Preparation of 1, 8-diamino-3, 6-dioxaoctane bifunctional derivative

Abstract

The invention discloses a preparation method of a 1, 8-diamino-3, 6-dioxaoctane bifunctional derivative, which comprises the following steps of: preparing a 1, 8-diamino-3, 6-dioxaoctane bifunctional derivative; the invention specifically provides a preparation method of a compound as shown in a formula I. The preparation method comprises the following step: in an organic solvent, in the presence of a condensing agent, carrying out condensation reaction on a compound as shown in a formula II and a compound as shown in a formula IV to prepare the compound as shown in the formula I, in the compound shown in the formula IV, an R group is a trifluoromethylsulfonyloxy group, a p-nitrobenzenesulfonyloxy group or halogen. The preparation method has the advantages of high yield and purity, cheap raw materials, and suitableness for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the preparation of a 1,8-diamino-3,6-dioxaoctane bifunctional derivative. Background Art

[0002] 1,8-Diamino-3,6-dioxaoctane is an organic compound with the chemical formula C 6 H 12 N 2 O 2 . It is composed of 6 carbon atoms and 2 nitrogen atoms, connected by 2 oxygen atoms in the middle. It is a colorless transparent liquid at room temperature and pressure, soluble in water and common organic solvents. The 1,8-diamino-3,6-dioxaoctane molecule contains two amino groups and two glycol ether groups. These functional groups are polar functional groups, so this compound is a polar molecule with polar interactions and can interact with polar molecules and ions. Because the molecule has a high polarity, the interaction between molecules is strong, which makes the boiling point of the compound relatively high.

[0003] 1,8-Diamino-3,6-dioxaoctane is an important raw material for the synthesis of macrocyclic coordination compounds and is widely used in supramolecular chemistry, especially in crown ether chemistry research. In addition, due to the two amino groups at the 1,8 positions of its structure, it can also be used as a connector for proteases for the modification and coupling of bioactive molecules. 1,8-Diamino-3,6-dioxaoctane can be used as a pharmaceutical chemical intermediate, such as tenapano, a drug for the treatment of constipation-type irritable bowel syndrome in adults. Tenapano can also be used to treat hyperphosphatemia in patients with heart and kidney diseases undergoing dialysis. In short, 1,8-diamino-3,6-dioxaoctane is an important organic compound with a wide range of applications. It has important applications and development prospects in the fields of organic synthesis, semiconductor materials, drugs, coatings, etc.

[0004] However, in the application of 1,8-diamino-3,6-dioxooctane, one amino group is often first derivatized and protected, and after the unprotected amino group is derivatized, the protecting group is removed and the other amino group is derivatized. In the amino protection process, a large excess of 1,8-diamino-3,6-dioxooctane (about 10 equivalents, Chemical Communications, 2006, 11, 1182-1184; CN115612090A) is required to control the proportion of the single-protected product. Although the preparation method of the double derivative is disclosed in the prior art, the reaction raw materials are expensive and not suitable for industrial production. Summary of the invention

[0005] In view of the defects of the existing preparation methods, such as high reaction temperature and expensive reaction raw materials, the present invention provides a new preparation method for 1,8-diamino-3,6-dioxaoctane bifunctional derivatives. The preparation method has high yield and purity, and the raw materials are cheap, which is suitable for industrial production.

[0006] Specifically, the present application provides a method for preparing a compound of formula I, which comprises the following steps: in an organic solvent, in the presence of a condensing agent, a compound of formula II and a compound of formula IV undergo the following condensation reaction to prepare a compound of formula I; in the compound of formula IV, the R group is trifluoromethylsulfonyloxy, p-nitrobenzenesulfonyloxy or halogen;

[0007] .

[0008] In some embodiments, in the condensation reaction, the organic solvent is anhydrous tetrahydrofuran or N, N-dimethylacetamide.

[0009] In some embodiments, in the condensation reaction, the molar volume ratio of the compound of formula II to the organic solvent is 0.6 mol / L-2 mol / L.

[0010] In some embodiments, in the condensation reaction, the condensation agent is sodium hydride or a mixture of sodium hydride and tetrabutylammonium halide; the tetrabutylammonium halide is, for example, tetrabutylammonium iodide or tetrabutylammonium bromide.

