 2 is OH or C1-C6 alkoxy;

[0040] R 3 is OH, optionally substituted C1-C6 alkylsulfonyloxy, optionally substituted benzenesulfonyloxy or halogen;

[0041] R 4 is OH or halogen;

[0042] And R 3 、R 4 Not halogen at the same time.

[0043] 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 It is a methoxy group.

[0044] 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 For Cl.

[0045] 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 3For Cl.

[0046] In some embodiments of the present invention, the organic solvent B is selected from C1-C6 alkyl alcohols, 6-10 aromatic hydrocarbons, C6-C 10 Aliphatic hydrocarbons, halogenated C1-C7 alkanes, amides, ketones, esters, ethers, nitriles, one or more mixed solvents in water; in some typical embodiments, the organic solvent B is selected from methanol, ethanol, n-propanol, isopropanol, acetone, N, N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, one or more mixed solvents in water; in some more typical embodiments, the organic solvent B is selected from isopropanol, acetone, N, N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, one or more mixed solvents in water A mixed solvent of two or more; in some more typical embodiments, the organic solvent B is selected from one or a mixed solvent of isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and water; in some more typical embodiments, the organic solvent B is selected from one or a mixed solvent of isopropanol, N,N-dimethylformamide, tetrahydrofuran, acetonitrile and 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.

[0047] In some embodiments of the present invention, the reaction of route II is carried out in the presence of an alkaline reagent B; in some typical embodiments, the alkaline reagent B is selected from one or a mixture of two or more of alkali metal carbonates, DBU, tetra(C1-C6 alkyl)ammonium halides, and alkali metal hydrides; in some more typical embodiments, 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 hydride; in some more typical embodiments, the reaction of route II is carried out in the presence of an alkaline reagent B; in some ... In the embodiment, the alkaline agent B is selected from one or a mixture of two or more of potassium carbonate, cesium carbonate, DBU, tetrabutylammonium iodide, and sodium hydrogen; 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.

[0048] In some embodiments of the present invention, the reaction of route II 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 two or more 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 two or more 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.

[0049] 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 therein.

[0050] 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 to 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 to 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 to 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 to 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 to 1. The molar ratio of reagent B is 1:0.5 to 3; in some 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.

[0051] 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.

[0052] In some embodiments of the present invention, the reaction time of the Route II reaction is 0 to 48 h; in some typical embodiments, the reaction time of the Route II reaction is 4 to 32 h; in some more typical embodiments, the reaction time of the Route II reaction is 2 to 24 h; in some most typical embodiments, the reaction time of the Route II reaction is 3 h, 4 h, 5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 9.5 h, 10 h, 10.5 h, 11 h, 11.5 h, 12 h, 24 h or any range therein.

[0053] 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.

[0054] 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.

[0055] The present invention also provides a method for preparing a compound of formula I or a salt thereof, characterized in that it comprises the following reaction steps:

[0056] (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 reagent B in an organic solvent B to obtain a compound of formula III or a salt thereof;

[0057] (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 reagent A and a reducing agent in an organic solvent A to produce the compound of formula I or its salt;

[0058] in,

[0059] R 1 and R 2 The definition of is the same as that in Route I;

[0060] The definitions of the compound of formula I and the compound of formula II are the same as those in Scheme 1;

[0061] R 3 and R 4 The definition of is the same as that in Route II;

[0062] The definitions of alkaline reagent A, organic solvent A and reducing agent are the same as those in Scheme 1;

[0063] The definitions of alkaline reagent B and organic solvent B are the same as those in Scheme II.

[0064] In some embodiments of the present invention, the reaction conditions of step (1) are as shown in the aforementioned Scheme II and the reaction conditions of step (2) are as shown in the aforementioned Scheme I.

[0065] In some embodiments of the present invention, R 1 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 its salt to generate a compound of Formula I-2 or its salt,

[0066] In some embodiments of the present invention, R 1 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 a salt thereof to generate a compound of Formula I-1 or a salt thereof.

[0067] The present invention also provides a method for preparing a compound of formula I-1 or a salt thereof, which is characterized by comprising 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.

[0068] The present invention also provides a method for preparing a compound of formula I-1 or a salt thereof, which is characterized by comprising 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 produce a compound of formula I or a salt thereof.

[0069] The compound of formula V of the present invention can be purchased or prepared according to existing technologies, including but not limited to WO2013163244A1 and WO2014153055A2; the compound of formula IV of the present invention can be purchased or prepared according to existing technologies, including but not limited to WO2003047570A1, WO2014025978A1, and IN2012CH00514A.

[0070] In the present invention, the hydrogen spectrum data of the compounds were measured by Bruker 400 MHz.

[0071] In the present invention, the infrared chromatographic data of the compounds were measured by Bruker nanoIR3.

