Preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole

Abstract

The present invention discloses a preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole. The preparation process route is as follows: The starting reactant is tetrahydrophthalic anhydride, which undergoes a reduction reaction in step (1) to generate compound a, then undergoes a substitution reaction in step (2) to generate compound b, and finally undergoes a ring-closure reaction in step (3) to obtain the target product. The present invention can react in a low-temperature system, with safe operation, reduced cost, convenient treatment, and a high yield.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole. Background Art

[0002] Isoindole is a very important nitrogen-containing heterocyclic skeleton and is the key parent nucleus structure of many bioactive and pharmaceutically active molecules. It has biological and pharmacological activities such as anti-cancer, bactericidal, antidepressant, and anti-atherosclerotic activities, and has good scientific research value and development prospects. Isoindoline derivatives are widespread in nature. However, with the continuous progress of technology, the types existing in nature can no longer meet people's needs. Exploring new compounds with biological activities, especially new synthetic isoindolines that are easily available as raw materials, easy to operate, and environmentally friendly, is an important topic in the field of organic chemistry.

[0003] N-Bn-3A,4,7,7A-tetrahydroisoindole is a new type of synthetic isoindoline and plays an important role in pharmaceutical and agricultural production. Currently, only Yasuda et al. (Reference: Yasuda M, Saito S, Arakawa Y, et al. Synthesis of Conformationally Defined Glutamic Acid Analogues from Readily Available Diels-Alder Adducts[J]. Chem Pharm Bull, 1995, 43(8):1318 - 1324) reported the synthesis method of N-Bn-3A,4,7,7A-tetrahydroisoindole, that is, using tetrahydrophthalic anhydride as the starting material, heating with benzylamine and ethanol to 165 - 175 °C under nitrogen protection for 2 h. After washing, drying, concentration under reduced pressure, and recrystallization, the intermediate product (3aR,7aS)-2-benzyl-3A,4,7,7A-tetrahydro-1H-isoindole-1,3(2H)-dione was obtained (Step 1). Then, under nitrogen protection, the product N-Bn-3A,4,7,7A-tetrahydroisoindole was obtained by reduction with LiAlH 4 The synthetic route is shown as follows:

[0004]

[0005] Energy conservation and safety are two key factors for whether a synthetic route can be applied to actual production. In Step 1, the reaction temperature reaches 165 - 175 °C, which belongs to high-temperature operation. The range of temperature and the heating rate need to be strictly controlled according to regulations. The safety risk during product production is relatively high and the energy consumption is too high. Secondly, in Step 2, LiAlH is used 4As a reducing agent, this substance undergoes explosive decomposition upon contact with water and can only maintain a metastable state at room temperature. It will decompose into Li 3 AlH 6 and LiH over time. Therefore, the operational safety during the synthesis process is relatively low, and the reducing agent is prone to storage failure, resulting in increased costs. SUMMARY OF THE INVENTION

[0006] In view of the above-mentioned defects of the prior art, the present invention provides a preparation process for N-Bn-3A,4,7,7A-tetrahydroisoindole, which is characterized in that the starting reactant is tetrahydrophthalic anhydride and includes step (1) reduction reaction, step (2) substitution reaction, and step (3) ring-closing reaction; the preparation process route is as follows:

[0007]

[0008] In some specific embodiments, the reducing agent in the step (1) reduction reaction is sodium borohydride, the substitution reagent in the step (2) substitution reaction is p-toluenesulfonyl chloride, and the reaction reagent in the step (3) ring-closing reaction is benzylamine.