[0011] In some embodiments, in the condensation reaction, the halogen is chlorine or bromine.

[0012] In some embodiments, in the condensation reaction, when the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the condensing agent is sodium hydride (eg, 60% sodium hydride); the molar ratio of the sodium hydride to the compound of formula II is preferably 2.1:1.

[0013] In some embodiments, in the condensation reaction, when the R group is a halogen, the condensing agent is a mixture of sodium hydride (e.g., 60% sodium hydride) and tetrabutylammonium halide; the molar ratio of the sodium hydride to the compound of formula II is preferably 2.3:1; the molar ratio of the tetrabutylammonium halide to the compound of formula II is preferably 0.1:1.

[0014] In some embodiments, in the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula II is 1:1.

[0015] In some embodiments, the reaction temperature of the condensation reaction is an ice-water bath (eg, below 5° C.) or room temperature.

[0016] In some embodiments, the method for preparing the compound of formula I further comprises preparing the compound of formula II by the following steps: in an organic solvent, ethanolamine and di-tert-butyl dicarbonate are subjected to an amino protection reaction as shown below to prepare the compound of formula II;

[0017] .

[0018] In some embodiments, in the amino protection reaction, the organic solvent is toluene.

[0019] In some embodiments, in the amino protection reaction, the mass volume ratio of the ethanolamine to the organic solvent is 1 g:3.1 mL.

[0020] In some embodiments, in the amino protection reaction, the mass ratio of ethanolamine to di-tert-butyl dicarbonate is 1:3.4.

[0021] In some embodiments, the reaction temperature of the amino protection reaction is room temperature.

[0022] In some embodiments, when the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the method for preparing the compound of formula I further comprises preparing the compound of formula IV by the following steps: in an organic solvent, in the presence of a base, the compound of formula III and a sulfonyl chloride or an acid anhydride undergo a condensation reaction as shown below to generate a compound of formula IV; the sulfonyl chloride or acid anhydride is trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethylsulfonic anhydride or p-nitrobenzenesulfonic anhydride;

[0023] .

[0024] In some embodiments, in the condensation reaction, the organic solvent is dichloromethane.

[0025] In some embodiments, in the condensation reaction, the molar volume ratio of the compound of formula III to the organic solvent is 0.4 mol / L.

[0026] In some embodiments, in the condensation reaction, the base is triethylamine.

[0027] In some embodiments, in the condensation reaction, the molar ratio of the base to the compound of formula III is 1.2:1.

[0028] In some embodiments, in the condensation reaction, the molar ratio of the sulfonyl chloride or anhydride to the compound of formula III is 1.1:1.

[0029] In some embodiments, the reaction temperature of the condensation reaction is room temperature.

[0030] In some embodiments, when the R group is bromine or chlorine, the method for preparing the compound of formula I further comprises preparing the compound of formula IV by the following steps: the compound of formula III is subjected to a substitution reaction with carbon tetrabromide or dichlorothionyl as shown below to generate the compound of formula IV;

[0031] .

[0032] In some embodiments, when R is bromine, the reaction system of the substitution reaction further includes an organic solvent and triphenylphosphine;

[0033] The organic solvent is preferably tetrahydrofuran; the molar volume ratio of the compound of formula III to the organic solvent is preferably 0.8 mol / L;

[0034] The molar ratio of triphenylphosphine to the compound of formula III is preferably 1.5:1.

[0035] In some embodiments, in the substitution reaction, the molar ratio of carbon tetrabromide to the compound of formula III is 1.2:1.

[0036] In some embodiments, when R is bromine, the process further comprises the following steps: mixing the product obtained after the substitution reaction with toluene and anhydrous calcium chloride.

[0037] In some embodiments, when R is bromine, the reaction temperature of the substitution reaction is room temperature.

[0038] In some embodiments, when R is chlorine, no additional organic solvent is added to the reaction system of the substitution reaction, and the molar volume ratio of the compound of formula III to thionyl chloride is 2.1 mol / L.

[0039] In some embodiments, when R is chlorine, the reaction temperature of the substitution reaction is heated to reflux.

[0040] In some embodiments, the method for preparing the compound of formula I further comprises preparing a compound of formula III by the following steps: in an organic solvent, 2-(2-aminoethoxy)ethanol and phthalic anhydride undergo a condensation reaction as shown below to obtain a compound as shown in formula III;

[0041] .

