Intermediate for synthesizing spermidine, synthesis method and application

Abstract

The invention provides an intermediate for synthesizing spermidine, a synthesis method and application, and relates to the technical field of drug synthesis, the chemical name of an intermediate compound is (3-(4-((t-butyloxycarboryl) amino) butylamido) propyl) carbamide tert-butyl ester, and the synthesis method of the intermediate compound comprises the following steps: sequentially reacting N-Boc-2-oxopyrrolidine with 1, 2-dichloroethane to obtain a reaction product; according to the application of the intermediate compound in synthesis of spermidine, raw materials are cheap and easy to obtain, the process is simple, reaction conditions are mild, and industrialization is easy to achieve.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to an intermediate for synthesizing spermidine, a synthesis method and application. Background Art

[0002] As an important raw material, spermidine is widely used in the synthesis of pharmaceutical intermediates. There are biosynthesis and chemical synthesis methods for the synthesis of spermidine. Chinese patent applications CN 111996220A and CN 114958894 A introduce the biosynthesis method of spermidine. As for the chemical synthesis method of spermidine, currently, 1,4-butanediamine and acrylonitrile are used as raw materials, and spermidine is obtained through addition and cyano hydrogenation reduction in two steps. Chinese patents CN 102659605 A, CN109096122 A, CN 111302953A, and CN 113548971 A introduce the synthesis methods that are different from the above chemical synthesis routes. The above chemical synthesis routes have the disadvantages of harsh reaction conditions, high safety hazards, high equipment requirements, and complicated processes, which are not conducive to industrial production. The present invention aims to provide a preparation method of spermidine with cheap and easy-to-obtain raw materials, simple processes, and easy industrial production. Summary of the invention

[0003] The purpose of the present invention is to provide an intermediate for synthesizing spermidine, a synthesis method and use thereof, so as to solve the above technical problems.

[0004] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0005] An intermediate compound for synthesizing spermidine, the chemical name of the intermediate compound is (3-(4-((tert-butyloxycarbonyl)amino)butyramido)propyl)carbonamide tert-butyl ester, and the chemical structural formula of the intermediate compound is as follows:

[0006]

[0007] The present invention provides a method for synthesizing an intermediate compound for synthesizing spermidine. The method comprises the following steps for synthesizing: N-Boc-2-oxopyrrolidine (I) is reacted with 1,3-propylenediamine (II) and di-tert-butyl dicarbonate (III) in sequence to obtain compound IV, wherein compound IV is an intermediate compound for synthesizing spermidine. The synthesis route is as follows:

[0008]

[0009] The reaction conditions for the reaction of N-Boc-2-oxopyrrolidine (I), 1,3-propylenediamine (II) and di-tert-butyl dicarbonate (III) to obtain compound IV are as follows:

[0010] First, compound I, compound II and compound III are converted to compound IV in a common alcohol solvent or dipolar solvent or tetrahydrofuran or acetonitrile or no solvent, preferably ethanol, isopropanol, tetrahydrofuran, acetonitrile, alone or in a mixed solvent, at room temperature to reflux temperature;

[0011] Second, the mass ratio of compound I, compound II and compound III is 1:(0.5-1.5):(0.5-2), preferably 1:(1-1.2):(1-1.5);

[0012] Third, the alcohol solvent is preferably ethanol and isopropanol, and the amide solvent is preferably DMF.

[0013] In the present invention, compound I, that is, N-Boc-2-oxopyrrolidine, can be purchased commercially or prepared according to a known method. Specifically, I can be obtained by reacting 2-pyrrolidone with Boc2O. The reaction process is as follows:

[0014]

[0015] The present invention provides a method for synthesizing spermidine or its salt using an intermediate compound IV. The synthesis method comprises the following steps: subjecting compound I, compound II and compound III to a reaction as shown below to obtain compound IV; reacting compound IV with a reducing agent to reduce the amide to an amine to obtain compound V; directly treating the compound V with an acid to remove the Boc protecting group to obtain a spermidine salt; and treating the compound V with an alkali to obtain free spermidine V. The synthesis route is as follows:

[0016]

[0017] Among the above reaction conditions for treating compound V with an acid, hydrochloric acid and phosphoric acid are preferred.

[0018] Among the above reaction conditions for treating the salt of spermidine with a base, sodium hydroxide and potassium hydroxide are preferred.

[0019] In the reaction conditions for reducing compound IV to compound V, the reducing agent is borane dimethyl sulfide or lithium aluminum tetrahydride or diisobutylaluminum hydride or red aluminum, preferably diisobutylaluminum hydride or lithium aluminum tetrahydride.