[0009] Specifically, the preparation process is as follows:

[0010] Step (1) Reduction reaction: Sodium borohydride is dissolved in tetrahydrofuran, and the temperature is lowered to -5 to 0 °C; tetrahydrophthalic anhydride is dissolved in tetrahydrofuran, and while controlling the temperature at -5 to 0 °C, it is added to the reaction system, and the reaction is carried out under insulation for 2 to 2.5 h; an aqueous hydrochloric acid solution is added to quench the reaction, diluted with water, extracted with methyl tert-butyl ether, dried to obtain a crude reduction intermediate;

[0011] The crude reduction intermediate is dissolved in a mixed solution of tetrahydrofuran:water, and the temperature is lowered to -5 to 0 °C; sodium borohydride is added again while controlling the temperature at -5 to 5 °C, and stirred at room temperature overnight; an aqueous hydrochloric acid solution is added to quench the reaction, diluted with water, extracted with ethyl acetate, dried, and separated by column chromatography to obtain compound a;

[0012] The step (2) substitution reaction: Compound a is dissolved in dichloromethane, triethylamine is added, and the temperature is lowered to -10 to -5 °C; p-toluenesulfonyl chloride is dissolved in dichloromethane and then added to the reaction system, and the temperature is controlled at -5 to 0 °C and stirred overnight; ice water is added to quench the reaction, the phases are separated, washed with brine, dried, and separated by column chromatography to obtain compound b;

[0013] The step (3) ring-closing reaction: Compound b and benzylamine are added to toluene and stirred until dissolved, then heated to reflux and stirred for the reaction; cooled to room temperature, toluene and benzylamine are directly concentrated and removed; water is added to the concentrate, extracted with ethyl acetate, the phases are separated, dried, and separated by column chromatography to obtain N-Bn-3A,4,7,7A-tetrahydroisoindole.

[0014] In some specific embodiments, the drying in steps (1) to (3) is drying with anhydrous sodium sulfate.

[0015] In some specific embodiments, steps (1) to (3) are all carried out under the protection of an inert gas, and the inert gas is selected from one or more of nitrogen, helium, and argon. Further, nitrogen is preferably used as the inert gas.

[0016] In some specific embodiments, the molar ratio of tetrahydrophthalic anhydride to sodium borohydride in step (1) is 1:4 to 5.

[0017] In some specific embodiments, the molar ratio of tetrahydrophthalic anhydride to sodium borohydride in step (1) is 1:5.

[0018] Further, the equivalent ratio of tetrahydrophthalic anhydride to sodium borohydride to THF to water in step (1) is 1:5:58.5 (v / wt):4.5 (v / wt).

[0019] In some specific embodiments, the molar ratio of the first and second feedings of sodium borohydride in step (1) is 1:1.5 to 4, preferably 1:4.

[0020] In some specific embodiments, the molar ratio of compound a to TsCl to TEA in step (2) is 1:3:3.

[0021] Further, the equivalent ratio of compound a to TsCl to TEA to DCM in step (2) is 1:3:3:10 (v / wt.).

[0022] In some specific embodiments, the molar ratio of compound b to benzylamine in step (3) is 1:4.

[0023] Further, the equivalent ratio of compound b to benzylamine to toluene in step (3) is 1:4:10 (v / wt.).

[0024] In some specific embodiments, the concentration of the hydrochloric acid aqueous solution is 6 mol / L.

[0025] More specifically, the preparation process is as follows:

[0026] Step (1) Reduction reaction: Under the protection of an inert gas, in terms of the amount of substance, 1 to 2 parts of sodium borohydride are dissolved in dry tetrahydrofuran (THF), and the temperature is lowered to -5 to 0 °C for use as the reaction system; 1 part of tetrahydrophthalic anhydride is dissolved in dry tetrahydrofuran, and the temperature is controlled at -5 to 0 °C and added dropwise to the reaction system. After the addition is complete, continue to stir the reaction at a constant temperature for 2 to 2.5 h; monitor the disappearance of the raw materials by thin-layer chromatography (TLC). After the reaction is completed, add an aqueous hydrochloric acid solution to quench the reaction, dilute with water, extract with methyl tert-butyl ether (MTBE), and dry with anhydrous sodium sulfate to obtain the crude reduction intermediate.

[0027] The crude reduction intermediate is dissolved in a mixed solution of THF:H 2 O, and the temperature is lowered to -5 to 0 °C; 3 to 4 parts of sodium borohydride are added in batches at a temperature of -5 to 5 °C. After the addition is complete, stir at room temperature overnight; monitor the completion of the reaction of the reduction intermediate by TLC, add an aqueous hydrochloric acid solution to quench the reaction, dilute with water, extract with ethyl acetate (EA), and dry with anhydrous sodium sulfate. Separate by column chromatography to obtain compound a.