[0042] In some embodiments, in the condensation reaction, the organic solvent is toluene.

[0043] In some embodiments, in the condensation reaction, the molar volume ratio of the 2-(2-aminoethoxy)ethanol to the organic solvent is 1.0 mol / L.

[0044] In some embodiments, in the condensation reaction, the molar ratio of the 2-(2-aminoethoxy)ethanol to phthalic anhydride is 1:1.

[0045] In some embodiments, the reaction temperature of the condensation reaction is heated to reflux.

[0046] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0047] The reagents and raw materials used in the present invention are commercially available.

[0048] The positive progressive effect of the present invention is that the present invention provides a new preparation method of 1,8-diamino-3,6-dioxaoctane bifunctional derivatives, the preparation method has high yield and purity, and the reaction raw materials are cheap, which is suitable for industrial production. DETAILED DESCRIPTION

[0049] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0050] Example 1 Preparation of Compound II:

[0051]

[0052] Under nitrogen protection, add 100 mL of toluene and 64 g of ethanolamine to the reaction flask. Add 218 g of di-tert-butyl dicarbonate dissolved in 100 mL of toluene to the resulting solution at room temperature, and react at room temperature for 4-5 hours. Wash the reaction solution with 5% sodium chloride solution (100 mL×3), and concentrate the organic phase to obtain 161 g of oily liquid with a yield of 100%. MS (M+H): 162, 1 H NMR (400 MHz, CDCl 3 ): δ(ppm) 1.43 (s, 9H), 3.2-3.1 (bs, 1H), 3.25 (bd, 2H), 3.65(t, 2H, J = 5.04 Hz), 1H 5.13 (bs, 1H)

[0053] Example 2 Preparation of Compound III:

[0054]

[0055] Add 11.0g 2-(2-aminoethoxy)ethanol (100mmol), 14.8g phthalic anhydride (100mmol), 105mL toluene to the reaction flask, heat to reflux, react for 8 hours while reflux and remove water, cool to room temperature, wash with water (30mL*2 times), concentrate the organic phase to dryness under reduced pressure, add 50mL n-heptane, stir for 30 minutes, filter, and vacuum dry to obtain 22.7g of white solid, yield: 96.6%. MS (M+H + ): 236, 1 H NMR (400MHz, CDCl 3 ): δ(ppm) 3.61 (m, 2H), 3.69 (m, 2H), 3.75 (t, 2H), 3.91 (t, 2H), 5.21(bs, 1H), 7.73 (m, 2H), 7.85(m, 2H).

[0056] Example 3 Preparation of Compound IV:

[0057]

[0058] Method 1: R is a sulfonyloxy derivative

[0059] Add 23.5g of compound III (100mmol), 12.1g of triethylamine (120mmol), and 118ml of dichloromethane to the reaction flask and cool it to below 5℃ with an ice-water bath. Under stirring, control the temperature not to exceed 10℃, and add 105mmol of sulfonyl chloride (or anhydride) dissolved in 118mL of dichloromethane to the solution. After the addition is complete, remove the ice-water bath and continue stirring until TLC shows that compound III has reacted completely. Add 100mL of water to the reaction solution, stir at room temperature for 2-3 hours, and separate the liquids. The organic phase is washed with 1M hydrochloric acid (50mL*2), 5% sodium bicarbonate solution (50mL*2), and 50mL of water in turn. After the organic phase is concentrated to dryness under reduced pressure, add 118mL of n-heptane, stir at room temperature for 10-20 minutes, filter, and dry in vacuo.

[0060] R is trifluoromethanesulfonyloxy

[0061] 33.4 g of light yellow solid was obtained, yield: 91.0%. MS (M+H + ):368. 1 H NMR (400 MHz, CDCl 3 ) δppm: 3.55 (m, 4H), 3.60 (t, 2H), 3.80 (t, 2H), 3.85 (t, 2H), 4.29 (t, 2H),7.65 (m, 2H), 7.81 (m, 2H).

[0062] R is 4-nitrobenzenesulfonyloxy

[0063] The yellow solid was obtained in an amount of 30.1 g, with a yield of 96.2%. MS (M+H + ):314. 1 H NMR (400 MHz, CDCl 3 ) δppm: 3.71-3.75 (m, 4H), 3.91 (t, 2H), 4.31-4.33 (d, 2H), 7.71-7.75 (m, 2H), 7.81-7.85 (m, 2H) 8.41 (d, 2H), 8.14 (dd, 2H).

