Synthesis method of important intermediate (S)-2-Boc-aminomethylpyrrolidine of L-sulpiride

Abstract

The invention discloses a preparation method of an important intermediate (S)-2-Boc-aminomethylpyrrolidine of an antipsychotic drug levosulpiride, which comprises the following steps: by taking N-Cbz-L-prolinol and MsCl as initial raw materials, reacting under an alkaline condition to generate (S)-1-Cbz-2-pyrrolidine methyl methanesulfonate; the preparation method comprises the following steps: firstly, carrying out an affinity substitution reaction on (S)-1-Cbz-2-pyrrolidine methyl methanesulfonate and tert-butyl carbamate under a microwave condition to generate an intermediate (S)-1-Cbz-2-Boc-aminomethylpyrrolidine, and finally, hydrogenating (S)-1-Cbz-2-Boc-aminomethylpyrrolidine to obtain the product (S)-2-Boc-aminomethylpyrrolidine. The method provided by the invention is reasonable in process selection, short in step, mild in reaction condition, simple and convenient in post-treatment, high in product yield, green, efficient, easy to amplify and environment-friendly, and dangerous processes such as strong reducing agents such as lithium aluminum hydride and borane are avoided in the reaction.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemical industry, and in particular to a new preparation method of (S)-2-Boc-aminomethylpyrrolidine, an important intermediate of the antipsychotic drug levorotatory sulpiride. Background Art

[0002] (S)-2-Boc-aminomethylpyrrolidine is an important fine chemical intermediate, widely used in medicine, materials, biochemistry and other fields. In the field of materials science, (S)-2-Boc-aminomethylpyrrolidine can be used to synthesize polymers, high molecular materials or functional films with specific functions; (S)-2-Boc-aminomethylpyrrolidine has specific biological activity, and is also used in biochemical research, such as as an inhibitor, substrate or ligand of enzymes or proteins. Through interaction with biological macromolecules, its biological function, regulatory mechanism or signal transduction pathway can be revealed; in the chemical industry, (S)-2-Boc-aminomethylpyrrolidine can be used to synthesize various fine chemicals, fragrances, dyes, etc. Its unique chemical properties enable it to participate in a variety of chemical reactions, thereby preparing chemical products with specific properties and uses; in the process of drug research and development, (S)-2-Boc-aminomethylpyrrolidine is often used as a starting material or key intermediate for the synthesis of complex drug molecules. Its unique structure enables it to be effectively linked to other drug fragments to construct drug candidates with specific biological activities. For example, (S)-2-Boc-aminomethylpyrrolidine is a The compound is an important chiral drug intermediate of the antipsychotic drug levorotatory sulpiride, so the preparation of the compound has high practical value.

[0003] The existing synthetic routes for synthesizing (S)-2-Boc-aminomethylpyrrolidine at home and abroad are mainly the reduction of various protected pyrrolidine-2-carboxamides.

[0004] 1. The synthetic routes of patents WO2008016811 (By: Ghosh, Manuka; et al), patent WO2018049271 (By: Beck, et al) and literature Synthesis and in vitro antibacterial activity of 7-[(2s)-2-aminomethyl-pyrrolidine-1-yl]-quinolone derivatives. (By: Chen, Shengxi; et al.) Zhongguo Kangshengsu Zazhi (2004), 29 (7), 397-400, 422. are as follows:

[0005]

[0006] The third step of this route, amide reduction reaction, uses lithium aluminum tetrahydride. The reaction process is dangerous and the reaction steps are long, which is not conducive to industrial production.

[0007] 2. The synthesis route of chiral thiourea-phosphine organocatalysts derived from L-proline. Tetrahedron Letters (2014), 55 (46), 6377-6380 (By: Nguyen, Thi-Huong; et al) is as follows:

[0008]

[0009] The second step of this route, the amide reduction reaction, uses borane and reacts under the reflux of tetrahydrofuran. The reaction is relatively dangerous, has a long reaction step, and the yield is not high, which has certain limitations for large-scale production.