[0028] Step (2) Substitution reaction: Under the protection of an inert gas, in terms of the amount of substance, 1 part of compound a is dissolved in dry dichloromethane (DCM), 3 to 4 parts of triethylamine (TEA) are added, and the temperature is lowered to -10 to -5 °C; 2.5 to 3.2 parts of p-toluenesulfonyl chloride (TsCl) are dissolved in dry DCM and then slowly added dropwise to the reaction system. After the addition is complete, control the temperature at -5 to 0 °C and stir overnight; monitor the disappearance of the raw materials by TLC. After the reaction is completed, add ice water to quench the reaction, separate the phases, wash with brine, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain compound b.

[0029] Step (3) Ring-closure reaction: Under the protection of an inert gas, in terms of the amount of substance, 1 part of compound b and 3.5 to 5 parts of benzylamine are added to dry toluene and stirred until dissolved, then the temperature is raised to 110 to 140 °C and refluxed with continuous stirring; monitor the disappearance of the raw materials by TLC. Cool to room temperature and directly concentrate to remove toluene and benzylamine; add water to the concentrate, extract with EA to separate the phases, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain N-Bn-3A,4,7,7A-tetrahydroisoindole.

[0030] Compared with the synthetic method technology of N-Bn-3A,4,7,7A-tetrahydroisoindole reported by Yasuda et al. earlier, the present invention has the following advantages and beneficial effects: Both step (1) and step (2) are carried out in a low-temperature system, increasing the safety of operation and production economy; in addition, this method avoids the use of dangerous substances such as LiAlH 4 etc., and uses sodium borohydride as a reducing agent. Since sodium borohydride is stable at normal temperature and pressure and is also relatively stable to water vapor and oxygen in the air, it is convenient to operate and process. Moreover, the present invention has optimized the feeding ratio of sodium borohydride, ensuring a high yield. Detailed implementation manners

[0031] In order to better understand the purpose, technical means, creative features and effects of the present invention, the present invention will be described below through embodiments, but the present invention is not limited to the following implemented cases.

[0032] It should be noted that this specific embodiment is not used to limit the implementable conditions of the present invention, so it has no technical substantial meaning. Any modification of the structure, change of the proportional relationship or adjustment of the size, without affecting the effects that the present invention can produce and the purposes that can be achieved, should still fall within the scope that can be covered by the technical content disclosed by the present invention.

[0033] Examples 1 to 7 correspond to step (1); Examples 8 to 10 correspond to step (2); Examples 11 to 13 correspond to step (3). Examples 1 to 10 are repeated in parallel multiple times to ensure that there are sufficient reactants for subsequent steps.

[0034] Example 1

[0035] Under nitrogen protection, sodium borohydride (0.62 g, 16.43 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the temperature was controlled at 0 °C and added dropwise to the reaction system. After the addition was completed, the mixture was kept warm and stirred for 2 h. After monitoring by TLC that the raw materials disappeared and the reaction ended, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 3.86 g of the crude reduction intermediate.

[0036] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H 2 O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (4.97 g, 147.87 mmol) was added in batches at a temperature of -5 to 5 °C. After the addition was completed, the mixture was stirred at room temperature overnight. After monitoring by TLC that the reduction intermediate reaction was completed, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with EA, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 3.62 g (25.45 mmol) of compound a, with a yield of 77.4%.

[0037] Example 2

[0038] Under nitrogen protection, sodium borohydride (1.24 g, 32.86 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the temperature was controlled at 0 °C and added dropwise to the reaction system. After the addition was completed, the reaction was continued with stirring at the same temperature for 2 h. After the reaction was monitored by TLC and the raw materials disappeared, the reaction was quenched by adding 6 mol / L hydrochloric acid aqueous solution, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 4.5 g of the crude reduction intermediate.