[0064] Method 2: R is bromine

[0065] 23.5g of compound III (100mmol) and 393g of triphenylphosphine (150mmol) were added to 120mL of anhydrous tetrahydrofuran, and 39.8g of carbon tetrabromide (120mmol) was added in batches under stirring. After the addition was completed, the mixture was reacted at room temperature until TLC showed that compound III disappeared, and then the mixture was concentrated to dryness under reduced pressure. 470mL of toluene and 80g of anhydrous calcium chloride were added to the residue, stirred at room temperature for 16 hours, and filtered. The filtrate was concentrated to about 50mL under reduced pressure, 500mL of n-heptane was added, cooled to 0°C, stirred at this temperature for 2 hours, filtered, and the filter cake was rinsed with n-heptane and dried under vacuum to obtain 24.3g of a slightly yellow solid with a yield of 81.5%. (M+H + ): 298, 3.41(t, 2H), 3.76-3.81(m, 4H), 3.92(t, 2H), 7.70-7.74(m, 2H), 7.79-7.85(m, 2H)

[0066] Method 3: R is chlorine

[0067] 23.5 g of compound III (100 mmol) and 47 mL of thionyl chloride were added to the reaction flask, heated to reflux, and kept warm to react until TLC showed that compound III disappeared. The reaction solution was concentrated to dryness under reduced pressure, 50 mL of n-heptane was added, and after stirring for 20-30 minutes, it was concentrated to dryness under reduced pressure again, 100 mL of n-heptane was added, cooled to 0°C, kept warm and stirred for 2 hours, filtered, and the filter cake was rinsed with n-heptane and vacuum dried to obtain 19.8 g of a slightly yellow solid, with a yield of 78.0% MS (M+H + ): 254, 3.44(t, 2H), 3.77-3.82 (m, 4H), 3.91(t, 2H), 7.71-7.75(m, 2H), 7.78-7.83(m, 2H)

[0068] Example 4 Preparation of Compound I:

[0069] Method 1: R is a sulfonyloxy derivative

[0070]

[0071] Dissolve 16.1g of compound II (100mmol) in 80mL of anhydrous tetrahydrofuran and place in an ice-water bath to below 5°C. Control the temperature not to exceed 5°C, add 4.2g of NaH (60%, 210mmol), and stir in an ice-water bath for 0.5-1 hour. Then control the temperature not to exceed 5°C, and add a solution of 100mol of compound IV dissolved in 80mL of anhydrous tetrahydrofuran. After the addition, remove the ice-water bath, stir at room temperature until TLC shows that compound IV reacts completely, and heat if it does not react. Cool the mixture to 0°C in an ice-water bath, control the temperature not to exceed 5°C, and drop 5mL of ethanol solution and 200mL of saturated sodium bicarbonate solution in sequence. Concentrate under reduced pressure to about 150mL, add 80mL of ethyl acetate, separate the liquids, and wash the organic phase with water (80mL*2 times). Concentrate the organic phase under reduced pressure to dryness to obtain an oily liquid. 1 H NMR (400 MHz, CDCl 3 ): δ(ppm) 1.36 (s, 9 H), 3.18-3.61 (m, 12 H), 7.58 (bs, 1 H), 7.74 (dd, 2 H), 7.80 (dd, 2 H).

[0072] R is trifluoromethylsulfonyloxy: react at room temperature until the sulfonate disappears, and post-treatment to obtain 33.2 g, yield: 87.8%

[0073] R is p-nitrobenzenesulfonyloxy: react at about 35°C until the sulfonate disappears, and post-treatment to obtain: 25.3 g, yield: 66.9%.

[0074] Method 2: R is halogen

[0075] Dissolve 100mmol of compound IV, 10mmol of tetrabutylammonium halide, and 16.9g of compound II (105mmol) in 50mL of N,N-dimethylacetamide, and cool to below 5°C with an ice-water bath. Keep the temperature below 5°C, and slowly add 5.76g of NaH (60%, 240mmol). After the addition, continue stirring for 2 hours in an ice-water bath. Remove the ice-water bath, and stir at room temperature until TLC shows that compound IV disappears. Keep the temperature below 30°C, and slowly drop 9.2g of ethanol, 100mL of water, and 200mL of toluene. Adjust the pH to 6-7 under stirring, separate the liquids, wash the organic phase with 5% sodium bicarbonate solution (50mL*2 times), and concentrate the organic phase under pressure to obtain compound I.