[0010] In summary, the existing synthesis process route of (S)-2-Boc-aminomethylpyrrolidine still has technical problems and is not suitable for industrial production and expansion. In view of the shortcomings of the existing synthesis technology, it is necessary to provide a new synthesis method for preparing (S)-2-Boc-aminomethylpyrrolidine to solve the above-mentioned technical problems. Summary of the invention

[0011] The purpose of the present invention is to provide a method for synthesizing (S)-2-Boc-aminomethylpyrrolidine, which mainly solves the technical problems of long reaction steps, dangerous reaction process and difficulty in scaled-up production in the prior art.

[0012] In order to solve the above technical problems, the technical solution of the present invention is:

[0013] A method for preparing (S)-2-Boc-aminomethylpyrrolidine comprises the following steps:

[0014] S1: N-Cbz-L-prolinol and MsCl were used as raw materials and stirred at room temperature to prepare (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester;

[0015] S2: (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester prepared in step S1 and tert-butyl carbamate are reacted under alkaline and microwave conditions to obtain (S)-1-Cbz-2-Boc-aminomethylpyrrolidine;

[0016] S3: (S)-1-Cbz-2-Boc-aminomethylpyrrolidine prepared in step S2 is catalytically hydrogenated under the action of Pd / C to obtain the target product (S)-2-Boc-aminomethylpyrrolidine.

[0017] As an improved technical solution, in step S1, the molar ratio of N-Cbz-L-prolinol to MsCl is 1:(1.0-1.6).

[0018] In step S1, the specific reaction is to mix the dichloromethane solution of N-Cbz-L-prolinol and triethylamine, add methylsulfonyl chloride at -15 to 0°C (preferably 0°C), and after the addition is completed, the reaction system is heated to room temperature for reaction, and the reaction raw materials and products in the reaction system are monitored in real time by thin layer chromatography and liquid chromatography as a basis for judging the end of the reaction. After the reaction is completed, it is only necessary to quench the reaction, extract, wash, dry, and remove the solvent, and the next step of the reaction can be carried out without purification.

[0019] As an improved technical solution, in step S2, the molar ratio of (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester to tert-butyl carbamate is 1:(0.9-1.5).

[0020] As an improved technical solution, in step S2, the organic solvent used in the reaction is one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, 1,4-dioxane and N,N-dimethylformamide (preferably tetrahydrofuran).

[0021] As an improved technical solution, in step S2, a base selected from pyridine, N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate and sodium hydroxide (preferably potassium carbonate) is added to the reaction system to adjust the pH of the reaction system, and the molar ratio of the base to (S)-1-Cbz-2-pyrrolidine methanesulfonate is (1.5-2.5):1; and a catalytic amount of DMAP is added at the same time, and the molar ratio of DMAP to (S)-1-Cbz-2-pyrrolidine methanesulfonate is (0.15-0.25):1.

[0022] As an improved technical solution, in step S2, the reaction conditions are: microwave output power is 100-300 W, reaction temperature is 30-80° C. (preferably 50° C.), and reaction time is 1-5 h.

[0023] As an improved technical solution, in step S3, Pd / C is added into the reaction system, and the mass ratio of Pd / C to (S)-1-Cbz-2-Boc-aminomethylpyrrolidine is (0.05-0.15):1.

[0024] As an improved technical solution, in step S3, the reaction temperature is 45-65°C (preferably 50°C), the pressure of the reaction system is 30-70psi (preferably 55psi), and the reaction time is 8-12h.

[0025] The reaction formula of the present invention is shown in (II):

[0026]

[0027] (II) Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0028] (1) The present invention uses N-Cbz-L-prolinol and MsCl as raw materials to react at room temperature to generate (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester. The reaction conditions of this step are mild, the reaction conversion rate is high, the reaction raw materials are cheap and easy to obtain, and the next step reaction can be directly carried out without purification.

[0029] (2) The present invention uses homemade (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester as a raw material to react with tert-butyl carbamate under microwave irradiation conditions, and the conversion rate reaches 78% in two hours, which greatly shortens the reaction time and improves the reaction yield. The post-treatment only requires washing and pulping, and the process is simple.