[0039] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H 2 O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (4.97 g, 131.44 mmol) was added portionwise while controlling the temperature at -5 to 5 °C. After the addition was completed, the mixture was stirred overnight at room temperature. After the reduction intermediate reaction was monitored by TLC and completed, the reaction was quenched by adding 6 mol / L hydrochloric acid aqueous solution, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Compound a (4.5 g, 31.65 mmol) was obtained by column chromatography separation, with a yield of 96.3%.

[0040] Example 3

[0041] Under nitrogen protection, sodium borohydride (2.49 g, 65.72 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the temperature was controlled at 0 °C and added dropwise to the reaction system. After the addition was completed, the reaction was continued with stirring at the same temperature for 2 h. After the reaction was monitored by TLC and the raw materials disappeared, the reaction was quenched by adding 6 mol / L hydrochloric acid aqueous solution, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 3.7 g of the crude reduction intermediate.

[0042] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H 2 O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (3.73 g, 98.58 mmol) was added portionwise while controlling the temperature at -5 to 5 °C. After the addition was completed, the mixture was stirred overnight at room temperature. After the reduction intermediate reaction was monitored by TLC and completed, the reaction was quenched by adding 6 mol / L hydrochloric acid aqueous solution, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Compound a (3.9 g, 27.43 mmol) was obtained by column chromatography separation, with a yield of 83.5%.

[0043] Example 4

[0044] Under nitrogen protection, sodium borohydride (3.11 g, 82.15 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the solution was added dropwise to the reaction system at 0 °C. After the addition was complete, the mixture was stirred at the same temperature for 2 h. After monitoring by TLC that the raw materials had disappeared and the reaction was completed, the reaction was quenched by adding 6 mol / L aqueous hydrochloric acid solution, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 3.5 g of the crude reduction intermediate.

[0045] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H2O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (3.11 g, 82.15 mmol) was added in portions at -5 to 5 °C. After the addition was complete, the mixture was stirred at room temperature overnight. After monitoring by TLC that the reduction intermediate reaction was completed, the reaction was quenched by adding 6 mol / L aqueous hydrochloric acid solution, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Column chromatography separation gave 3.7 g (26.00 mmol) of compound a, with a yield of 79.1%.

[0046] Example 5

[0047] Under nitrogen protection, sodium borohydride (1.24 g, 32.86 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the solution was added dropwise to the reaction system at 0 °C. After the addition was complete, the mixture was stirred at the same temperature for 2 h. After monitoring by TLC that the raw materials had disappeared and the reaction was completed, the reaction was quenched by adding 6 mol / L aqueous hydrochloric acid solution, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 4.57 g of the crude reduction intermediate.

[0048] The crude reduction intermediate was dissolved in 247.5 mL of THF:H 2 O (10:1) mixed solution, and the temperature was lowered to 0 °C. Sodium borohydride (3.73 g, 98.58 mmol) was added in portions at -5 to 5 °C. After the addition was complete, the mixture was stirred at room temperature overnight. After monitoring by TLC that the reduction intermediate reaction was completed, the reaction was quenched by adding 6 mol / L aqueous hydrochloric acid solution, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Column chromatography separation gave 4.1 g (28.83 mmol) of compound a, with a yield of 87.8%.

[0049] Example 6

[0050] Under nitrogen protection, sodium borohydride (1.24 g, 32.86 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the temperature was controlled at 0 °C and added dropwise to the reaction system. After the addition was complete, the reaction was continued with stirring at the same temperature for 2 h. After monitoring by TLC that the raw materials disappeared and the reaction ended, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 4.5 g of the crude reduction intermediate.

[0051] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H 2 O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (2.49 g, 67.72 mmol) was added in batches at a temperature controlled between -5 and 5 °C. After the addition was complete, the mixture was stirred at room temperature overnight. After monitoring by TLC that the reduction intermediate reaction was complete, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Column chromatography separation gave 3.2 g (22.5 mmol) of compound a, with a yield of 68.5%.