[0072] In the present invention, the LC-MS of the compounds was measured by Agilent 6410B QQQ LC / MS.

[0073] In the present invention, the purity of the compound was measured by HPLC, and the specific chromatographic conditions were as follows:

[0074] Chromatographic column: SHIMADZU AQ-C18 150*4.6mm, 3μm;

[0075] Mobile phase A: Dissolve 1.0 mL of trifluoroacetic acid in 1000 mL of purified water, shake well, filter, sonicate, and set aside;

[0076] Mobile phase B: Dissolve 1.0 mL of trifluoroacetic acid in 1000 mL of acetonitrile, shake well, filter, sonicate, and set aside;

[0077] Detection wavelength: 230 nm, Peakwidth>0.1 min (2 s response time) (2.5 Hz);

[0078] Flow rate: 1.0 mL / min;

[0079] Injection volume: 10 μL;

[0080] Column temperature: 30°C;

[0081] Collection time: 36 minutes;

[0082] Needle washing solution: acetonitrile;

[0083] 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.

[0084] The invention provides a new preparation route of arylmethoxyisoindoline derivatives, and the products prepared by the preparation route have good yield and purity.

[0085] It is readily understood by those skilled in the art that the error ranges of the parameters listed in the present invention also fall within the scope of protection of the present invention, and the error ranges include but are not limited to the degree of expected experimental error, technical error, and instrument error of a given technology for measuring the value.

[0086] 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 Scheme I, when R in the compound of Formula II 1 When R in the compound of formula I is H, 1 It should also be H.

[0087] It is easy for those skilled in the art to understand that the determination of the reaction endpoint can be achieved based on the experience, experimental phenomena, technical means monitoring, etc. of those skilled in the art; 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.

[0088] Reaction time refers to the time from the addition of the first material to the end of the reaction.

[0089] In the present invention, unless otherwise specified, the following terms have the following meanings:

[0090] “N” stands for Mol / L.

[0091] "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, methyloxycarbonyl, 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), oN-bromosuccinimide (oNbs), pN-bromosuccinimide (pNbs), (trimethylsilyl)ethoxymethyl (SEM), tert-butyl (t-Bu) or 2,2,2-trichloroethoxycarbonyl (Troc), etc.

[0092] "OTs" refers to p-toluenesulfonyloxy; "OMs" refers to methylsulfonyloxy; "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.

[0093] C1-C6 alkyl alcohol refers to an alkyl alcohol with a 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.

[0094] 6-10 membered aromatic hydrocarbons are aromatic hydrocarbons with carbon atoms 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.

[0095] C6-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.

[0096] Halogenated C1-C7 alkanes refer to halogenated alkanes with carbon number ranging from 1 to 7, including but not limited to one or more of iodomethane, ethyl bromide, isopropyl bromide, benzyl chloride, bromobenzene, p-methoxyiodobenzene, p-fluoroiodobenzene or m-methylbromobenzene; amides such as one or more of acetamide, dimethylacetamide, hexamethylphosphoramide or dimethylformamide (DMF).

[0097] C6-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.

[0098] 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.

[0099] 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, or a mixed solvent of two or more thereof.

[0100] 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-ethylbutyl 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 2-methyltetrahydrofuran, or a mixed solvent of two or more thereof.

[0101] Nitriles refer to organic compounds formed by connecting carbon atoms containing a hydrocarbon group and a cyano group, including but not limited to acetonitrile, propionitrile, butyronitrile, or benzonitrile, or a mixed solvent of two or more thereof.

[0102] The ratio of mobile phase in HPLC is volume ratio.

[0103] “10% palladium carbon” means that the mass fraction of palladium in palladium carbon accounts for 10% of the total mass of palladium carbon.

[0104] "0.5%-10% palladium on carbon / hydrogen" refers to a combination of 0.5%-10% palladium on carbon and hydrogen.

[0105] "Raney nickel / hydrogen" refers to a combination of Raney nickel and hydrogen.

[0106] "Room temperature" refers to 20°C-25°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] FIG1 shows the liquid phase spectrum of the hydrochloride of the compound of formula I-1 prepared in Example 6 measured by LC-MS.

[0108] Figure 2 shows the H NMR spectrum of the hydrochloride of the compound of formula I-1 prepared in Example 6 1 H-NMR (DMSO-d6).

[0109] FIG3 shows the HPLC spectrum of the hydrochloride salt of the compound of formula I-1 prepared in Example 6.

[0110] FIG4 shows the infrared chromatogram of the hydrochloride of the compound of formula I-1 prepared in Example 6.

[0111] FIG5 shows the liquid phase spectrum measured by LC-MS of the compound of formula III-1 prepared in Example 3.

