A preparation method of cis-2,3-norbornane dicarboxylic anhydride

Abstract

The present invention belongs to the technical field of compound preparation, and specifically relates to a method for preparing cis-2,3-norbornane dicarboxylic anhydride. The reaction formula is as follows: The present invention has mild conditions and no special requirements for equipment. Most of the solvents used are aqueous solutions and a small amount of organic solvents. The operation is simple and suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and specifically relates to a method for preparing cis-2,3-norbornane dicarboxylic anhydride. Background Art

[0002] Cis-2,3-norbornane dicarboxylic anhydride (norbornane) is an important intermediate for the preparation of lurasidone hydrochloride, which is an atypical antipsychotic drug developed by Sumitomo Pharma Co., Ltd. of Japan and was first launched in the United States on October 28, 2010 under the trade name Latuda. Lurasidone hydrochloride has a high affinity for both 5-HT2A receptors and dopamine D2 receptors, and has a significant therapeutic effect on both positive and negative symptoms of patients with mental illness. Summary of the invention

[0003] The present invention aims to provide a novel method for preparing cis-2,3-norbornane dicarboxylic anhydride.

[0004] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing cis-2,3-norbornane dicarboxylic anhydride comprises the following steps:

[0006] S1. Using nadic anhydride represented by the structural formula of compound (I) as a starting material, hydrolyzing at room temperature in the presence of an aqueous solution of a common solvent or an alkali solution, filtering, and obtaining an intermediate represented by the structural formula of compound (II) or a carboxylate thereof;

[0007] S2. The intermediate represented by the structural formula of compound (II) or its carboxylate salt is transformed at 80-100°C in the presence of an aqueous solution of a common solvent or an alkali solution to obtain a mixture of two configurations, and the mixture is separated in an aqueous solution of a common solvent or an alkali solution to obtain the intermediate represented by the structural formula of compound (III) or its carboxylate salt;

[0008] S3. In the presence of an aqueous solution of a common solvent or an alkaline solution, using palladium carbon, nickel or ruthenium as a catalyst, hydrogenating the intermediate represented by the structural formula of compound (III) or its carboxylate, and drying to obtain a compound represented by the structural formula (IV);

[0009] S4. In the presence of an organic solvent, the compound of the structural formula (Ⅳ) is ring-closed using acetic anhydride, concentrated and crystallized to obtain a norbornane of the structural formula (Ⅴ);

[0010] The reaction formulas of the above steps S1 to S4 are as follows:

[0011]

[0012] Preferably, the common solvent is selected from one of acetone, ethanol, methanol or tetrahydrofuran.

[0013] Preferably, the alkali solution is selected from one of a sodium hydroxide solution and a potassium hydroxide solution.

[0014] Preferably, the organic solvent is selected from one of acetone, tetrahydrofuran or ethyl acetate.

[0015] Preferably, in step S1, the mass ratio of nadic anhydride having the structural formula shown in compound (I) to an aqueous solution or alkaline solution of a common solvent is 1:2-3.

[0016] Preferably, in step S2, the mass ratio of the intermediate represented by the structural formula of compound (II) or its carboxylate to the aqueous solution or alkaline solution of a common solvent is 1:2-3.

[0017] The method has mild conditions and no special requirements on equipment. Most of the solvents used are aqueous solutions and a small amount of organic solvents. The operation is simple and suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 H NMR spectrum of compound (II) prepared in Example 1 of the present invention;

[0019] Figure 2 The H-NMR spectrum of compound (III) prepared in Example 1 of the present invention;

[0020] Figure 3 The H NMR spectrum of compound (IV) prepared in Example 1 of the present invention;

[0021] Figure 4 The H NMR spectrum of compound (V) prepared in Example 1 of the present invention;

[0022] Figure 5 The NMR carbon spectrum of compound (V) prepared in Example 1 of the present invention;

[0023] Figure 6 Mass spectrum of compound (V) prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The specific embodiments of the present invention are described in detail below.

[0025] Example 1

[0026] A method for preparing cis-2,3-norbornane dicarboxylic anhydride comprises the following steps:

[0027] S1. Using 10.0 g of nadic anhydride represented by the structural formula of compound (I) as the starting material, hydrolyzing in the presence of 20.0 g of 50% vol ethanol at room temperature of 25°C for 1 h, filtering, and obtaining 11.1 g of the intermediate wet material represented by the structural formula of compound (II);

[0028] S2. Take 10.0 g of the intermediate having the structural formula shown in compound (II), transform it at 90°C in the presence of 20.0 g of 50% vol ethanol to obtain a mixture of two configurations, and the mixture is resolved in 50% vol ethanol to obtain 2.2 g of the intermediate wet material having the structural formula shown in compound (III);

[0029] S3. In the presence of 50% vol ethanol, using palladium carbon as a catalyst, 1.5 g of the intermediate represented by the structural formula of compound (III) was hydrogenated, filtered, and dried to obtain 0.92 g of the compound represented by the structural formula (IV);

[0030] S4. In the presence of acetone, the compound of the structural formula (Ⅳ) was ring-closed using acetic anhydride, concentrated and crystallized, and dried to obtain 0.81 g of norbornane of the structural formula (Ⅴ); the weight yield was 8.1%;

[0031] The reaction formulas of the above steps S1 to S4 are as follows:

[0032]