[0052] Example 7

[0053] Under nitrogen protection, sodium borohydride (1.24 g, 32.86 mmol) was dissolved in 5 mL of dry THF, and the temperature was lowered to 0 °C. Tetrahydrophthalic anhydride (5.0 g, 32.86 mmol) was dissolved in 40 mL of dry THF, and the temperature was controlled at 0 °C and added dropwise to the reaction system. After the addition was complete, the reaction was continued with stirring at the same temperature for 2 h. After monitoring by TLC that the raw materials disappeared and the reaction ended, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with MTBE, and dried over anhydrous sodium sulfate to obtain 4.52 g of the crude reduction intermediate.

[0054] The crude reduction intermediate was dissolved in a mixed solution of 247.5 mL of THF:H 2 O (10:1), and the temperature was lowered to 0 °C. Sodium borohydride (5.59 g, 147.87 mmol) was added in batches at a temperature controlled between -5 and 5 °C. After the addition was complete, the mixture was stirred at room temperature overnight. After monitoring by TLC that the reduction intermediate reaction was complete, 6 mol / L hydrochloric acid aqueous solution was added to quench the reaction, diluted with water, extracted with EA, and dried over anhydrous sodium sulfate. Column chromatography separation gave 3.73 g (26.23 mmol) of compound a, with a yield of 79.8%.

[0055] Example 8

[0056] Under nitrogen protection, compound a (8.6 g, 60.48 mmol) was dissolved in 70 mL of dry DCM. After complete dissolution, triethylamine (18.36 g, 181.44 mmol) was added, and the temperature was lowered to -10 °C for use as the reaction system. p-Toluenesulfonyl chloride (28.83 g, 151.2 mmol) was dissolved in 16 mL of dry DCM and then slowly added to the reaction system. After the addition was complete, the temperature was controlled at -5 to 0 °C and stirred overnight. After monitoring by TLC that the raw materials disappeared and the reaction ended, the reaction was quenched with ice water, phase separation was carried out, washed with brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 23.6 g (52.38 mmol) of compound b, with a yield of 86.6%.

[0057] Example 9

[0058] Under nitrogen protection, compound a (8.6 g, 60.48 mmol) was dissolved in 70 mL of dry DCM. After complete dissolution, triethylamine (18.36 g, 181.44 mmol) was added, and the temperature was lowered to -10 °C for use as the reaction system. p-Toluenesulfonyl chloride (34.59 g, 181.44 mmol) was dissolved in 16 mL of dry DCM and then slowly added to the reaction system. After the addition was complete, the temperature was controlled at -5 to 0 °C and stirred overnight. After monitoring by TLC that the raw materials disappeared and the reaction ended, the reaction was quenched with ice water, phase separation was carried out, washed with brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 25.2 g (55.93 mmol) of compound b, with a yield of 92.5%.

[0059] Example 10

[0060] Under nitrogen protection, compound a (8.6 g, 60.48 mmol) was dissolved in 70 mL of dry DCM. After complete dissolution, triethylamine (18.36 g, 181.44 mmol) was added, and the temperature was lowered to -10 °C for use as the reaction system. p-Toluenesulfonyl chloride (36.88 g, 193.54 mmol) was dissolved in 16 mL of dry DCM and then slowly added to the reaction system. After the addition was complete, the temperature was controlled at -5 to 0 °C and stirred overnight. After monitoring by TLC that the raw materials disappeared and the reaction ended, the reaction was quenched with ice water, phase separation was carried out, washed with brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 24.2 g (53.71 mmol) of compound b, with a yield of 88.8%.

[0061] Example 11

[0062] Under nitrogen protection at room temperature, compound b (7.0 g, 15.54 mmol) and benzylamine (5.83 g, 54.39 mmol) were stirred and dissolved in 70 mL of dry toluene. After that, the temperature was raised to 125 °C and refluxed with continuous stirring for 4 h. The disappearance of the raw materials was monitored by TLC. After the reaction was cooled to room temperature, toluene and benzylamine were directly concentrated and removed. Water was added to the concentrate, and it was extracted with EA and separated into phases. After drying with anhydrous sodium sulfate, column chromatography was used for separation to obtain 2.8 g (13.10 mmol) of N-Bn-3A,4,7,7A-tetrahydroisoindole, with a yield of 84.3%.