[0030] (3) The present invention uses homemade (S)-1-Cbz-2-Boc-aminomethylpyrrolidine to react with Pd / C under certain temperature and pressure conditions to obtain the target product (S)-2-Boc-aminomethylpyrrolidine. By effectively controlling the reaction temperature and pressure and the amount of catalyst, the reaction raw materials can be 100% converted, the product yield and purity are high, and the post-processing process is simple. In summary, the method provided by the present invention has short steps, simple operation, safety and reliability, good process stability, low energy consumption, cheap and easy-to-obtain reaction raw materials, and high product yield. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0032] The yield calculation method of the product in the following examples and comparative examples is as follows:

[0033] Yield (%) = (actual product yield / theoretical product yield) × 100%.

[0034] Example 1

[0035] S1: A stirred solution of N-Cbz-L-prolinol (9.34mmol) in dry CH2Cl2 (28mL) and triethylamine (2.30mL, 16.5mmol) was cooled to 0°C in an ice-water bath. At this temperature, methylsulfonyl chloride (14.86mmol) was added dropwise to the mixture. After the addition was complete, the reaction solution naturally warmed to room temperature and the reaction solution was stirred at room temperature for 3 hours. The reaction was tracked by HPLC and TLC. After the reaction was completed, water (7mL) was added to quench the reaction mixture. The organic phase was separated, and then the aqueous phase was extracted 3 times with dichloromethane CH2Cl2 (10mL). The organic phases were combined and washed with saturated brine (20mL). The organic layer was then dried with anhydrous Na2S04, the desiccant was filtered off, and the mixture was evaporated to no solvent at room temperature to obtain 2.92g of a light yellow oily (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester with a yield of 100%. No purification was required and the next step was directly carried out.

[0036] S2: Potassium carbonate (14 mmol) and DMAP (1.5 mmol) in THF (10 mL) were placed in a microwave tube, and then tert-butyl carbamate (13.4 mmol) in THF (20 mL) and (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester in THF (30 mL) were added in sequence at room temperature to obtain a suspension, and the obtained suspension was irradiated at a microwave power of 200 W and a reaction temperature of 50° C. for 2 h. The reaction was tracked by HPLC and TLC. After the reaction was completed, the reaction solution was cooled to 0° C., water (10 mL) was added to quench the reaction mixture, and the pH was neutralized to 7 with 1 M hydrochloric acid, the organic solvent was removed, and the residue was extracted with CH2Cl2 (3×30 ml). Combine the organic phases, dry the organic layer over anhydrous MgSO4, filter to remove the desiccant, and evaporate to concentrate to 10 ml at room temperature. Add methyl tert-butyl ether (30 ml) to the concentrate to precipitate a large amount of solid, filter, and dry the filtered solid to obtain (S)-1-Cbz-2-Boc-aminomethylpyrrolidine, a light yellow solid, 2.92 g, yield: 78%.

[0037] S3: (S)-1-Cbz-2-Boc-aminomethylpyrrolidine (3.5 g) was added to 100 ml of ethanol, and 10% Pd / C (0.35 g) was added. The resulting mixture was heated to 55°C overnight in 50 psi of H2. The reaction was followed by HPLC and TLC. After the reaction was completed, the catalyst was filtered off and the catalyst was thoroughly washed with methanol. The solvent was removed, the residue was added to 20 mL of H2O, and 3N HCl was used to make it weakly acidic. The mixture was extracted with ether (3×50 ml) to remove impurities. The aqueous phase was then made alkaline with 2N NaOH, extracted with CH2Cl2 (4×60 ml), the combined organic phase was washed with saturated brine, the organic phase was dried with anhydrous MgSO4, the desiccant was removed by filtration, and the title compound (S)-2-Boc-aminomethylpyrrolidine was concentrated by evaporation at room temperature to obtain a light yellow liquid, 2.08 g, with a yield of 99%.

[0038] Comparative Example 1

[0039] Compared with Example 1, the solvent in S2 in this example is dichloromethane, and the reaction is irradiated at 40°C for 5 hours. Other conditions are the same as in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 1.12 g, with a yield of 30% (there is residual raw material).

[0040] Comparative Example 2

[0041] Compared with Example 1, the solvent in S2 in this example is dichloroethane, the reaction is irradiated at 50°C, and the other conditions are the same as in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 1.69 g, with a yield of 45% (raw materials remain).