[0020] The beneficial effects of the present invention are:

[0021] The invention provides an intermediate compound for synthesizing spermidine, and provides a synthesis method of the intermediate compound and a use of the intermediate compound for synthesizing spermidine. The invention has cheap and readily available raw materials, a simple process, mild reaction conditions, and is easy to realize industrialization. DETAILED DESCRIPTION

[0022] In order to facilitate the understanding of the present invention, the present invention is described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0024] Specific embodiments of the present invention are described below.

[0025] The synthesis of intermediate compound IV follows the following synthetic route:

[0026]

[0027] Example 1. In this example, an intermediate compound IV for synthesizing spermidine was prepared. The preparation process was as follows: In a 250 ml reaction bottle, 10.40 g of compound I was dissolved in 150 ml of THF, 4.58 g of compound II was added, and the mixture was stirred evenly. The mixture was heated to reflux and the reaction was continued for 8 hours while maintaining reflux. The mixture was cooled to room temperature, and 15.93 g of compound III was added. The reaction was continued for 2 hours at room temperature. The reaction was completed by TLC inspection. The tetrahydrofuran solvent was concentrated and recovered. The residue was separated and purified by column chromatography to obtain 18.57 g of product with a yield of 92%.

[0028] The H NMR spectrum data of the obtained product are as follows: 1H NMR (CDCl3, 400 MHz): 7.10 (brs, 0.4H), 6.91 (brs, 0.6H), 5.20 (brs, 0.6H), 5.08 (brs, 1.4H), 3.25 (m, 2H), 3.13 (m, 4H), 2.21 (m, 2H), 1.79 (m, 2H), 1.61 (m, 2H), 1.41 (s, 18H).

[0029] Example 2. In this example, an intermediate compound IV for synthesizing spermidine was prepared. The preparation process was as follows: In a 250 ml reaction bottle, 9.25 g of compound I was dissolved in 140 ml of ethanol, 3.52 g of compound II was added, and the mixture was stirred evenly. The mixture was heated to reflux temperature and the reaction was continued at reflux for 8 hours. The mixture was cooled to room temperature, and 10.91 g of compound III was added. The reaction was continued at room temperature for 2 hours. The reaction was completed by TLC inspection. The solvent was concentrated and recovered. The residue was purified by column chromatography to obtain 16.20 g of product with a yield of 95%.

[0030] Example 3. In this example, an intermediate compound IV for synthesizing spermidine was prepared. The preparation process was as follows: In a 250 ml reaction bottle, 11.00 g of compound I was dissolved in 120 ml of acetonitrile, 4.45 g of compound II was added, and the mixture was stirred evenly. The mixture was heated to reflux temperature, and the reflux reaction was maintained for another 8 hours. The mixture was cooled to room temperature, and 13.6 g of compound III was added. The reaction was continued at room temperature for 2 hours. The reaction was completed by TLC inspection. The solvent was concentrated and recovered. The residue was purified by column chromatography to obtain 18.57 g of product with a yield of 87%.

[0031] Example 4. In this example, an intermediate compound IV for synthesizing spermidine was prepared. The preparation process was as follows: In a 250 ml reaction bottle, 11.00 g of compound I was dissolved in 120 ml of DMF, 4.45 g of compound II was added, and the mixture was stirred evenly. The mixture was heated to 90°C and kept at this temperature for 6 hours. The mixture was cooled to room temperature, and 13.6 g of compound III was added. The mixture was allowed to react for 2 hours at room temperature. The reaction was confirmed to be complete by TLC. The volatiles were removed by concentration, and the residue was separated and purified by column chromatography to obtain 18.15 g of product with a yield of 85%.

[0032] Example 5. In this example, an intermediate compound IV for synthesizing spermidine was prepared. The preparation process was as follows: In a 100 ml reaction bottle, 4.00 g of compound I and 1.76 g of compound II were mixed and stirred evenly, heated to 80°C, and the temperature was maintained to continue the reaction for 6 hours, cooled to 0°C, 5.66 g of compound III was added, and the reaction was continued at room temperature for 2 hours. The reaction was completed by TLC inspection. After the reaction mixture was cooled, it was separated and purified by column chromatography to obtain 6.13 g of product with a yield of 79%.