[0063] Example 12

[0064] Under nitrogen protection at room temperature, compound b (7.0 g, 15.54 mmol) and benzylamine (6.66 g, 62.15 mmol) were stirred and dissolved in 70 mL of dry toluene. After that, the temperature was raised to 125 °C and refluxed with continuous stirring for 4 h. The disappearance of the raw materials was monitored by TLC. After the reaction was cooled to room temperature, toluene and benzylamine were directly concentrated and removed. Water was added to the concentrate, and it was extracted with EA and separated into phases. After drying with anhydrous sodium sulfate, column chromatography was used for separation to obtain 3.2 g (14.99 mmol) of N-Bn-3A,4,7,7A-tetrahydroisoindole, with a yield of 96.5%.

[0065] Example 13

[0066] Under nitrogen protection at room temperature, compound b (7.0 g, 15.54 mmol) and benzylamine (8.33 g, 77.7 mmol) were stirred and dissolved in 70 mL of dry toluene. After that, the temperature was raised to 125 °C and refluxed with continuous stirring for 4 h. The disappearance of the raw materials was monitored by TLC. After the reaction was cooled to room temperature, toluene and benzylamine were directly concentrated and removed. Water was added to the concentrate, and it was extracted with EA and separated into phases. After drying with anhydrous sodium sulfate, column chromatography was used for separation to obtain 2.86 g (13.42 mmol) of N-Bn-3A,4,7,7A-tetrahydroisoindole, with a yield of 86.4%.

[0067] It can be seen from Examples 1 to 4 that the total amount of sodium borohydride in the two experiments is the same, but by adjusting the feeding ratio of sodium borohydride in the first and second times in step (1), the yield of compound a can be greatly affected, and a higher yield can be optimized.

[0068] From the results of the above examples, it can be known that the yields of Example 2 in step (1), Example 9 in step (2), and Example 12 in step (3) are relatively high, which are 96.3%, 92.5%, and 96.5% respectively. The total yield of the three examples can reach 86%.

[0069] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative efforts. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art shall fall within the protection scope determined by the claims.

Claims

1. Preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole, characterized in that, the starting reactant is tetrahydrophthalic anhydride, including step (1) reduction reaction, step (2) substitution reaction, and step (3) ring closure reaction; the preparation process route is as follows: the reducing agent in the step (1) reduction reaction is sodium borohydride, the substitution reagent in the step (2) substitution reaction is p-toluenesulfonyl chloride, and the reaction reagent in the step (3) ring closure reaction is benzylamine; the molar ratio of tetrahydrophthalic anhydride to sodium borohydride in the step (1) is 1:5, and the molar ratio of the first and second feedings of sodium borohydride in the step (1) is 1:4; the specific step (3) ring closure reaction is: under the protection of an inert gas, in terms of molar amount, 1 part of compound b and 3.5 - 5 parts of benzylamine are added to dry toluene and stirred to dissolve, then heated to 110 - 140 °C for reflux and continuously stirred for reaction.