[0033] Example 2

[0034] A method for preparing cis-2,3-norbornane dicarboxylic anhydride comprises the following steps:

[0035] S1. Using 10.0 g of nadic anhydride represented by the structural formula of compound (I) as the starting material, in the presence of 30.0 g of 75% vol acetone, stirring at room temperature of 25°C for 1 h for hydrolysis, filtering, and obtaining 1.22 g of the intermediate wet material represented by the structural formula of compound (II);

[0036] S2. Take 11.0 g of the intermediate having the structural formula shown in compound (II), transform at 100 ° C in the presence of 20 g 75% vol acetone to obtain a mixture of two configurations, and the mixture is resolved in 80% vol methanol to obtain 2.5 g of the intermediate wet material having the structural formula shown in compound (III);

[0037] S3. In the presence of 75% tetrahydrofuran, 2.2 g of the intermediate represented by the structural formula of compound (III) was hydrogenated with nickel as a catalyst and dried to obtain 1.3 g of the compound represented by the structural formula (IV);

[0038] S4. In the presence of ethyl acetate, the compound represented by the structural formula (Ⅳ) was ring-closed using acetic anhydride, concentrated and crystallized, and dried to obtain 0.99 g of norbornane represented by the structural formula (Ⅴ); the weight yield was 9.9%;

[0039] The reaction formulas of the above steps S1 to S4 are as follows:

[0040]

[0041] Example 3

[0042] A method for preparing cis-2,3-norbornane dicarboxylic anhydride comprises the following steps:

[0043] S1. Using 10.0 g of nadic anhydride represented by the structural formula of compound (I) as the starting material, stirring and hydrolyzing at room temperature of 25°C for 1 h in the presence of 25.0 g of 65% wt sodium hydroxide solution, filtering, and obtaining 13.3 g of the wet material of the carboxylate of the intermediate represented by the structural formula of compound (II);

[0044] S2. Take 12.0 g of the carboxylate salt of the intermediate shown in the formula of compound (II), transform it at 80 ° C in the presence of 25 g of 65% wt sodium hydroxide solution to obtain a mixture of two configurations, and the mixture is resolved in 70% vol tetrahydrofuran to obtain 3.1 g of the carboxylate salt of the intermediate shown in the formula of compound (III);

[0045] S3. In the presence of 70% vol tetrahydrofuran, ruthenium was used as a catalyst to hydrogenate 3.0 g of the intermediate carboxylate of the structural formula shown in compound (III) and dried to obtain 2.3 g of the compound of the structural formula shown in (IV);

[0046] S4. In the presence of tetrahydrofuran, the compound represented by the structural formula (Ⅳ) was ring-closed using acetic anhydride, concentrated and crystallized, and dried to obtain 1.3 g of norbornane represented by the structural formula (Ⅴ); the yield was 13.0%.

[0047] The reaction formulas of the above steps S1 to S4 are as follows:

[0048]

[0049] The above embodiments are merely preferred implementations of the present invention. Any simple modification, amendment and substitution of the above embodiments based on the technical essence of the present invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing cis-2,3-norbornane dicarboxylic anhydride, characterized in that: The steps include: S1. Using nadic anhydride represented by the structural formula of compound (I) as a starting material, hydrolyzing at room temperature in the presence of an aqueous solution of a common solvent or an alkali solution, filtering, and obtaining an intermediate represented by the structural formula of compound (II) or a carboxylate thereof; S2. The intermediate represented by the structural formula of compound (II) or its carboxylate salt is transformed at 80-100°C in the presence of an aqueous solution of a common solvent or an alkali solution to obtain a mixture of two configurations, and the mixture is separated in an aqueous solution of a common solvent or an alkali solution to obtain the intermediate represented by the structural formula of compound (III) or its carboxylate salt; S3. In the presence of an aqueous solution of a common solvent or an alkaline solution, using palladium carbon, nickel or ruthenium as a catalyst, hydrogenating the intermediate represented by the structural formula of compound (III) or its carboxylate, and drying to obtain a compound represented by the structural formula (IV); S4. In the presence of an organic solvent, the compound of the structural formula (Ⅳ) is ring-closed using acetic anhydride, concentrated and crystallized to obtain a norbornane of the structural formula (Ⅴ); The reaction formulas of the above steps S1 to S4 are as follows: The common solvent is selected from one of ethanol, methanol or tetrahydrofuran.

2. The method for preparing cis-2,3-norbornane dicarboxylic anhydride according to claim 1, characterized in that: The alkali solution is selected from one of a sodium hydroxide solution and a potassium hydroxide solution.

3. The method for preparing cis-2,3-norbornane dicarboxylic anhydride according to claim 1, characterized in that: The organic solvent is selected from one of acetone, tetrahydrofuran or ethyl acetate.

4. The method for preparing cis-2,3-norbornane dicarboxylic anhydride according to claim 1, characterized in that: Step S1. The mass ratio of nadic anhydride having a structural formula as shown in compound (I) to an aqueous solution or alkaline solution of a common solvent is 1:2-3.

5. The method for preparing cis-2,3-norbornane dicarboxylic anhydride according to claim 1, characterized in that: Step S2. The mass ratio of the intermediate or its carboxylate represented by the structural formula of compound (II) to the aqueous solution or alkaline solution of a common solvent is 1:2-3.

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