[0112] Figure 6 shows the H NMR spectrum of the compound of formula III-1 prepared in Example 3 1 H-NMR (DMSO-d6). DETAILED DESCRIPTION

[0113] For the sake of clarity, the present invention is further described in detail below in conjunction with the examples, but it should be understood that the examples do not limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

[0114] Example 1 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

[0115] Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction flask and dissolved in 200 mL of isopropanol. 1.34 g of solid tetrabutylammonium iodide and 30.56 g of solid potassium carbonate were added with stirring at room temperature, followed by 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine. 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).

[0116] Example 2 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

[0117] Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction flask and dissolved in 200 mL of acetonitrile. 50 g of DBU was added with stirring at room temperature, followed by 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine. The temperature was raised to 30-40°C and the reaction was carried out for 24 h. The reaction solution was cooled, filtered, and concentrated to obtain 35.23 g of a solid (i.e., the title compound).

[0118] Example 3 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

[0119] Under nitrogen, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to a reaction flask and dissolved in 200 mL of DMF. 19.26 g of cesium carbonate powder was added with stirring at room temperature, followed by 30.09 g of 4-(4-(chloromethyl)benzyl)morpholine. The temperature was raised to 60°C and the reaction was allowed to react for 4 h. The reaction solution was cooled, filtered, and concentrated to obtain 37.10 g of a solid (i.e., the title compound).

[0120] Example 4 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

[0121] Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to the reaction flask, dissolved in 200 mL of DMF, and the temperature was lowered to 0 ° C. 4 g of commercially available sodium hydrogen hydrate (wherein 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 h. The reaction solution was cooled, filtered, and concentrated to obtain 30.74 g of a solid (i.e., the title compound).

[0122] Example 5 Preparation of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate (compound of formula III-1)

[0123] Under nitrogen protection, 20 g of methyl 2-formyl-3-hydroxybenzoate was added to a reaction flask 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 phase transfer catalyst were added with stirring at room temperature. 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 36.75 g of a solid (i.e., the title compound).

[0124] 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)

[0125] Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate prepared in Example 5 was added to the reaction flask 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. The temperature was controlled not to exceed 5 ° C. The reaction was continued for 8 h. 20 mL The reaction was quenched with 2N dilute hydrochloric acid, concentrated to remove most of the solvent, added with 100 mL of saturated brine, extracted three times with 50 mL of isopropyl acetate, and concentrated the organic phase to obtain 15.9 g of a solid. The solid was dissolved in 40 mL of isopropyl acetate, heated to reflux, and after the solution was clear, 15 mL of n-heptane was added. The temperature was lowered to 10°C over 15 h, and filtered to obtain 14.5 g of a solid (i.e., the title compound) with a purity of 99.87%.

[0126] Example 7 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound of Formula I-1)

[0127] Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate prepared in Example 2 was added to the reaction flask and dissolved in 260 mL of tetrahydrofuran. The mixture was 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. The reaction was quenched by adding 50 mL of 2N dilute hydrochloric acid, filtered, and the filtrate was concentrated to about 150 mL. The pH was adjusted to 6-8 with sodium acetate, extracted three times with 50 mL of isopropyl acetate, and the organic phases were combined and concentrated to obtain 17.2 g of a solid. The solid was dissolved in 75 mL of ethanol, heated to reflux, and after the solution was clear, 20 mL of water was added dropwise. The temperature was lowered to 10°C for 15 h and filtered to obtain 12.32 g of a solid (i.e., the title compound) with a purity of 97.85%.

[0128] Example 8 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound of Formula I-1)

[0129] Under nitrogen, 20 g of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate prepared in Example 3 was added to a reaction flask 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 on carbon (50% water) was added and the 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 filtrates were concentrated to give 16.5 g of a solid. The solid was dissolved in 45 mL of acetonitrile and the temperature was raised to reflux. After the solution was clear, 15 mL of n-heptane was added. The temperature was lowered to 10° C. over 15 h and the mixture was filtered to give 15.06 g of a solid (i.e., the title compound) with a purity of 94.91%.

[0130] Example 9 Preparation of (S)-3-(4-(4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindol-2-yl)piperidine-2,6-dione (Compound of Formula I-1)

[0131] Under nitrogen protection, 20 g of methyl 2-formyl-3-((4-(morpholinomethyl)benzyl)oxy)benzoate prepared in Example 5 was added to the reaction flask and dissolved in 180 mL of tetrahydrofuran. The mixture was cooled to 0 ° C. 4.62 g of (S)-3-aminopiperidine-2,6-dione was dissolved in 45 mL of tetrahydrofuran and stirred for 1 h. The mixture was cooled to -50 ° C. 90 mL of 1N diisobutylaluminum hydride toluene solution was added dropwise with the temperature controlled not to exceed -45 ° C. The mixture was then 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 three times with 100 mL of toluene. The organic phase was washed twice with saturated brine and 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, and 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%.