[0042] Comparative Example 3

[0043] Compared with Example 1, the solvent in S2 in this example is dichloroethane, and the reaction is irradiated at 50°C for 5 hours. Other conditions are the same as in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 1.61 g, with a yield of 43% (there is residual raw material).

[0044] Comparative Example 4

[0045] Compared with Example 1, the solvent in S2 in this example is dichloroethane, the reaction is irradiated at 75°C, and the other conditions are the same as in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 1.69 g, with a yield of 45% (raw materials remain).

[0046] Comparative Example 5

[0047] Compared with Example 1, the solvent in S2 in this example is dichloroethane, and the reaction is irradiated at 75°C for 5 hours. Other conditions are the same as in Example 1 to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 1.65 g, with a yield of 44% (there is residual raw material).

[0048] Comparative Example 6

[0049] Compared with Example 1, the solvent in S2 in this example is tetrahydrofuran, the reaction is carried out for 5 hours, and other conditions are the same as those in Example 1 to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 2.81 g, with a yield of 75%.

[0050] Comparative Example 7

[0051] Compared with Example 1, the solvent in S2 in this example is tetrahydrofuran, the reaction temperature is 80°C, and the other conditions are the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 2.62 g, with a yield of 70%.

[0052] Comparative Example 8

[0053] Compared with Example 1, the solvent in S2 in this example is 1,4-dioxane, the reaction temperature is 50°C, and the other conditions are the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 2.85 g, with a yield of 76%.

[0054] Comparative Example 9

[0055] Compared with Example 1, the solvent in S2 in this example is 1,4-dioxane, the reaction temperature is 80°C, and the other conditions are the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 2.70 g, with a yield of 72%.

[0056] Comparative Example 10

[0057] Compared with Example 1, the solvent in S2 in this example is N,N-dimethylformamide, the reaction temperature is 50°C, and the other conditions are the same as those in Example 1. The target product (S)-2-Boc-aminomethylpyrrolidine is obtained by drying, with a total of 2.62 g and a yield of 70%.

[0058] Comparative Example 11

[0059] Compared with Example 1, the solvent in S2 in this example is N,N-dimethylformamide, the reaction temperature is 80°C, and the other conditions are the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 2.55 g, with a yield of 68%.

[0060] Comparative Example 12

[0061] Compared with Example 1, DMAP was not added to S2 in this example, and other conditions were the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 1.12 g, with a yield of 30%.

[0062] Comparative Example 13

[0063] Compared with Example 1, the base in S2 in this example is pyridine, and the other conditions are the same as those in Example 1, to obtain the target product (S)-2-Boc-aminomethylpyrrolidine, a total of 1.80 g, with a yield of 48%.

[0064] Comparative Example 14

[0065] Compared with Example 1, the base in S2 in this example is triethylamine and the other conditions are the same as those in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 1.42 g, with a yield of 38%.

[0066] Comparative Example 15

[0067] Compared with Example 1, the base in S2 in this example is N,N-diisopropylethylamine and other conditions are the same as those in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 1.95 g, with a yield of 52%.

[0068] Comparative Example 16

[0069] Compared with Example 1, the base in S2 in this example is cesium carbonate and the other conditions are the same as those in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, with a total of 2.81 g and a yield of 75%.

[0070] Comparative Example 17

[0071] Compared with Example 1, the base in S2 in this example is sodium carbonate and the other conditions are the same as those in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 2.62 g, with a yield of 70%.

[0072] Comparative Example 18

[0073] Compared with Example 1, the base in S2 in this example is sodium hydroxide and the other conditions are the same as those in Example 1, and the target product (S)-2-Boc-aminomethylpyrrolidine is obtained, a total of 1.35 g, with a yield of 36%.

[0074] The preparation conditions and product yields of the above-mentioned comparative examples 1-11 are summarized in Table 1, and the preparation conditions and product yields of comparative examples 12-18 are summarized in Table 2.