[0076] R is chlorine: tetrabutylammonium halide is tetrabutylammonium iodide, after post-treatment, 27.2g, yield: 72.0%

[0077] R is bromine: tetrabutylammonium halide is tetrabutylammonium bromide, post-treatment to obtain 29.8g, yield: 78.8%

[0078] Example 5 Preparation of Compound VI:

[0079]

[0080] 3.78 g of compound I was dissolved in ethyl acetate, and a 2M HCl solution in ethyl acetate was added at room temperature. After the addition was completed, the mixture was stirred at room temperature until TLC showed that compound I disappeared. The mixture was filtered and dried under reduced pressure to obtain 3.10 g of a white solid. Yield: 98.4%, MS (M+H + ):279.

[0081] Example 6 Preparation of Compound VI:

[0082]

[0083] Add 3.78g of compound I, 20mL of ethanol, and 2g of hydrazine hydrate (80%) to the reaction flask. Heat to reflux and keep the reaction warm until TLC shows that compound I disappears, cool to room temperature, concentrate to dryness under reduced pressure, add 50mL of tetrahydrofuran and 2g of citric acid, stir for 3-4 hours, filter, and wash the filter cake with 20mL of tetrahydrofuran. Add the filter cake to water, adjust the pH to 9-10 with sodium carbonate, extract with toluene (10mL*3 times), combine the organic phases, wash the organic phases with 10mL of saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 2.1g of oily liquid, yield: 84.7%. MS (M+H + ):249.

[0084] Comparative Example

[0085] 1. Referring to the method of method 1 in Example 3, when R is methylsulfonyloxy or R is p-toluenesulfonyloxy, the compound of formula IV is prepared, and the results are as follows:

[0086] R is p-toluenesulfonyloxy

[0087] 37.1 g of white solid was obtained, yield: 95.4%. MS (M+H + ):390. 1 H NMR (400 MHz, CDCl 3) δppm: 2.41 (s, 3H), 3.51 (m, 4H), 3.58 (t, 2H), 3.66 (t, 2H), 3.84 (t, 2H), 4.06 (t, 2H), 7.30 (d, 2H), 7.68 (m, 2H), 7.74 (d, 2H), 7.80 (m, 2H).

[0088] R is methylsulfonyloxy

[0089] 30.1 g of white solid was obtained, yield: 96.2%. MS (M+H + ):314. 1 H NMR (400 MHz, CDCl 3 ) δppm: 2.98 (s, 3H), 3.71-3.76 (m, 4H), 3.88 (t, 2H), 4.27-4.31 (m, 2H), 7.70-7.75 (m, 2H), 7.82-7.84 (m, 2H).

[0090] 2. Referring to the method of method 1 in Example 4, when R is methylsulfonyloxy or R is p-toluenesulfonyloxy, the compound of formula I was prepared, and the results were as follows:

[0091] R is methylsulfonyloxy: reflux reaction until the sulfonate disappears, and column purification is performed to obtain 5.5 g, with a yield of 14.6%.

[0092] R is p-toluenesulfonyloxy: reflux reaction until the sulfonate disappears: 13.8 g, yield: 36.5%.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: in an organic solvent, in the presence of a condensing agent, a compound of formula II and a compound of formula IV undergo the following condensation reaction to prepare a compound of formula I; in the compound of formula IV, the R group is trifluoromethylsulfonyloxy, p-nitrobenzenesulfonyloxy or halogen; 。 2. The preparation method according to claim 1, characterized in that The method for preparing the compound of formula I satisfies one or more of the following conditions: (1) In the condensation reaction, the organic solvent is anhydrous tetrahydrofuran or N, N-dimethylacetamide; (2) In the condensation reaction, the molar volume ratio of the compound of formula II to the organic solvent is 0.6 mol / L-2 mol / L; (3) In the condensation reaction, the halogen is chlorine or bromine; (4) In the condensation reaction, when the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the condensation agent is sodium hydride; the molar ratio of the sodium hydride to the compound of formula II is preferably 2.1:1; (5) In the condensation reaction, when the R group is a halogen, the condensation agent is a mixture of sodium hydride and tetrabutylammonium halide; the tetrabutylammonium halide is, for example, tetrabutylammonium iodide or tetrabutylammonium bromide; the molar ratio of the sodium hydride to the compound of formula II is preferably 2.3:1; the molar ratio of the tetrabutylammonium halide to the compound of formula II is preferably 0.1:1; (6) In the condensation reaction, the molar ratio of the compound of formula IV to the compound of formula II is 1:

1.