2. The preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole according to claim 1, characterized in that, the step (1) reduction reaction is: sodium borohydride is dissolved in tetrahydrofuran, and the temperature is lowered to -5 - 0 °C; tetrahydrophthalic anhydride is dissolved in tetrahydrofuran, and the temperature is controlled at -5 - 0 °C and added to the reaction system, and the reaction is carried out under insulation for 2 - 2.5 h; hydrochloric acid aqueous solution is added to quench the reaction, diluted with water, extracted with methyl tert-butyl ether, dried to obtain the crude reduction intermediate; the crude reduction intermediate is dissolved in a mixed solution of tetrahydrofuran:water, and the temperature is lowered to -5 - 0 °C; sodium borohydride is added again at a temperature controlled at -5 - 5 °C, and stirred at room temperature overnight; hydrochloric acid aqueous solution is added to quench the reaction, diluted with water, extracted with ethyl acetate, dried, and separated by column chromatography to obtain compound a; the step (2) substitution reaction is: compound a is dissolved in dichloromethane, triethylamine is added, and the temperature is lowered to -10 - -5 °C; p-toluenesulfonyl chloride is dissolved in dichloromethane and then added to the reaction system, and the temperature is controlled at -5 - 0 °C and stirred overnight; ice water is added to quench the reaction, phase separation is carried out, washed with brine, dried, and separated by column chromatography to obtain compound b; the step (3) ring closure reaction is: compound b and benzylamine are added to toluene and stirred to dissolve, then heated to reflux and stirred for reaction; cooled to room temperature, directly concentrated to remove toluene and benzylamine; water is added to the concentrate, extracted with ethyl acetate for phase separation, dried, and separated by column chromatography to obtain N-Bn-3A,4,7,7A-tetrahydroisoindole.

3. The preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole according to claim 2, characterized in that, the steps (1) - (3) are all carried out under the protection of an inert gas, and the inert gas is selected from one or more of nitrogen, helium, and argon.

4. The preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole according to claim 2, characterized in that, the molar ratio of compound a, p-toluenesulfonyl chloride, and triethylamine in the step (2) is 1:3:

3.

5. The preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole according to claim 2, characterized in that, In step (3), the molar ratio of compound b to benzylamine is 1:

4.

6. The preparation process of N-Bn-3A,4,7,7A-tetrahydroisoindole according to any one of claims 1 to 2, characterized in that the reduction reaction in step (1) is specifically as follows: under the protection of an inert gas, in terms of amount of substance, 1 to 2 parts of sodium borohydride are dissolved in dry tetrahydrofuran, cooled to -5 to 0 °C, and used as the reaction system; 1 part of tetrahydrophthalic anhydride is dissolved in dry tetrahydrofuran, and the temperature is controlled at -5 to 0 °C and added dropwise to the reaction system. After the addition is completed, continue to stir the reaction at the same temperature for 2 to 2.5 h; monitor the disappearance of the raw materials by thin-layer chromatography. After the reaction is completed, add an aqueous hydrochloric acid solution to quench the reaction, dilute with water, extract with methyl tert-butyl ether, and dry with anhydrous sodium sulfate to obtain a crude reduction intermediate; The crude reduction intermediate is dissolved in a mixed solution of THF:H 2 O, and the temperature is lowered to -5 to 0 °C; 3 to 4 portions of sodium borohydride are added in batches while controlling the temperature at -5 to 5 °C. After the addition is complete, the mixture is stirred at room temperature overnight; after monitoring the completion of the reaction of the reduction intermediate by TLC, the reaction is quenched by adding an aqueous hydrochloric acid solution, diluted with water, extracted with ethyl acetate (EA), dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound a; the substitution reaction in step (2) is specifically as follows: under the protection of an inert gas, in terms of amount of substance, 1 part of compound a is dissolved in dry dichloromethane, 3 to 4 parts of triethylamine are added, and the temperature is cooled to -10 to -5 °C; 2.5 to 3.2 parts of p-toluenesulfonyl chloride are dissolved in dry DCM and then slowly added dropwise to the reaction system. After the addition is completed, control the temperature at -5 to 0 °C and stir overnight; monitor the disappearance of the raw materials by TLC. After the reaction is completed, add ice water to quench the reaction, separate the phases, wash with brine, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain compound b; the ring-closing reaction in step (3) is specifically as follows: under the protection of an inert gas, in terms of amount of substance, 1 part of compound b and 3.5 to 5 parts of benzylamine are added to dry toluene and stirred until dissolved, then heated to 110 to 140 °C and refluxed with continuous stirring; monitor the disappearance of the raw materials by TLC. After cooling to room temperature, directly concentrate to remove toluene and benzylamine; add water to the concentrate, extract with EA and separate the phases, dry with anhydrous sodium sulfate, and separate by column chromatography to obtain N-Bn-3A,4,7,7A-tetrahydroisoindole.

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