[0132] The above-described embodiments merely illustrate several implementations of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, and all such variations and improvements fall within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula I or a salt thereof, characterized in that: The compound of formula III or its salt and the compound of formula II or its salt react in the presence of a reducing agent in an organic solvent A to generate a compound of formula I or its salt, in, R 1 is H or an amino protecting group; R 2 It is OH or C1-C6 alkoxy.

2. The method according to claim 1, characterized in that R 1 is H, tert-butyloxycarbonyl, benzyloxycarbonyl, tert-methoxycarbonyl or benzyl, preferably, R 1 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.

3. 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 one or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, palladium carbon / hydrogen, Raney nickel / hydrogen, diisobutylaluminum hydride. Preferably, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, 10% palladium carbon / hydrogen, diisobutylaluminum hydride. Preferably, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride. Preferably, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride. Preferably, the reducing agent is one or more 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.

4. The method according to claim 1, characterized in that: The organic solvent A is selected from C1-C6 alkyl alcohol, 6-10 aromatic hydrocarbons, C6-C 10 A mixed solvent of one or more of aliphatic hydrocarbons, halogenated C1-C7 alkanes, amides, ketones, esters, ethers, and nitriles. Preferably, the organic solvent A is selected from 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 methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile. Preferably, the organic solvent A is selected from 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 alkali metal carbonates, DBU, tetra(C1-C4 alkyl)ammonium halides, C6-C 10 Preferably, the alkaline reagent A is selected from one or more of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, triethylamine, diisopropylethylamine, preferably, the alkaline reagent A is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium iodide, triethylamine, diisopropylethylamine, preferably, the alkaline reagent A is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, DBU, tetrabutylammonium fluoride, tetrabutylammonium iodide, triethylamine, diisopropylethylamine, preferably, the alkaline reagent The alkaline agent A is selected from potassium carbonate, sodium carbonate, tetrabutylammonium iodide, diisopropylethylamine, DBU or a mixture of two or more thereof. Preferably, the alkaline agent A is selected from potassium carbonate, triethylamine, diisopropylethylamine or a mixture of two or more thereof. Preferably, the alkaline agent A is selected from a mixture of tetrabutylammonium iodide and DBU, potassium carbonate, diisopropylethylamine, sodium carbonate, tetrabutylammonium iodide or triethylamine. Preferably, the alkaline agent A is selected from potassium carbonate or triethylamine. Preferably, the alkaline agent A is selected from diisopropylethylamine.

5. 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 is in the form of a compound of formula IS or its salt, preferably, more than 90% by weight of the compound of formula I or its salt is in the form of a compound of formula IS or its salt, preferably, 100% by weight of the compound of formula I or its salt is in the form of a compound of formula IS or its salt, more preferably, the compound of formula IS or its salt is in the form of a compound of formula I-1 or its salt.

6. A compound of formula III or a salt thereof, in, R 2 is OH or C1-C6 alkoxy, preferably, R 2 is OH, methoxy, ethoxy, n-propoxy or isopropoxy, preferably, R 2 is methoxy or ethoxy, more preferably, R 2 It is a methoxy group.

7. Use of the compound according to 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 a salt thereof is present in the form of a compound of formula IS or a salt thereof, preferably, more than 90% by weight of the compound of formula I or a salt thereof is present in the form of a compound of formula IS or a salt thereof, preferably, 100% by weight of the compound of formula I or a salt thereof is present in the form of a compound of formula IS or a salt thereof, more preferably, the compound of formula IS or a salt thereof is present in the form of a compound of formula I-1 or a salt thereof.

8. 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 C1-C6 alkoxy; R 3 is OH, optionally substituted C1-C6 alkylsulfonyloxy, optionally substituted benzenesulfonyloxy or halogen; R 4 is OH or halogen; And R 3 , R 4 Not halogen at the same time.

9. 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 For Cl.

10. The method according to claim 8, characterized in that Route II: react in the presence of alkaline reagent B and phase transfer catalyst, react in organic solvent B, The organic solvent B is selected from C1-C6 alkyl alcohol, 6-10 aromatic hydrocarbons, C6-C 10 Aliphatic hydrocarbons, halogenated C1-C7 alkanes, amides, ketones, esters, ethers, nitriles, one or more mixed solvents in water, preferably, the organic solvent B is selected from methanol, ethanol, n-propanol, isopropanol, acetone, N,N-dimethylformamide, tert-butanol, tetrahydrofuran, acetonitrile, one or more mixed solvents in 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(C1-C6 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.

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