[0033] The synthesis of spermidine from intermediate compound IV follows the following synthetic route:

[0034]

[0035] Example 6. In this example, spermidine was prepared. The preparation process was as follows: In a 500 ml reaction bottle, 10.80 g of compound IV ((3-(4-((tert-butyloxycarbonyl)amino)butyramido)propyl)carbonamide tert-butyl ester) was dissolved in 100 ml of dry dichloromethane and cooled to -78°C. Dibal-H (1.5 M toluene solution, 60.0 ml) was added. The reaction was continued to stir at low temperature for 5 hours, then slowly warmed to room temperature and reacted for another 2 hours. The mixture was cooled in an ice-water bath, 40.0 ml of concentrated hydrochloric acid was added dropwise, and the reaction was continued to stir for 2 hours. After standing, the organic phase was separated, and the organic phase was extracted twice with 25 ml of water. The aqueous layers were combined and washed twice with 50 ml of ethyl acetate. After concentration, the mixture was redissolved with ethanol, cooled in an ice-water bath, and 18.0 g of sodium hydroxide was added in batches. The precipitated solid was filtered out. The resulting solution was concentrated to obtain a crude product. 3.13 g of the product was obtained by column chromatography with a yield of 72%. The H NMR spectrum data of the obtained product are as follows: 1H NMR (CDCl3, 400 MHz): 2.65 (t, 2H), 2.56 (m, 4H), 2.47 (t, 2H), 1.52 (m, 2H), 1.37 (m, 4H), 1.13 (br, 5H).

[0036] Example 7, in a 500 ml reaction bottle, 10.30 g of compound IV (tert-butyl (3-(4-((tert-butoxycarbonyl)amino)butyramido)propyl)carbonamide) was dissolved in 100 ml of dry tetrahydrofuran, cooled to -20°C, 1.3 g of lithium aluminum tetrahydride was added in batches, the reaction was continued with stirring at low temperature for 5 hours, then the temperature was raised to room temperature and the reaction was continued for another 5 hours, cooled in an ice-water bath, 10 ml of methanol was added dropwise, stirring was continued for 1 hour, the insoluble matter was filtered out, concentrated, and the crude product was subjected to column chromatography to obtain 2.90 g of product with a yield of 70%.

[0037] Example 8, in a 250 ml reaction bottle, 5.00 g of compound IV (tert-butyl (3-(4-((tert-butoxycarbonyl)amino)butyramido)propyl)carbonamide) was dissolved in 50 ml of dry tetrahydrofuran, cooled to -78 ° C, borane (10.0 M dimethyl sulfide solution, 1.8 ml) was added, and the reaction was continued to stir at low temperature for 5 hours, then slowly warmed to room temperature and reacted for another hour, cooled in an ice-water bath, 10 ml of methanol was added dropwise, and stirring was continued for 1 hour. The volatiles were distilled off, and 50 ml of methanol was added for distillation. The crude product was subjected to column chromatography to obtain 1.26 g of product with a yield of 62%.

[0038] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0039] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An intermediate compound for synthesizing spermidine, characterized in that: The name of the intermediate compound is (3-(4-((tert-butyloxycarbonyl)amino)butyramido)propyl)carbonamide tert-butyl ester, and the chemical structure is as follows:

2. A method for synthesizing an intermediate compound for synthesizing spermidine, characterized in that: N-Boc-2-oxopyrrolidine reacts with 1,3-propylenediamine and di-tert-butyl dicarbonate to obtain an intermediate compound for synthesizing spermidine. The synthetic route is as follows:

3. The method for synthesizing an intermediate compound for synthesizing spermidine according to claim 2, characterized in that: To a reactor charged with N-Boc-2-oxopyrrolidine, 1,3-propylenediamine and di-tert-butyl dicarbonate were added stepwise.

4. The method for synthesizing an intermediate compound for synthesizing spermidine according to claim 2, characterized in that: The mass ratio of N-Boc-2-oxopyrrolidine: 1,3-propylenediamine: di-tert-butyl dicarbonate is 1: (0.5~1.5): (0.5~2).

5. The method for synthesizing an intermediate compound for synthesizing spermidine according to claim 2, characterized in that: The solvent in the reaction is an alcohol solvent, a dipolar solvent, tetrahydrofuran or acetonitrile, or a mixed solvent, and the reaction temperature is from room temperature to reflux temperature.

6. Use of an intermediate compound for synthesizing spermidine, characterized in that: A reducing agent is used to reduce the amide in the intermediate compound to an amine, and then an acid is used to remove the Boc group to obtain the acid salt of spermidine, and then a base is used to neutralize the acid to obtain free spermidine. The synthetic route is as follows:

7. The use of an intermediate compound for synthesizing spermidine according to claim 6, characterized in that: In the synthetic route, the reducing agent is borane dimethyl sulfide, lithium aluminum tetrahydride, diisobutyl aluminum hydride or red aluminum, the acid is hydrochloric acid, phosphoric acid or trifluoroacetic acid, and the base is sodium hydroxide or potassium hydroxide.

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