3. The preparation method according to claim 1, characterized in that: The method for preparing the compound of formula I also includes preparing the compound of formula II by the following steps: in an organic solvent, ethanolamine and di-tert-butyl dicarbonate are subjected to an amino protection reaction as shown below to prepare the compound of formula II; 。 4. The preparation method according to claim 3, characterized in that: The preparation method of the compound of formula II satisfies one or more of the following conditions: (1) In the amino protection reaction, the organic solvent is toluene; (2) In the amino protection reaction, the mass volume ratio of the ethanolamine to the organic solvent is 1 g:3.1 mL; (3) In the amino protection reaction, the mass ratio of ethanolamine to di-tert-butyl dicarbonate is 1:3.

4.

5. The preparation method according to claim 1, characterized in that: When the R group is trifluoromethylsulfonyloxy or p-nitrobenzenesulfonyloxy, the preparation method of the compound of formula I further comprises preparing a compound of formula IV by the following steps: in an organic solvent, in the presence of a base, the compound of formula III and a sulfonyl chloride or an acid anhydride undergo a condensation reaction as shown below to generate a compound of formula IV; the sulfonyl chloride or acid anhydride is trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethylsulfonic anhydride or p-nitrobenzenesulfonic anhydride; 。 6. The preparation method according to claim 5, characterized in that: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the condensation reaction, the organic solvent is dichloromethane; (2) In the condensation reaction, the molar volume ratio of the compound of formula III to the organic solvent is 0.4 mol / L; (3) In the condensation reaction, the base is triethylamine; (4) In the condensation reaction, the molar ratio of the base to the compound of formula III is 1.2:1; (5) In the condensation reaction, the molar ratio of the sulfonyl chloride or acid anhydride to the compound of formula III is 1.1:

1.

7. The preparation method according to claim 1, characterized in that: When the R group is bromine or chlorine, the preparation method of the compound of formula I further comprises preparing a compound of formula IV by the following steps: the compound of formula III is subjected to a substitution reaction with carbon tetrabromide or dichlorothionyl as shown below to generate a compound of formula IV; 。 8. The preparation method according to claim 7, characterized in that: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) When R is bromine, the reaction system of the substitution reaction further includes an organic solvent and triphenylphosphine; The organic solvent is preferably tetrahydrofuran; the molar volume ratio of the compound of formula III to the organic solvent is preferably 0.8 mol / L; The molar ratio of triphenylphosphine to the compound of formula III is preferably 1.5:1; (2) In the substitution reaction, the molar ratio of carbon tetrabromide to the compound of formula III is 1.2:1; (3) When R is bromine, the method further comprises the following steps: mixing the product obtained after the substitution reaction with toluene and anhydrous calcium chloride; (4) When R is chlorine, no additional organic solvent is added to the reaction system of the substitution reaction, and the molar volume ratio of the compound of formula III to dithionyl chloride is 2.1 mol / L.

9. The preparation method according to claim 5 or 7, characterized in that: The method for preparing the compound of formula I also includes preparing a compound of formula III by the following steps: in an organic solvent, 2-(2-aminoethoxy)ethanol and phthalic anhydride undergo a condensation reaction as shown below to obtain a compound as shown in formula III; 。 10. The preparation method according to claim 9, characterized in that: The preparation method of the compound of formula III satisfies one or more of the following conditions: (1) In the condensation reaction, the organic solvent is toluene; (2) In the condensation reaction, the molar volume ratio of the 2-(2-aminoethoxy)ethanol to the organic solvent is 1.0 mol / L; (3) In the condensation reaction, the molar ratio of 2-(2-aminoethoxy)ethanol to phthalic anhydride is 1:1.

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