[0075] From the comparison of Example 1 and Comparative Examples 1-11, it can be seen that different solvents and different reaction temperatures have different yields of the product. The yields of dichloromethane and dichloroethane are significantly lower than those of other solvents; the yields of N,N-dimethylformamide are slightly lower; the yields of 1,4-dioxane and tetrahydrofuran are not much different. Considering environmental factors, the preferred conditions are tetrahydrofuran as solvent, reaction temperature of 50°C, and 2h.

[0076] From the comparison of Example 1 and Comparative Examples 12-18, it can be seen that the yield of the product varies greatly with or without the addition of a catalyst and different bases. Adding a catalyst can significantly improve the yield. The yield of pyridine, triethylamine, N,N-diisopropylethylamine, and sodium hydroxide as the base is significantly low, and sodium carbonate is slightly lower. Cesium carbonate and potassium carbonate are almost the same, but cesium carbonate is more expensive, so the preferred condition is potassium carbonate plus DMAP.

[0077] Table 1

[0078]

[0079] Table 2

[0080]

[0081]

[0082] The method uses low-cost N-Cbz-L-prolinol and MsCl as raw materials to synthesize (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester under mild conditions, then synthesizes (S)-1-Cbz-2-Boc-aminomethyl pyrrolidine under microwave irradiation, and finally catalytically hydrogenates (S)-1-Cbz-2-Boc-aminomethyl pyrrolidine to obtain a product (S)-2-Boc-aminomethyl pyrrolidine to synthesize a target product. The reaction time is short, and dangerous processes such as using a strong reducing agent such as lithium aluminum hydroxide and borane are avoided. The product yield is high and large-scale production can be carried out.

[0083] In addition, it should be understood that after reading the contents of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing (S)-2-Boc-aminomethylpyrrolidine, characterized in that: The following steps are involved: S1: Add a base to an organic solution of N-Cbz-L-prolinol, and then dropwise add MsCl. After the reaction is completed, post-treatment is performed to obtain (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester; S2: Add a base and DMAP to an organic solution of tert-butyl carbamate, and dropwise add (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester obtained in step S1, and complete the reaction. Post-treatment is performed to obtain (S)-1-Cbz-2-Boc-aminomethylpyrrolidine; S3: Add the (S)-1-Cbz-2-Boc-aminomethylpyrrolidine obtained in step S2 into a solvent and perform pressure hydrogenation under the conditions of 10% Pd / C and H2. After the reaction is completed, filter, concentrate, and slurry to obtain the target product (S)-2-Boc-aminomethylpyrrolidine.

2. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S1, the molar ratio of N-Cbz-L-prolinol to MsCl is 1:(1.0-1.6).

3. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S1, the molar ratio of N-Cbz-L-prolinol to the base is 1:(1.0-2.5).

4. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S1, the reaction conditions are: the temperature of the reactants added to the reaction is -15 to 0°C, the reaction temperature is 10 to 30°C, and the reaction time is 2.5 to 6.0 hours.

5. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S2, the molar ratio of (S)-1-Cbz-2-pyrrolidine methanesulfonic acid methyl ester to tert-butyl carbamate is 1:(0.9-1.5).

6. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S2, the organic solvent used in the reaction is one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, 1,4-dioxane and N,N-dimethylformamide.

7. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: The base used in the reaction is one of pyridine, N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, sodium carbonate and sodium hydroxide.

8. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S2, a base is added to the reaction system to adjust the pH of the reaction system, and the molar ratio of the base to (2S)-1-Cbz-2-pyrrolidine methanesulfonate is (1.5-2.5):1; at the same time, a catalytic amount of DMAP is added, and the molar ratio of DMAP to (S)-1-Cbz-2-pyrrolidine methanesulfonate is (0.05-0.20):

1.

9. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S2, the reaction conditions are: microwave output power is 100-300W, reaction temperature is 30-80°C, and reaction time is 1-5h.

10. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S3, Pd / C is added into the reaction system, and the mass ratio of Pd / C to (S)-1-Cbz-2-Boc-aminomethylpyrrolidine is (0.05-0.15):

1.

11. The method for preparing (S)-2-Boc-aminomethylpyrrolidine according to claim 1, characterized in that: In step S3, the reaction temperature is 45-65° C., the pressure of the reaction system is 30-70 psi, and the reaction time is 8-12 h.

Images